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Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations

Open AccessPublished:October 25, 2021DOI:https://doi.org/10.1016/j.cllc.2021.10.009

      Abstract

      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non–small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

      Keywords

      Introduction

      Lung cancer was the leading cause of cancer-related mortality worldwide in 2020 and non–small cell lung cancer (NSCLC) accounts for approximately 90% of all lung cancer cases.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      World Health Organization. Cancer - key facts. Accessed from: https://www.who.int/news-room/fact-sheets/detail/cancer. 2018. Accessed at: February 16, 2021.

      In a pooled analysis across 151 global studies including 33,162 patients with NSCLC/adenocarcinoma (ADC), approximately 29% of patients had epidermal growth factor receptor (EGFR) mutations.
      • Midha A
      • Dearden S
      • McCormack R
      EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
      The prevalence of EGFR mutation was highest in the Asia-Pacific (47%) region and lowest in Oceania (12%). The most common EGFR-TKI-sensitive activating mutations are exon 19 deletions (ex19del) (45%) and exon 21_L858R (L858R) (44%) mutations, and the least common are exon 20 mutations (2.0%).
      • Graham RP
      • Treece AL
      • Lindeman NI
      • et al.
      Worldwide frequency of commonly detected EGFR mutations.
      The T790M mutation is the most common resistance mutation associated with first- (1G) and second-generation (2G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) treatment.
      • Graham RP
      • Treece AL
      • Lindeman NI
      • et al.
      Worldwide frequency of commonly detected EGFR mutations.
      There are currently a variety of treatment strategies under development for mNSCLC with activating EGFR mutations, see Figures 1, and 2.
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      • Sugawara S
      • Oizumi S
      • Minato K
      • et al.
      Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      • Fukuoka M
      • Wu Y-L
      • Thongprasert S
      • et al.
      Biomarker analyses and final overall survival results from a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
      • Inoue A
      • Kobayashi K
      • Maemondo M
      • et al.
      Updated overall survival results from a randomized Phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial.
      • Zhou C
      • Wu YL
      • Chen G
      • et al.
      Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802).
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
      • Wu YL
      • Zhou C
      • Liam CK
      • et al.
      First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the Phase III, randomized, open-label, ENSURE study.
      • Kato T
      • Yoshioka H
      • Okamoto I
      • et al.
      Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroup analysis of LUX-Lung 3.
      • Yang JCH
      • Wu YL
      • Schuler M
      • et al.
      Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, Phase 3 trials.
      • Sequist LV
      • Yang JC
      • Yamamoto N
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial.
      • Wu YL
      • Zhou C
      • Hu CP
      • et al.
      Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised Phase 3 trial.
      • Paz-Ares L
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the Phase IIb LUX-Lung 7 trial.
      • Wu YL
      • Cheng Y
      • Zhou X
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, Phase 3 trial.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, Phase 3 study.
      • Sequist LV
      • Wu Y
      • Schuler M
      • et al.
      Subsequent therapies post-afatinib among patients with EGFR mutation-positive (EGFRm+) NSCLC in LUX-Lung 3, 6 and 7: Topic: Medical oncology (Abstract PS02.20).
      • Mok TS
      • Wu YL
      • Ahn MJ
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      • Hanna N
      • Shepherd FA
      • Fossella FV
      • et al.
      Randomized phase iii trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.
      Unfortunately, the majority of existing trials are not designed to specifically address the question of optimal treatment order, particularly in the context of first-line (1L) EGFR-TKI followed by second-line (2L) EGFR-TKI. Ongoing studies will provide valuable information about the relevance of treatment order and the initiation of 2L therapy.
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      ORCHARD: a Phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      ,
      • Remon J
      • Menis J
      • Hasan B
      • et al.
      The APPLE trial: feasibility and activity of AZD9291 (osimertinib) treatment on positive PLasma T790M in EGFR-mutant NSCLC patients. EORTC 1613.
      It is also important to understand the relevance of testing for T790M mutations in the context of acquired resistance to 1G and 2G EGFR-TKIs to determine optimal treatment options. Mutation type affects response to EGFR-TKIs and accounting for the mutation type may help to decide which patients would most likely benefit from differing alternative 1L treatment. This review aims to identify potential treatment approaches in mNSCLC with activating EGFR mutations from the multiple treatment options available and how tumor, patient, and treatment factors may be considered to develop personalized treatment plans for these patients.
      Figure 1:
      Figure 1Indirect comparison of sequential median progression free survival estimates based on current treatment options for mNSCLC with activating EGFR mutations for patients who develop T790M mutation after 1L therapy with 1G or 2G EGFR-TKI.
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      • Sugawara S
      • Oizumi S
      • Minato K
      • et al.
      Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      • Fukuoka M
      • Wu Y-L
      • Thongprasert S
      • et al.
      Biomarker analyses and final overall survival results from a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
      • Inoue A
      • Kobayashi K
      • Maemondo M
      • et al.
      Updated overall survival results from a randomized Phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial.
      • Zhou C
      • Wu YL
      • Chen G
      • et al.
      Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802).
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
      • Wu YL
      • Zhou C
      • Liam CK
      • et al.
      First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the Phase III, randomized, open-label, ENSURE study.
      • Kato T
      • Yoshioka H
      • Okamoto I
      • et al.
      Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroup analysis of LUX-Lung 3.
      • Yang JCH
      • Wu YL
      • Schuler M
      • et al.
      Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, Phase 3 trials.
      • Sequist LV
      • Yang JC
      • Yamamoto N
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial.
      • Wu YL
      • Zhou C
      • Hu CP
      • et al.
      Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised Phase 3 trial.
      • Paz-Ares L
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the Phase IIb LUX-Lung 7 trial.
      • Wu YL
      • Cheng Y
      • Zhou X
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, Phase 3 trial.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, Phase 3 study.
      • Sequist LV
      • Wu Y
      • Schuler M
      • et al.
      Subsequent therapies post-afatinib among patients with EGFR mutation-positive (EGFRm+) NSCLC in LUX-Lung 3, 6 and 7: Topic: Medical oncology (Abstract PS02.20).
      • Mok TS
      • Wu YL
      • Ahn MJ
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      Figure 2:
      Figure 2Indirect comparison of sequential median progression free survival estimates based on current treatment options for mNSCLC with activating EGFR mutations for patients who do not develop T790M mutation after 1L therapy.
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      • Sugawara S
      • Oizumi S
      • Minato K
      • et al.
      Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      • Fukuoka M
      • Wu Y-L
      • Thongprasert S
      • et al.
      Biomarker analyses and final overall survival results from a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
      • Inoue A
      • Kobayashi K
      • Maemondo M
      • et al.
      Updated overall survival results from a randomized Phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial.
      • Zhou C
      • Wu YL
      • Chen G
      • et al.
      Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802).
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
      • Wu YL
      • Zhou C
      • Liam CK
      • et al.
      First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the Phase III, randomized, open-label, ENSURE study.
      • Kato T
      • Yoshioka H
      • Okamoto I
      • et al.
      Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroup analysis of LUX-Lung 3.
      • Yang JCH
      • Wu YL
      • Schuler M
      • et al.
      Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, Phase 3 trials.
      • Sequist LV
      • Yang JC
      • Yamamoto N
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Park K
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial.
      • Wu YL
      • Zhou C
      • Hu CP
      • et al.
      Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised Phase 3 trial.
      • Paz-Ares L
      • Tan EH
      • O'Byrne K
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the Phase IIb LUX-Lung 7 trial.
      • Wu YL
      • Cheng Y
      • Zhou X
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, Phase 3 trial.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, Phase 3 study.
      • Sequist LV
      • Wu Y
      • Schuler M
      • et al.
      Subsequent therapies post-afatinib among patients with EGFR mutation-positive (EGFRm+) NSCLC in LUX-Lung 3, 6 and 7: Topic: Medical oncology (Abstract PS02.20).
      • Mok TS
      • Wu YL
      • Ahn MJ
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      • Hanna N
      • Shepherd FA
      • Fossella FV
      • et al.
      Randomized phase iii trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.

      Randomized Clinical Trials With EGFR-TKIs in mNSCLC With Activating EGFR Mutations

      Single-Agent EGFR-TKIs

      Historically, platinum-based chemotherapy was the only choice for 1L treatment for patients with mNSCLC. The discovery of targetable mutations led to increased treatment options with 1G EGFR-TKIs demonstrating superior benefit in mNSCLC with activating EGFR mutations compared with chemotherapy.
      • Inoue A
      • Kobayashi K
      • Maemondo M
      • et al.
      Updated overall survival results from a randomized Phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
      ,
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial.
      ,
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
      The IPASS and NEJ002 were some of the initial trials comparing EGFR-TKI with chemotherapy, demonstrating considerably longer median progression-free survival (mPFS) for patients receiving gefitinib.
      • Maemondo M
      • Inoue A
      • Kobayashi K
      • et al.
      Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
      ,
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      The results of the randomized, phase III trials, OPTIMAL/CTONG-0802 and EURTAC, supported erlotinib as standard 1L therapy, demonstrating considerably improved PFS in patients who received erlotinib compared with chemotherapy.
      • Zhou C
      • Wu YL
      • Chen G
      • et al.
      Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802).
      ,
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
      Trials comparing the 2G EGFR-TKI, afatinib, with chemotherapy further broadened the evidence base for the use of EGFR-TKIs as 1L therapy.
      • Wu YL
      • Sequist LV
      • Tan EH
      • et al.
      Afatinib as first-line treatment of older patients with EGFR mutation-positive non-small-cell lung cancer: subgroup analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 trials.
      In the phase III LUX-Lung 3 and LUX-Lung 6 trials, afatinib provided PFS benefit compared with platinum-doublet chemotherapy (pemetrexed and cisplatin or gemcitabine and cisplatin).
      • Sequist LV
      • Yang JC
      • Yamamoto N
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      ,
      • Wu YL
      • Zhou C
      • Hu CP
      • et al.
      Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised Phase 3 trial.
      Post-hoc analysis of LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 trials has shown that afatinib exhibits activity in uncommon EGFR point mutations or duplications in exons 18-21 but not in de novo T790M mutations or exon 20 insertions.
      • Yang JCH
      • Sequist LV
      • Geater SL
      • et al.
      Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.
      The ARCHER 1050 trial demonstrated that the 2G EGFR-TKI, dacomitinib, improved mPFS compared with the 1G gefitinib.
      • Wu YL
      • Cheng Y
      • Zhou X
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, Phase 3 trial.
      Outcomes for mNSCLC with activating EGFR mutations have improved significantly with the introduction of third generation (3G) EGFR-TKIs. In the FLAURA trial, 1L osimertinib provided significantly longer mPFS (18.9 months), and median overall survival (mOS) (38.6 months) compared with standard EGFR-TKIs in the overall population (gefitinib or erlotinib; 10.2 months [mPFS]; 31.8 months [mOS]).
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
      • Ramalingam SS
      • Vansteenkiste J
      • Planchard D
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      OS improvement with 1L osimertinib was seen despite the fact that 47% of patients assigned to 1L standard EGFR-TKI, who received any 2L therapy, received osimertinib as first subsequent treatment. Although osimertinib demonstrated PFS benefit compared with EGFR-TKIs regardless of race in the FLAURA trial, OS benefit was not observed in Asian patients (HR for OS 1.0 [95% CIs: 0.75-1.32]).
      • Ramalingam SS
      • Vansteenkiste J
      • Planchard D
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      EGFR-TKIs are now the standard of care in the 1L setting for mNSCLC with activating EGFR mutations and ongoing trials are investigating if EGFR-TKI-based combination treatments could further improve patient outcomes.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Loong HH
      • Kwan SS
      • Mok TS
      • Lau YM
      Therapeutic strategies in EGFR mutant non-small cell lung cancer.
      ,

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      See Table 1 for some pertinent ongoing trials in this setting.
      Table 1Active Clinical Trials in mNSCLC With Activating EGFR Mutations
      TitleTrial identifierPhaseIntervention/treatmentLine of therapyPrimary endpoint
      A Biomarker-directed phase II Platform Study in Patients With Advanced Non–Small Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib TherapyNCT03944772IIOsimertinib + savolitinib versus osimertinib + gefitinib versus osimertinib + necitumumab versus carboplatin + pemetrexed + durvalumab versus osimertinib + alectinib versus osimertinib +selpercatinib versus observational cohortSecond lineObjective response rate
      Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH)NCT03778229IIOsimertinib+savolitinibSecond lineObjective response rate
      Atezolizumab in Combination With Bevacizumab, Carboplatin, and Pemetrexed for EGFR-mutant Metastatic Non–small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors: a Single Arm phase II StudyNCT03647956IIAtezolizumab + bevacizumab + 

      carboplatin + pemetrexed
      Second lineObjective response rate
      Single Arm phase II Trial of Atezolizumab and Bevacizumab in Epidermal Growth Factor Receptor (EGFR) Mutant Non–Small Cell Lung Cancer in Patients With Progressive Disease After Receiving Osimertinib (TOP 1901)NCT04099836IIAtezolizumab + bevacizumabSecond lineObjective response rate
      A Prospective, Multi-center, Interventional Study of Osimertinib Combined With Anlotinib in Acquired EGFR T790M Mutated NSCLC Patients With Gradual Progression on Osimertinib TreatmentNCT04438902IIOsimertinib + anlotinibSecond lineProgression free survival from randomization until disease progression
      A Randomized phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR-Mutant Non–small Cell Lung Cancer With Leptomeningeal MetastasisNCT04148898IIOsimertinib versus osimertinib + bevacizumabFirst lineIntracranial progression-free and objective response rate
      Randomized phase II study of osimertinib plus ramucirumab and osimertinib for chemotherapy‐naive patients with non–squamous non‐small cell lung cancer harbouring EGFR mutationsCN-02188497IIOsimertinib versus osimertinib + ramucirumabFirst lineProgression free survival
      An Open-Label Randomized phase II Study of Combining Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor (TKI)-naïve Epidermal Growth Factor Receptor (EGFR)-Mutant Locally Advanced or Metastatic NSCLCNCT03909334IIOsimertinib versus osimertinib + ramucirumabFirst lineProgression free survival from randomization to disease progression
      A phase II Study of Osimertinib in Combination With Selumetinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung CancerNCT03392246IIOsimertinib + selumetinibFirst lineBest objective response
      Open Label, Multi-center phase Ib / II Study of Glumetinib Combined With Osimertinib in the Treatment of Relapsed and Metastatic Non–small Cell Lung Cancer Patients Who Failed to Receive EGFR InhibitorsNCT04338243IIOsimertinib + glumetinibSecond lineObjective response rate
      A phase II Trial of Osimertinib and Abemaciclib With a Focus on Non–Small Cell Lung Cancer Patients With EGFR Activating Mutations With Osimertinib ResistanceNCT04545710IIOsimertinib + abemaciclibSecond lineProgression free survival at 6 mo
      A phase II, Open-Label, Multicenter, Single-Arm, Prospective Clinical Study to Investigate the Efficacy, and Safety of Tislelizumab Combined With Chemotherapy in Non–squamous NSCLC With EGFR Sensitizing Mutation Who Failed EGFR TKI TherapyNCT04405674IITislelizumab + carboplatin/

      nabpaclitaxel, followed by tislelizumab + pemetrexed
      Second line1 y progression free survival rate
      A Prospective, Single-center, One-arm Clinical Study of Apatinib Combined With Chemotherapy for Patients Who Progressed After First Line EGFR-TKI Treatment Without T790M MutationNCT03758677IIApatinib + chemotherapySecond lineProgression free survival
      Open-Label, Randomized Trial of Nivolumab (BMS-936558) Plus Pemetrexed/Platinum or Nivolumab Plus Ipilimumab (BMS-734016) versus Pemetrexed Plus Platinum in stage IV or Recurrent Non–Small Cell Lung Cancer (NSCLC) Subjects With Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor TherapyNCT02864251IIINivolumab + pemetrexed/

      platinum or nivolumab + ipilimumab versus pemetrexed + platinum
      Second or third lineProgression free survival
      A phase III, Randomized, Double-blind Study to Assess the Efficacy, and Safety of Lazertinib Versus Gefitinib as the First-line Treatment in Patients With Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non–Small Cell Lung CancerNCT04248829IIILazertinib versus gefitinibFirst lineProgression free survival
      Phase III Study Comparing Osimertinib Monotherapy to Combination Therapy With Osimertinib, Carboplatin and Pemetrexed for Untreated Patients With Advanced Non–squamous Non–Small Cell Lung Cancer With Concurrent EGFR and TP53 MutationsNCT04695925IIIOsimertinib versus osimertinib + chemotherapyFirst lineProgression free survival from randomization to disease progression
      A phase III, Randomized, Double-Blind, Placebo-Controlled Study of Platinum Plus Pemetrexed Chemotherapy Plus Osimertinib Versus Platinum Plus Pemetrexed Chemotherapy Plus Placebo in Patients With EGFRm, Locally Advanced or Metastatic NSCLC Who Have Progressed Extracranially Following First-Line Osimertinib Therapy (COMPEL)NCT04765059IIIOsimertinib + pemetrexed + 

      cisplatin or carboplatin versus placebo + pemetrexed + cisplatin or carboplatin
      Second lineProgression free survival from randomization to disease progression
      Randomized phase III Study of Combination AZD9291 (Osimertinib) and Bevacizumab Versus AZD9291 (Osimertinib) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non–Small Cell Lung Cancer (NSCLC)NCT04181060IIIOsimertinib versus osimertinib + bevacizumabFirst lineProgression free survival from randomization to disease progression
      A phase III, Randomized Study of Amivantamab, and Lazertinib Combination Therapy Versus Osimertinib Versus Lazertinib as First-Line Treatment in Patients With EGFR-Mutated Locally Advanced or Metastatic Non–Small Cell Lung Cancer.NCT04487080IIIAmivantamab + lazertinib versus osimertinib + placebo versus lazertinib + placeboFirst lineProgression free survival from randomization to disease progression
      A Multi-center, Randomized, Double-Blind Study of Gefitinib in Combination With Anlotinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non–Small Cell Lung Cancer.NCT04028778IIIGefitinib + anlotinib versus gefitinib versus placeboFirst lineProgression free survival

      Combination of EGFR-TKIs With Chemotherapy

      The NEJ005/TCOG0902 was one of the first randomized studies to evaluate efficacy when combining EGFR-TKI with chemotherapy in patients with mNSCLC with activating EGFR mutations.
      • Sugawara S
      • Oizumi S
      • Minato K
      • et al.
      Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
      Concurrent versus sequential alternating gefitinib and chemotherapy as 1L therapy revealed similar responses between treatment arms.
      • Sugawara S
      • Oizumi S
      • Minato K
      • et al.
      Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
      Updated analyses have confirmed PFS was improved with the 1L combination therapy compared with gefitinib monotherapy, and the concurrent regimen provides a mOS of 41.9 months.
      • Oizumi S
      • Sugawara S
      • Minato K
      • et al.
      Updated survival outcomes of NEJ005/TCOG0902: a randomised Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations.
      The subsequent NEJ009 study further confirmed the PFS benefit offered by 1L gefitinib combined with carboplatin and pemetrexed chemotherapy.
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      The NEJ009 trial also revealed a mOS benefit, with the chemotherapy, and gefitinib combination demonstrating longer mOS compared with gefitinib alone (50.9 months vs. 38.8 months). Another phase III trial provided further support for improved mPFS and mOS outcomes following gefitinib and chemotherapy treatment compared with gefitinib monotherapy.
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      The randomized phase II JMIT study demonstrated improved PFS with the addition of pemetrexed to gefitinib as 1L therapy in non–squamous mNSCLC with activating EGFR mutations.
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      All these studies have been conducted in Asian patients and there is limited evidence of the EGFR-TKI with chemotherapy approach in non–Asian patients. It should also be noted that treatment-related adverse events are increased with combination therapy compared with monotherapies.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      Results of trials examining EGFR-TKI and chemotherapy combinations are summarized in Table 2.
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      ,
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      ,
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      ,
      • Oizumi S
      • Sugawara S
      • Minato K
      • et al.
      Updated survival outcomes of NEJ005/TCOG0902: a randomised Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations.
      Table 2Randomized Controlled Trials Examining EGFR-TKIs and Chemotherapy Combinations
      • Noronha V
      • Patil VM
      • Joshi A
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      ,
      • Cheng Y
      • Murakami H
      • Yang PC
      • et al.
      Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
      ,
      • Hosomi Y
      • Morita S
      • Sugawara S
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      ,

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      TitlePhasemPFSmOS
      Concurrent regimenAlternating regimenConcurrent regimenAlternating regimen
      Randomized phase II study of continuous gefitinib plus chemotherapy versus alternation of gefitinib and chemotherapy in previously untreated non–small cell lung cancer (NSCLC) with sensitive EGFR mutations (NEJ005/TCOG0902)II17.5 mo (95% CIs: 9.7-21.9 mo)15.3 mo (95% CIs: 11.2-17.4 mo)41.9 mo (95% CIs: 31.8-58.0 mo)30.7 mo (95% CIs: 22.7-38.3 mo)
      HR 0.68 (95% CIs: 0.42-1.12)HR 0.58 (95% CIs: 0.34-0.97)
      Combination regimenMonotherapyCombination regimenMonotherapy
      NEJ009 trial: A randomized phase III study of gefitinib (G) in combination with carboplatin (C) plus pemetrexed (P) versus G alone in patients with advanced non–squamous non–small cell lung cancer (NSCLC) with EGFR mutationIII20.9 mo (95% CIs: 17.94-24.20 mo)11.9 mo (95% CIs: 8.97-13.40 mo)50.9 mo (95% CIs: 41.77-62.50 mo)38.8 mo (95% CIs: 31.10-47.33 mo)
      HR 0.49 (95% CIs: 0.39-0.62)HR 0.72 (95% CIs: 0.55-0.95)
      A study of pemetrexed and gefitinib versus gefitinib in non–small cell lung cancer (NSCLC)II15.8 mo (95% CIs: 12.6-18.3 mo)10.9 mo (95% CIs: 9.7-13.8 mo)OS data are immature
      HR 0.68 (95% CIs: 0.48-0.96)
      A randomized study to compare gefitinib versus chemotherapy with gefitinib in EGFR mutation positive Non–Small cell lung cancer in palliative settingIII16 mo (95% CIs: 13.5-18.5 mo)(estimated)8 mo (95% CIs: 7.0-9.0 mo)(estimated)Not reached (estimated)17 mo (95% CIs: 13.5-20.5 mo)(estimated)
      HR 0.51 (95% CIs: 0.39-0.66)HR 0.45 (95% CIs: 0.31-0.65)

      Anti–Angiogenic and EGFR-TKI Combination

      Angiogenesis and EGFR pathways share downstream signaling targets and can function exclusive of each other during oncogenesis.
      • Byers LA
      • Heymach JV
      Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer.
      In mNSCLC with activating EGFR mutations, increased EGFR-signaling upregulates vascular endothelial growth factor (VEGF) pathway, contributing to resistance to EGFR-TKIs.
      • Le X
      • Nilsson M
      • Goldman J
      • et al.
      Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC.
      The addition of bevacizumab (anti–VEGF antibody) or ramucirumab (anti–VEGF receptor 2 antibody) to EGFR-TKIs has demonstrated considerable clinical benefit with improved PFS, supporting the rationale for dual EGFR and VEGF inhibition.
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      • Zhou Q
      • Wu YL
      • Cheng Y
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      • Stinchcombe TE
      • Jänne PA
      • Wang X
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a Phase 2 randomized clinical trial.
      • Maemondo M
      • Fukuhara T
      • Saito H
      • et al.
      NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
      The combination of erlotinib and ramucirumab demonstrated a mPFS of 19.4 months in the RELAY trial and the combination of erlotinib and bevacizumab showed a mPFS of 18.0 months, 17.9 months, 16.9 months and 16.0 months in the CTONG1509, ACCRU RC1126, NEJ026, and JO25567 trials respectively.
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      • Zhou Q
      • Wu YL
      • Cheng Y
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      • Stinchcombe TE
      • Jänne PA
      • Wang X
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a Phase 2 randomized clinical trial.
      Trials investigating the combination of erlotinib and bevacizumab have not shown benefit in OS and OS data for erlotinib and ramucirumab remains immature, although RELAY demonstrated PFS2 benefit for erlotinib and ramucirumab compared with erlotinib and placebo.
      • Maemondo M
      • Fukuhara T
      • Saito H
      • et al.
      NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      • Yamamoto N
      • Seto T
      • Nishio M
      • et al.
      Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
      The CTONG1706 study (NCT02824458) is the first to investigate the efficacy and safety of apatinib (a VEGFR2-TKI) with gefitinib as 1L combination therapy, demonstrating a longer mPFS in patients receiving apatinib and gefitinib compared with placebo and gefitinib (13.7 months vs. 10.2 months).
      • Zhang L
      • Zhao H
      • Zhang Z
      • et al.
      ACTIVE: Apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled Phase III trial (CTONG1706) (Abstract LBA50).
      Increased efficacy with combination approaches comes at a cost of increased treatment-related adverse events compared to monotherapies.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      Results of trials examining EGFR-TKI and anti–angiogenic combinations are summarized in Table 2, Table 3.
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      • Zhou Q
      • Wu YL
      • Cheng Y
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      • Stinchcombe TE
      • Jänne PA
      • Wang X
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a Phase 2 randomized clinical trial.
      • Maemondo M
      • Fukuhara T
      • Saito H
      • et al.
      NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      • Yamamoto N
      • Seto T
      • Nishio M
      • et al.
      Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
      • Zhang L
      • Zhao H
      • Zhang Z
      • et al.
      ACTIVE: Apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled Phase III trial (CTONG1706) (Abstract LBA50).

      ClinicalTrials.gov. Erlotinib hydrochloride with or without bevacizumab in treating patients with stage IV non-small cell lung cancer with epidermal growth factor receptor mutations. https://clinicaltrials.gov/ct2/show/results/NCT01532089?view=results. 2012. Accessed from: October 6, 2020. Accessed at: May 19, 2021.

      Table 3Randomized Controlled Trials Examining EGFR-TKIs and Anti–Angiogenics Combinations
      • Le X
      • Nilsson M
      • Goldman J
      • et al.
      Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC.
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      • Zhou Q
      • Wu YL
      • Cheng Y
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      • Stinchcombe TE
      • Jänne PA
      • Wang X
      • et al.
      Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a Phase 2 randomized clinical trial.
      • Maemondo M
      • Fukuhara T
      • Saito H
      • et al.
      NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      • Yamamoto N
      • Seto T
      • Nishio M
      • et al.
      Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
      • Zhang L
      • Zhao H
      • Zhang Z
      • et al.
      ACTIVE: Apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled Phase III trial (CTONG1706) (Abstract LBA50).
      TitlePhasemPFSmOS
      Combination regimenMonotherapyCombination regimenMonotherapy
      A phase II, open-label, randomized trial of RG1415 (erlotinib hydrochloride) plus bevacizumab versus RG1415 alone as a first line therapy for advanced or metastatic NSCLC patients with EGFR mutation (JO25567)II16.0 mo (95% CIs: 13.9-18.1 mo)9.7 mo (95% CIs: 5.7-11.1 mo)47.0 mo
      95% CIs data not available
      47.4 mo
      95% CIs data not available
      HR 0.54 (95% CIs: 0.36-0.79)HR 0.81 (95% CIs: 0.53-1.23)
      Compare bevacizumab in combination with erlotinib versus erlotinib alone in NSCLC patients activating EGFR mutations (ARTEMIS/CTONG1509)III18.0 mo (95% CIs: 15.2-20.7 mo)11.3 mo (95% CIs: 9.8-13.8 mo)OS data are immature
      HR 0.55 (95% CIs: 0.41-0.75)
      Erlotinib hydrochloride with or without bevacizumab in treating patients with stage IV non–small cell lung cancer with epidermal growth factor receptor mutations (ACCRU RC1126)III17.9 mo (95% CIs 13.3-24.1 mo)13.5 mo (95% CIs: 8.8-21.6 mo)32.4 mo (95% CIs: 26.9-54.4 mo)50.6 mo (95% CIs: 49.4-not reached)
      HR 0.81 (95% CIs: 0.50-1.31)HR 1.41 (95% CIs: 0.71-2.81)
      Randomized phase III study comparing erlotinib plus bevacizumab to erlotinib alone in patients with previously untreated non–small cell lung cancer harboring EGFR mutation (NEJ026)III16.9 mo (95% CIs:14.2-21.0 mo)13.3 mo (95% CIs: 11.1-15.3 mo)50.7 mo (95% CIs: 37.3-not reached)46.2 mo (95% CIs: 38.2-not reached)
      HR 0.61 (95% CIs: 0.42-0.88)HR 1.00 (95% CIs: 0.69- 1.48)
      A study of gefitinib with or without apatinib in patients with advanced non–squamous non–small cell lung cancer harboring EGFR mutations (ACTIVE/CTONG1706)III13.7 mo
      95% CIs data not available
      10.2 mo
      95% CIs data not available
      OS data are immature
      HR 0.71 (95% CIs: 0.53-0.95)
      Ramucirumab plus erlotinibPlacebo plus erlotinib
      A study of ramucirumab (LY3009806) in combination with erlotinib in previously untreated participants with EGFR mutation-positive metastatic NSCLC (RELAY)III19.4 mo (95% CIs: 15.4-21.6 mo)12.4 mo (95% CIs: 11.0-13.5 mo)OS data are immature
      HR 0.59 (95% CIs: 0.46-0.76)
      a 95% CIs data not available
      The real-world study BELLA (NCT04575415) using bevacizumab and EGFR-TKIs in Chinese patients with mNSCLC with activating EGFR mutations may provide useful information regarding the clinical efficacy and safety of this treatment regimen.

      ClinicalTrials.gov. Bevacizumab plus EGFR-TKIs in Chinese patients with EGFR-mutant NSCLC: a real-world study (BELLA). Accessed from: https://clinicaltrials.gov/ct2/show/NCT04575415. 2020. Accessed at: February 16, 2020.

      Randomized phase II trials of 1L bevacizumab and osimertinib or ramucirumab and osimertinib compared with osimertinib alone in the 1L setting are ongoing and they will inform about the combination of 3G EGFR TKI with an anti–angiogenic therapy.

      ClinicalTrials.gov. AZD9291 (osimertinib) with or without bevacizumab as initial treatment for patients with EGFR-mutant lung cancer. Accessed from: https://clinicaltrials.gov/ct2/show/NCT04181060. 2019. Accessed at: February 16, 2020.

      ClinicalTrials.gov. Osimertinib with or without bevacizumab in treating patients with EGFR positive non-small cell lung cancer and brain metastases. Accessed from: https://clinicaltrials.gov/ct2/show/NCT02971501. 2016. Accessed at: April 20, 2021.

      UMIN-CTR Clinical Trial. Randomized Phase II study of osimertinib plus bevacizumab and osimertinib for chemotherapy-naive patients with nonsquamous non-small cell lung cancer harboring EGFR mutations (investigator-initiated multicenter clinical trial, WJOG9717L). Accessed from: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034306. 2017. Accessed at: April 20, 2021.

      Osimertinib as First-Line or Second-Line Therapy

      Osimertinib as First-Line Therapy

      As previously mentioned, osimertinib has demonstrated longer mPFS and OS compared with 1G and 2G EGFR-TKIs.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      The findings from the FLAURA trial have established 1L osimertinib as the standard of care in mNSCLC with activating EGFR mutations.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      Additionally, a phase I/II single arm trial to evaluate the combination of bevacizumab and osimertinib demonstrated promising efficacy and tolerability in patients with T790M.
      • Yu HA
      • Schoenfeld AJ
      • Makhnin A
      • et al.
      Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a Phase 1/2 single-group open-label trial.
      T790M is an acquired gatekeeper mutation, a resistance mechanism to 1G and 2G EGFR-TKIs, sensitive to osimertinib, and is rarely present at diagnosis of mNSCLC with activating EGFR mutations. A recent simulation study investigated whether there is a T790M positivity rate at which upfront first- (1G) or second-generation (2G) EGFR-TKIs followed by osimertinib exceeds overall PFS compared with 1L osimertinib.
      • Haratake N
      • Toshihiro M
      • Takeharu Y
      • T S
      Optimizing sequential treatment with EGFR tyrosine kinase inhibitor with a simulation of the T790M mutation rate in EGFR–mutated lung cancer.
      Even with a simulated 100% T790M-positive mutation rate, upfront osimertinib therapy was found to provide a better mPFS than sequential 1G or 2G EGFR-TKIs followed by osimertinib.

      Osimertinib as Second-Line Therapy

      The AURA3 trial in patients with T790M mutations provides a 2L option with osimertinib following 1G/2G EGFR-TKIs as 1L (mPFS: 10.1 months [osimertinib] vs. 4.4 months [platinum therapy and pemetrexed]).
      • Mok TS
      • Wu YL
      • Ahn MJ
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      ,
      • Wu YL
      • Ahn MJ
      • Garassino MC
      • et al.
      CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3).
      The TREM trial confirms the efficacy of osimertinib as 2L for patients with T790M.
      • Eide IJZ
      • Helland Å
      • Ekman S
      • et al.
      Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).
      However, the randomized phase II study, WJOG8715L, did not find any benefit in PFS or OS in adding bevacizumab to osimertinib as 2L therapy for PFS and OS outcomes in patients with EGFR T790M+ mNSCLC.
      • Akamatsu H
      • Toi Y
      • Hayashi H
      • et al.
      Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan oncology group 8715L Phase 2 randomized clinical trial.

      Advantages and Disadvantages of Osimertinib in 1L or 2L Setting

      The FLAURA trial shows a clear rationale for using osimertinib in 1L in all patients with mNSCLC with activating EGFR mutations, including those with brain metastases, and the small number of cases where T790M is detected at disease onset.
      • Green JA
      Osimertinib-first or second line for epidermal growth factor (EGFR) mutation-positive non-small cell lung cancer?.
      Osimertinib causes less toxicity (because of its decreased affinity to wild-type EGFR) and also results in decreased central nervous system disease progression than earlier-generation EGFR-TKIs.
      • Le T
      • Gerber DE
      Newer-generation EGFR inhibitors in lung cancer: how are they best used?.
      Osimertinib is active as a 2L treatment after 1L treatment with 1G or 2G EGFR-TKIs in the setting of T790M mutation positive disease, and the AURA 3 trial has established osimertinib as the standard of care for patients who develop T790M mutation after 1L therapy with earlier-generation EGFR-TKIs.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      ,
      • Wu YL
      • Ahn MJ
      • Garassino MC
      • et al.
      CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3).
      However, reserving osimertinib for 2L therapy raises some concerns that patients would potentially not be tested for or found to be negative for T790M and miss the opportunity to receive osimertinib treatment. Not all patients will develop the T790M resistance mutation, and some patients may not receive or survive until 2L therapy. It is also not possible to predict at baseline what mechanisms of resistance will develop. A large number of clinical trials report a high attrition rate for patients switching from 1L to 2L therapy.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      Unequal access to the most sensitive methods for detecting T790M mutations may also have an impact on clinical outcomes as T790M mutations may be under-detected.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      A retrospective study which compared 1L afatinib with 1G EGFR-TKIs indicated a trend of improved outcomes for afatinib followed by osimertinib for T790M-positive NSCLC compared to 1G EGFR TKI followed by osimertinib.
      • Tamiya M
      • Tamiya A
      • Suzuki H
      • et al.
      Which is Better EGFR-TKI Followed by osimertinib: afatinib or gefitinib/erlotinib?.
      The ongoing phase II APPLE study (NCT02856893) will prospectively evaluate the strategy for sequential gefitinib followed by osimertinib.
      • Remon J
      • Menis J
      • Hasan B
      • et al.
      The APPLE trial: feasibility and activity of AZD9291 (osimertinib) treatment on positive PLasma T790M in EGFR-mutant NSCLC patients. EORTC 1613.
      Performed in patients with EGFR-mutated and EGFR-TKI-naïve mNSCLC, the study will help elucidate the value of a sequenced strategy of gefitinib followed by osimertinib compared with upfront osimertinib.
      • Remon J
      • Menis J
      • Hasan B
      • et al.
      The APPLE trial: feasibility and activity of AZD9291 (osimertinib) treatment on positive PLasma T790M in EGFR-mutant NSCLC patients. EORTC 1613.
      However, to definitively determine whether osimertinib is most beneficial as 1L or as 2L therapy, trials need to be designed to directly compare the survival outcomes with 1L osimertinib compared with 1L early-generation EGFR-TKI followed by 2L osimertinib in the setting of T790M mutation positive disease.
      • Le T
      • Gerber DE
      Newer-generation EGFR inhibitors in lung cancer: how are they best used?.

      Current Treatment Guidelines for Patients With mNSCLC

      National Comprehensive Cancer Network (NCCN) guidelines recommend 1L osimertinib (preferred), erlotinib, afatinib, gefitinib, and dacomitinib with 2L options for consideration based on 1L treatment received and/or disease characteristics (eg histology, mutation status).

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      Recent updates to the NCCN guidelines for patients with mNSCLC with sensitizing EGFR mutations include the Category 2 recommendation of erlotinib and ramucirumab (“other recommended”; Category 2A) and erlotinib and bevacizumab (“useful in certain circumstances”; Category 2B).

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      Similarly, the 1L options according to ESMO guidelines for patients with sensitizing EGFR mutations in mNSCLC are osimertinib (preferred), erlotinib, gefitinib, afatinib, dacomitinib, and erlotinib and bevacizumab, erlotinib and ramucirumab, as well as the addition of 1L carboplatin and pemetrexed to gefitinib (Category 1B) also for consideration.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      For 2L treatment in mNSCLC with activating EGFR mutations, ESMO guidelines recommend T790M mutation testing using initial liquid biopsy in case of EGFR-TKI resistance in those patients not previously treated with osimertinib.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      Osimertinib is recommended for patients with a T790M+ mutation. In those patients who test negative for T790M, platinum-based doublet is considered standard therapy.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      Atezolizumab and bevacizumab plus carboplatin plus paclitaxel is another potential 2L treatment option.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Reck M
      • Mok TSK
      • Nishio M
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label Phase 3 trial.

      Real-World Evidence

      A recent review showed that the proportion of patients with mNSCLC with activating EGFR mutations that receive subsequent 2L treatment in the clinical trial setting ranges from 41% to 82% (dacomitinib [41%], erlotinib [47%-70%,] gefitinib [49%-82%], osimertinib [59%], afatinib [71%], icotinib [73%]).
      • Gelatti ACZ
      • Drilon A
      • Santini FC
      Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).
      Analysis of treatment patterns from the US Flatiron Electronic Health Record-derived database revealed EGFR-TKIs as the most common 1L therapy (72.8%; n = 700), and 44% (n = 422) of patients with mNSCLC with activating EGFR mutations received 2L treatment (erlotinib [32.7%], chemotherapy [32.5%], afatinib [16.1%]).
      • Li Y
      • Appius A
      • Pattipaka T
      • Feyereislova A
      • Cassidy A
      • Ganti AK
      Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in the USA.
      The global ASTRIS real-world study, which included 3,015 patients, is currently the largest real-world treatment study using osimertinib in T790M-positive mNSCLC.
      • Marinis F
      • Wu YL
      • de Castro Jr., G
      • et al.
      ASTRIS: a global real-world study of osimertinib in >3000 patients with EGFR T790M positive non-small-cell lung cancer.
      Findings demonstrated clinical efficacy and safety comparable with that observed in previous clinical trials (ie AURA) with osimertinib as 2L therapy for patients who had received 1L EGFR-TKIs.
      • Marinis F
      • Wu YL
      • de Castro Jr., G
      • et al.
      ASTRIS: a global real-world study of osimertinib in >3000 patients with EGFR T790M positive non-small-cell lung cancer.
      Although biased by its retrospective design and eligibility criteria, the GioTag study investigated sequential 1L afatinib followed by 2L osimertinib in 203 patients with EGFR T790M-mutated mNSCLC.
      • Hochmair MJ
      • Morabito A
      • Hao D
      • et al.
      Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: updated analysis of the observational GioTag study.
      Median time on treatment, median treatment failure, and mOS (almost 4 years) were most encouraging in patients with ex19del disease.
      • Hochmair MJ
      • Morabito A
      • Hao D
      • et al.
      Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: updated analysis of the observational GioTag study.
      ,
      • Feinberg B
      • Halmos B
      • Gucalp R
      • Tang W
      • Moehring B
      • Hochmair MJ
      Making the case for EGFR TKI sequencing in EGFR mutation-positive NSCLC: a GioTag study US patient analysis.
      This supports 1L afatinib followed by osimertinib as a treatment option in ex19del disease, especially when considering the high rate of T790M-acquired mutation in this subgroup (∼75%).
      • Hochmair MJ
      • Buder A
      • Schwab S
      • et al.
      Liquid-biopsy-based identification of EGFR T790M mutation-mediated resistance to afatinib treatment in patients with advanced EGFR mutation-positive NSCLC, and subsequent response to osimertinib.
      The efficacy of osimertinib after afatinib in GioTag is aligned to the results of the AURA 3 study, demonstrating the possible role of an EGFR-TKI sequencing strategy in the setting of T790M mutation. As evidenced by meta-analyses, clinical trials, and real-world evidence such as the GioTag study, ex19del and L858R-positive tumors should potentially be considered as 2 different disease entities due to differences in sensitivity to EGFR-TKIs.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      ,
      • Hochmair MJ
      • Morabito A
      • Hao D
      • et al.
      Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: updated analysis of the observational GioTag study.
      ,
      • Li WQ
      • Cui JW.
      Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments.
      ,
      • Sheng M
      • Wang F
      • Zhao Y
      • et al.
      Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis.
      Unfortunately, all patients eventually develop resistance to osimertinib regardless if used as a 1L or 2L therapy, thereby making the treatment no longer effective.
      • Yang Z
      • Yang N
      • Ou Q
      • et al.
      Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients.
      Therefore, novel strategies combining EGFR-TKIs with other agents and/or the development of fourth-generation EGFR-TKIs to provide improved survival and duration of response for these patients are of utmost importance.

      Considerations for Choosing Therapy for Patients With mNSCLC With Activating EGFR Mutations

      EGFR-TKIs are the standard of care in patients with sensitizing EGFR mutations. Determining the optimal 2L therapy for patients following disease progression on 1L therapy depends largely on the molecular mechanisms driving resistance (eg T790M mutation, C797S mutation, mesenchymal-to-epithelial transition factor [MET] amplification, fusions, histologic transformation).
      • Liao BC
      • Griesing S
      • Yang JC
      Second-line treatment of EGFR T790M-negative non-small cell lung cancer patients.
      The most common resistance mechanism to 1G and 2G EGFR-TKIs is T790M mutation, occurring in up to two-thirds of cases and osimertinib is the treatment of choice in this case.
      • Yang JC
      • Ahn MJ
      • Kim DW
      • et al.
      Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase ii extension component.
      There is a paucity of 2L options for T790M-negative patients and this is an area of urgent unmet medical need. Current options include continuing with EGFR-TKIs, local therapy or systemic chemotherapy depending on patient characteristics.
      • Hirsh V
      • Singh J
      Optimal sequencing strategies in the treatment of EGFR mutation-positive non-small cell lung cancer: clinical benefits and cost-effectiveness.
      Small clinical benefits may be obtained in this population with afatinib plus bevacizumab and bevacizumab plus platinum-based chemotherapy compared with chemotherapy and targeted therapy.
      • Vavalà T
      • Follador A
      • Tiseo M
      • et al.
      BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients: Results from a multicenter Italian observational study.
      • Jiang Z
      • Zhang Y
      • Yang Y
      • Yue Z
      • Pan Z
      Efficacy of pemetrexed and carboplatin with or without bevacizumab in lung adenocarcinoma patients with EGFR non-T790M mutations after progression on first-line EGFR-tyrosine kinase inhibitors.
      • Hata A
      • Katakami N
      • Kaji R
      • et al.
      Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: multicenter, single-arm, phase 2 trial (ABC Study).
      Exploratory analyses have shown atezolizumab plus bevacizumab plus chemotherapy improved survival trend compared with bevacizumab plus chemotherapy but further research is needed to determine the optimal 2L option for T790M-negative patients.
      • Reck M
      • Mok TSK
      • Nishio M
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label Phase 3 trial.
      A phase 1 trial assessing the anti–HER3 antibody–drug conjugate, HER3-deruxtecan (DXd), in patients with T790M-negative acquired resistance to erlotinib, gefitinib, or afatinib, acquired resistance to osimertinib and other diverse mechanisms of EGFR-TKIs resistance demonstrated antitumor activity and further research is ongoing.
      • Janne PA
      • Baik CS
      • Su W-C
      • et al.
      Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC).

      ClinicalTrials.gov. HERTHENA-Lung01: patritumab deruxtecan in subjects with metastatic or locally advanced EGFR-mutated non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT04619004?term=NCT04619004&draw=2&rank=1. 2020. Accessed at: September 10, 2021.

      ClinicalTrials.gov. Patritumab deruxtecan in combination with osimertinib in subjects with locally advanced or metastatic EGFR-mutated non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT04676477?term=NCT04676477&draw=2&rank=1. 2020. Accessed at: September 10, 2021.

      The mechanisms of resistance to osimertinib are varied and continue to be investigated.
      • Le T
      • Gerber DE
      Newer-generation EGFR inhibitors in lung cancer: how are they best used?.
      The most common resistance mechanisms are MET amplification and the emergence of the tertiary EGFR resistance mutation, C797S. Other mechanisms identified included HER2 amplification and the emergence of PIK3CA, BRAF or KRAS mutations, and histologic transformations (Figure 3, Figure 4).
      • Ramalingam SS
      • Cheng Y
      • Zhou C
      • et al.
      Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study.
      • Schoenfeld AJ
      • Chan JM
      • Kubota D
      • et al.
      Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer.
      • Papadimitrakopoulou VA
      • Wu YL
      • Han JY
      • et al.
      Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study.
      • Lin C-C
      • Shih J-Y
      • Yu C-J
      • et al.
      Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.
      • Oxnard GR
      • Hu Y
      • Mileham KF
      • et al.
      Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.
      There may be some differences in the mechanism of resistance to osimertinib in 1L versus subsequent lines of treatment and most mechanisms of resistance to osimertinib are currently not targetable with approved treatments. Combined MET and EGFR inhibition to target osimertinib resistance driven by MET amplification is a compelling therapeutic approach. CHRYSALIS-1 evaluated the combination of lazertinib, a 3G EGFR-TKI, with amivantamab, which is a bispecific antibody that can inhibit tumor growth driven by EGFR, and MET receptors. CHRYSALIS-1 demonstrated durable responses for patients treated with amivantamab plus lazertinib who progressed on earlier osimertinib.
      • Bauml J
      • Cho BC
      • Park K
      • et al.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      Amivantamab has also demonstrated response in patients with both MET amplification and C797S mutations.
      • Haura EB
      • Cho BC
      • Lee JS
      • et al.
      JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
      Brigatinib plus cetuximab may provide an effective treatment option for patients with T790M and cis-C797S mutations with resistance to osimertinib.
      • Wang Y
      • Yang N
      • Zhang Y
      • et al.
      Effective Treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and cis-C797S triple mutations by brigatinib and cetuximab combination therapy.
      Acquired fusions in ALK, BRAF, FGFR3, HER2, RET, and other oncogenes have been identified on disease progression while receiving osimertinib therapy. Like the MET amplification, combining EGFR-TKIs with an inhibitor of the altered fusion protein is an emerging treatment strategy.
      • Piper-Vallillo AJ
      • Sequist LV
      • Piotrowska Z
      emerging treatment paradigms for EGFR-mutant lung cancers progressing on osimertinib: a review.
      ,
      • Rotow J
      • Patel J
      • Hanley M
      • et al.
      FP14.07 combination osimertinib plus selpercatinib for EGFR-mutant non-small cell lung cancer (NSCLC) with acquired RET fusions.
      Therefore, at least some mutations within EGFR gene and oncogenic aberrations which allow the consequences of EGFR inhibition to be bypassed appear to be actionable and could be used to treat patients who have progressed on osimertinib.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      Figure 3:
      Figure 3Resistance mechanisms reported following 1L osimertinib therapy (resistance mechanism reported may overlap with another).
      • Ramalingam SS
      • Cheng Y
      • Zhou C
      • et al.
      Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study.
      ,
      • Schoenfeld AJ
      • Chan JM
      • Kubota D
      • et al.
      Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer.
      Figure 4:
      Figure 4Resistance mechanisms reported following 2L or 3L osimertinib therapy (resistance mechanism reported may overlap with another).
      • Schoenfeld AJ
      • Chan JM
      • Kubota D
      • et al.
      Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer.
      • Papadimitrakopoulou VA
      • Wu YL
      • Han JY
      • et al.
      Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study.
      • Lin C-C
      • Shih J-Y
      • Yu C-J
      • et al.
      Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.
      • Oxnard GR
      • Hu Y
      • Mileham KF
      • et al.
      Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.
      Longer follow-up and prospective, multi-institutional studies, such as the ongoing ELIOS trial (NCT03239340) will be required to gain a more complete picture of osimertinib resistance.

      ClinicalTrials.gov. A molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib (ELIOS). Accessed from: https://clinicaltrials.gov/ct2/show/NCT03239340. 2017. Accessed at: September 8, 2021.

      The ongoing biomarker-directed ORCHARD study investigates 6 different treatment combinations in patients with mNSCLC with activating EGFR mutations with acquired resistance following 1L osimertinib therapy.
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      ORCHARD: a Phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      Findings from this study may provide additional insights into the correlation between biomarker profiles and the treatment effect, thereby guiding future treatment planning.
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      ORCHARD: a Phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      Further research is also required to enhance our understanding of treatment options for patients with unknown mechanisms of resistance or resistance to EGFR-TKIs.
      There is emerging evidence of biological difference between ex19del and L858R mutations.
      • Hong W
      • Wu Q
      • Zhang J
      • Zhou Y
      Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer.
      Taking into account major studies in the setting of ex19del subgroups, the FLAURA trial demonstrated the greatest mPFS with osimertinib (21.4 months), followed by RELAY with the erlotinib and ramucirumab combination (19.6 months), and both JO25567 and NEJ026 trials with the erlotinib and bevacizumab combination (18.0 months and 16.6 months respectively) among patients with ex19del mutations.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      ,
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      ,
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      A number of meta-analyses have shown that patients with L858R mutations derive more modest benefit to treatment with 1L EGFR-TKIs compared to patients with ex19del mutations,
      • Li WQ
      • Cui JW.
      Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments.
      ,
      • Sheng M
      • Wang F
      • Zhao Y
      • et al.
      Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis.
      ,
      • Hong W
      • Wu Q
      • Zhang J
      • Zhou Y
      Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer.
      • Zhang Y
      • Sheng J
      • Kang S
      • et al.
      Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis.
      • Lee CK
      • Wu YL
      • Ding PN
      • et al.
      Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with egfr tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis.
      although this may not be true in the setting of a dual-inhibition strategy of anti–angiogenic, and EGFR-TKI treatment.
      • Chen F
      • Chen N
      • Yu Y
      • Cui J
      Efficacy and safety of epidermal growth factor receptor (EGFR) inhibitors plus antiangiogenic agents as first-line treatments for patients with advanced EGFR-mutated non-small cell lung cancer: a meta-analysis.
      ,
      • Deng Z
      • Qin Y
      • Liu Y
      • Zhang Y
      • Lu Y
      Role of antiangiogenic agents combined with EGFR tyrosine kinase inhibitors in treatment-naïve lung cancer: a meta-analysis.
      In L858R mutations, the longest mPFS was observed with erlotinib and ramucirumab (19.4 months) followed by erlotinib and bevacizumab (17.4 months [NEJ026] and 13.9 months [JO25567]).
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      ,
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      ,
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      ,
      • Sheng M
      • Wang F
      • Zhao Y
      • et al.
      Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis.
      ,
      • Zhang Y
      • Sheng J
      • Kang S
      • et al.
      Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis.
      Patients with L858R in the FLAURA trial had a mPFS of 14.4 months.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      Data from the FLAURA trial indicate no OS benefit for patients with L858R (HR 1.0 [0.71-1.40]), while OS data is still awaited from the RELAY trial.
      • Ramalingam SS
      • Vansteenkiste J
      • Planchard D
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      It should be noted that there were differences in populations included in the RELAY, NEJ026, JO25567, and FLAURA trials which may have affected the above results. The RELAY trial did not include patients with central nervous system (CNS) metastases unlike the FLAURA (21% patients) and NEJ026 trials (32%), and the RELAY, NEJ026 and JO25567 trials included more patients with Eastern Cooperative Oncology Group performance status 0, compared with the FLAURA trial.
      • Soria JC
      • Ohe Y
      • Vansteenkiste J
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      ,
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      ,
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      RELAY, NEJ026, and JO25567 only included patients who were eligible for antiangiogenic therapy. However based on current data, patients with L858R mutations may be candidates for combination approaches of EGFR-TKI and antiangiogenic treatment in 1L setting, although this would need to be confirmed in prospective comparative studies. L858R mutations may have differing affinities and sensitivity to EGFR-TKIs, biological behavior of cells, and mechanisms of resistance which may contribute to poorer treatment outcomes compared to ex19del.
      • Li WQ
      • Cui JW.
      Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments.
      Patients with L858R also have increased chance of concomitant mutations compared with ex19del which impacts prognosis, resulting in reduced ORR, and PFS.
      • Li WQ
      • Cui JW.
      Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments.
      ,
      • Hong W
      • Wu Q
      • Zhang J
      • Zhou Y
      Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer.
      ,
      • Barnet MB
      • O'Toole S
      • Horvath LG
      • et al.
      EGFR-Co-mutated advanced NSCLC and response to EGFR tyrosine kinase inhibitors.
      The presence of co-occurring putative resistance mechanisms may correlate with a negative prognosis.
      • Oxnard GR
      • Hu Y
      • Mileham KF
      • et al.
      Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.
      ,
      • Yu HA
      • Suzawa K
      • Jordan E
      • et al.
      Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.
      ,
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      Prior therapy is associated with increased numbers of co-mutations.
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      Co-mutations in the tumor suppressor gene TP53 have been the most frequently detected mutation by next-generation sequencing analyses in patients with mNSCLC with activating EGFR mutations (55%-65%).
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      • Liu L
      • Liu J
      • Shao D
      • et al.
      Comprehensive genomic profiling of lung cancer using a validated panel to explore therapeutic targets in East Asian patients.
      • Testa U
      • Castelli G
      • Pelosi E
      Lung cancers: molecular characterization, clonal heterogeneity and evolution, and cancer stem cells.
      Mutations in TP53 are typically observed during advanced stages of tumorigenesis, suggesting a role in tumor progression rather than initiation.
      • Testa U
      • Castelli G
      • Pelosi E
      Lung cancers: molecular characterization, clonal heterogeneity and evolution, and cancer stem cells.
      Several publications have implicated TP53 mutant's critical role in primary TKI-resistance, interfering with the cell-cycle arrest mediated by EGFR-TKIs.
      • Canale M
      • Petracci E
      • Delmonte A
      • et al.
      Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors.
      • Huang S
      • Benavente S
      • Armstrong EA
      • Li C
      • Wheeler DL
      • Harari PM
      p53 modulates acquired resistance to EGFR inhibitors and radiation.
      • Labbése C
      • Cabanero M
      • Korpanty GJ
      • et al.
      Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
      • VanderLaan PA
      • Rangachari D
      • Mockus SM
      • et al.
      Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes.
      TP53 data have been consistent across trials, indicating that TP53 mutations are an indicator of poorer prognosis, and a consistent predictor of worse clinical outcomes following EGFR-TKI treatment.
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      ,
      • Canale M
      • Petracci E
      • Delmonte A
      • et al.
      Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors.
      ,
      • Labbése C
      • Cabanero M
      • Korpanty GJ
      • et al.
      Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
      The predictive role of TP53 mutations appears to be especially relevant in patients with ex19del, perhaps because patients with ex19del mutations are usually more responsive to EGFR-TKIs.
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      ,
      • Canale M
      • Petracci E
      • Delmonte A
      • et al.
      Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors.
      Patients with TP53 mutations may potentially benefit from EGFR-TKI and anti–angiogenic agent combination therapy, as evidenced by the RELAY data.
      • Nakagawa K.
      • Nadal E.
      • Garon E.B.
      • et al.
      RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
      Mutations in the C797S residue of EGFR have been found to interfere with drug binding of osimertinib and afatinib, indicating other treatment options may be more suitable in this situation.
      • Nakamura T
      • Nakashima C
      • Komiya K
      • et al.
      Mechanisms of acquired resistance to afatinib clarified with liquid biopsy.
      • Ou SI
      • Cui J
      • Schrock AB
      • et al.
      Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib.
      • Assadollahi V
      • Rashidieh B
      • Alasvand M
      • Abdolahi A
      • Lopez JA
      Interaction and molecular dynamics simulation study of Osimertinib (AstraZeneca 9291) anticancer drug with the EGFR kinase domain in native protein and mutated L844V and C797S.
      Co-mutations in PIK3CA (9%-12%) and CTNNB1 (5%-10%) are common in mNSCLC with activating EGFR mutations and may have a role in progression of disease. RB1 co-mutations are also commonly detected co-mutations (10%). The majority of RB1 mutant tumors also harbor TP53 mutations and might define a subset of EGFR mutant NSCLC at risk for transformation to small cell carcinoma following exposure to an EGFR-TKI.
      • Skoulidis F
      • Heymach JV
      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      As previously mentioned, osimertinib is the most effective, and also the only regulatory approved treatment for T790M mutations. However, the sensitivity of the mutation detection methods used, and frequency of testing may significantly affect treatment decisions. Liquid-biopsy based assessment (using droplet digital-based polymerase chain reaction testing [ddPCR]) of T790M mutation and its association with afatinib resistance and response to osimertinib identified the T790M mutation in 73% of patients after afatinib failure using ddPCR.
      • Hochmair MJ
      • Buder A
      • Schwab S
      • et al.
      Liquid-biopsy-based identification of EGFR T790M mutation-mediated resistance to afatinib treatment in patients with advanced EGFR mutation-positive NSCLC, and subsequent response to osimertinib.
      In the AURA phase II trial, 82% of the patients were eligible for screening, revealing 64% positivity for T790M mutation with the cobas EGFR Mutation Test.
      • Yang JC
      • Ahn MJ
      • Kim DW
      • et al.
      Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase ii extension component.
      Furthermore, the detection rate appeared unaffected by the prior EGFR-TKI treatment (gefitinib [69%], erlotinib [68%], and afatinib [68%]).
      • Yang JC
      • Ahn MJ
      • Kim DW
      • et al.
      Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase ii extension component.
      T790M mutations associated with EGFR-TKI acquired resistance when assessed by locked nucleic acid-based assay (LNA) improved detection (standard sequencing [51%]; LNA PCR [68%]).
      • Arcila ME
      • Oxnard GR
      • Nafa K
      • et al.
      Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay.
      Liang et al identified an incidence of 32% T790M mutations in their population.
      • Liang SK
      • Hsieh MS
      • Lee MR
      • Keng LT
      • Ko JC
      • Shih JY.
      Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma.
      The SNaPshot multiplex platform detected T790M mutations in 49% of patients assessed.
      • Sequist LV
      • Waltman BA
      • Dias-Santagata D
      • et al.
      Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
      Similarly, other researchers reported that T790M mutations were detected in 48% of patients that had a partial response to afatinib using a variety of sequencing methodologies (Cobas EGFR Mutation Test, ddPCR, etc.).
      • Tanaka K
      • Nosaki K
      • Otsubo K
      • et al.
      Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naïve patients with non-small cell lung cancer harboring EGFR mutations.
      Future studies may help to elucidate whether radiologic progression or plasmatic progression (detectable T790M mutation cDNA by liquid biopsy or reappearance of sensitizing EGFR mutations after initial clearance) occurs first, potentially improving treatment outcomes, and avoiding a delay in switching to 2L treatment.
      • Shin JY
      • Kim JO
      • Lee MR
      • Kim SR
      • Beck KS
      • Kang JH.
      A highly sensitive next-generation sequencing-based genotyping platform for egfr mutations in plasma from non-small cell lung cancer patients.
      Detection methods are not equally available everywhere, posing a caveat in cases requiring sensitive detection, such as in the context of T790M or TP53 mutations.
      • Roeper J
      • Kurz S
      • Grohé C
      • Griesinger F
      Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
      More frequent identification of concurrent mutations early in the treatment process, using next-generation sequencing, may help to develop more personalized treatment strategies for patients to overcome previously unidentified primary resistance mechanisms.
      • Gelatti ACZ
      • Drilon A
      • Santini FC
      Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

      Conclusion and Future Developments

      In summary, we have discussed the potential treatment approaches in mNSCLC with activating EGFR mutations. We have reviewed the clinical evidence supporting the use of EGFR-TKIs and which patients might potentially benefit most so that physicians may make the most appropriate therapy decision for the overall treatment plan for patients.
      • Planchard D
      • Popat S
      • Kerr K
      • et al.
      Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

      It is critical to optimize therapy by improving the assessment of molecular changes in tumors when analyzing mechanisms of resistance. Utilizing novel treatment options to understand and overcome potential resistance will help guide “precision medicine” for the best choice of therapies. Furthermore, 1L EGFR-TKIs in combination with anti–angiogenic agents (eg ramucirumab and bevacizumab) may provide an alternative treatment option to patients in some circumstances, such as patients with L858R mutations and/or co-mutations.
      • Seto T
      • Kato T
      • Nishio M
      • et al.
      Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
      • Nakagawa K
      • Garon EB
      • Seto T
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
      • Zhou Q
      • Wu YL
      • Cheng Y
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      • Saito H
      • Fukuhara T
      • Furuya N
      • et al.
      Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
      ,
      • Maemondo M
      • Fukuhara T
      • Saito H
      • et al.
      NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
      ,
      • Li WQ
      • Cui JW.
      Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments.
      The ongoing randomized phase II studies, RAMOSE and TORG1833, using osimertinib with or without ramucirumab are investigating the combination's efficacy in treatment-naïve mNSCLC with activating EGFR mutations.
      • Nakahara Y
      • Kato T
      • Isomura R
      • et al.
      A multicenter, open label, randomized Phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer: TORG1833.
      ,
      • Saltos A
      • Baik C
      • Sanborn RE
      • et al.
      P76.62 RAMOSE: An Open-Label Randomized Phase II Study of Osimertinib with or without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC.
      Additionally, a phase III study to evaluate the clinical efficacy of the combination of erlotinib and ramucirumab compared with osimertinib monotherapy for previously untreated patients with mNSCLC with L858R mutation is now ongoing in Japan (WJOG14420L/REVOL858R trial).

      NIPH Clinical Trials Search. Phase 3 clinical trial of the combination of erlotinib plus ramucirumab comparing with osimertinib in untreated advanced or recurrent non-small cell lung cancer with EGFR L858R mutation (REVOL858R trial). Accessed from: https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs051200142. 2021. Accessed at: March 11, 2021.

      The combination of osimertinib and chemotherapy as a 1L therapy is also being investigated in the FLAURA2 trial.

      ClinicalTrials.gov. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2). Accessed from: https://clinicaltrials.gov/ct2/show/NCT04035486. 2019. Accessed at: April 27, 2021.

      The MARIPOSA trial is currently assessing the efficacy of the combination of amivantamab and lazertinib, compared with osimertinib monotherapy. This study will provide further insight into potential treatments targeting co-mutations in mNSCLC.

      ClinicalTrials.gov. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Accessed from: https://clinicaltrials.gov/ct2/show/NCT04487080. 2020. Accessed at: March 11, 2021.

      The mutation landscape that emerges following the long-term use of EGFR-TKIs with chemotherapy and EGFR-TKIs with anti–angiogenics must be monitored closely in the future to assess potential new treatment requirements.
      The phase III ADAURA trial investigated the efficacy and safety of adjuvant osimertinib compared with placebo in patients with stage 1B-IIIA EGFR-mutated (ex19del or L858R) mNSCLC.
      • Wu YL
      • Tsuboi M
      • He J
      • et al.
      Osimertinib in resected EGFR-mutated non-small-cell lung cancer.
      At 24 months, disease-free survival was demonstrated to be significantly longer in the osimertinib arm in comparison with the placebo arm (overall hazard ratio for disease recurrence or death – 0.20; 99.12% CI – 0.14 to 0.30), suggesting adjuvant osimertinib may have a role in delaying disease recurrence. The results of this trial may affect future treatment options and substantially change the treatment landscape if osimertinib is used more often in early-stage NSCLC and other therapies will be needed on disease recurrence.
      Osimertinib is accepted as the standard of care in the 1L setting but more data needs to be generated regarding the efficacy of osimertinib either in comparison with or in combination with earlier generation EGFR-TKIs, chemotherapy, and anti–VEGF monoclonal antibodies. Table 1 lists pertinent ongoing trials in mNSCLC with activating EGFR mutations. The results of these trials may enhance the understanding of the mNSCLC with activating EGFR mutations as well as inform future treatment practice. In conclusion, as increasing information is available with regard to treatment options with EGFR-TKIs, it is critical to adapt EGFR-TKI use in order to optimally maximize patient outcomes.

      Acknowledgment

      The authors would like to acknowledge John Hurley and Kristi Gruver, Eli Lilly and Company, for medical writing assistance with the preparation of this manuscript, funded by Eli Lilly, and Company.

      Funding

      This article was funded by Eli Lilly and Company.

      Author Contributions

      Hidetoshi Hayashi: Conceptualization, Validation, Resources, Writing – Original Draft, Writing – Review & Editing. Ernest Nadal: Validation, Resources, Writing – Original Draft, Writing – Review & Editing, Visualization. Jhanelle E. Gray: Conceptualization, Validation, Resources, Writing – Review & Editing. Andrea Ardizzoni: Conceptualization, Validation, Investigation, Writing – Review & Editing. Nicola Caria: Conceptualization, Validation, Investigation, Resources, Writing – Review & Editing. Tarun Puri: Conceptualization, Validation, Investigation, Resources, Writing – Original Draft, Writing – Review & Editing, Visualization. Christian Grohe: Conceptualization, Validation, Investigation, Resources, Writing – Review & Editing.

      Conflicts of Interest

      H.H. reports lectures for AstraZeneca K.K., Boehringer Ingelheim Japan Inc, Bristol-Myers Squibb Co Ltd, Chugai Pharmaceutical Co Ltd, Eli Lilly Japan K.K., Kyorin pharmaceutical co ltd, Merck Biopharma Co, Ltd, MSD K.K., Novartis pharmaceuticals k.k, Ono Pharmaceutical Co Ltd, Shanghai Haihe Biopharm, Taiho Pharmaceutical Co Ltd, and Takeda Pharmaceutical Company Limited; consulting or advisory role for AstraZeneca K.K., Boehringer Ingelheim Japan Inc, Bristol-Myers Squibb Co Ltd, Chugai Pharmaceutical Co Ltd, Eli Lilly Japan K.K, Pfizer Japan Inc, Shanghai Haihe Biopharm, Takeda Pharmaceutical Company Limited and Merck Biopharma Co, Ltd; grants from AstraZeneca K.K., Boehringer Ingelheim Japan Inc, Chugai Pharmaceutical Co Ltd, and Ono Pharmaceutical Co Ltd; institutional research funding from AstraZeneca K.K., Astellas Pharma Inc, MSD K.K., Ono Pharmaceutical Co,Ltd, Nippon Boehringer Ingelheim Co,Ltd, Novartis Pharma K.K., grants, Pfizer Japan Inc, Bristol Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co,Ltd, Daiichi Sankyo Co, Ltd, Merck Serono Co, Ltd/ Merck Biopharma Co, Ltd, g, Takeda Pharmaceutical Co,Ltd, Taiho Pharmaceutical Co,Ltd, SymBio Pharmaceuticals Limited., AbbVie Inc, inVentiv Health Japan, ICON Japan K.K., GRITSONE ONCOLOGY.INC, PAREXEL International Corp., Kissei Pharmaceutical Co,Ltd, EPS Corporation., Syneos Health., Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc / IQVIA Services JAPAN K.K., EP-CRSU CO, LTD, Linical Co,Ltd, Eisai Co, Ltd, CMIC Shift Zero K.K., Kyowa Hakko Kirin Co,Ltd, Bayer Yakuhin, Ltd, EPS International Co,Ltd,., Otsuka Pharmaceutical Co, Ltd E.N. reports a consulting or advisory role and lectures for Merck Sharpe and Dohme, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Pfizer, Takeda, and AstraZeneca; institutional research funding from Pfizer, Roche, Merck-Serono and Bristol Myers Squibb; and reimbursement for travel, accommodations, or expenses from Merck Sharpe and Dohme, Bristol Myers Squibb, Pfizer, Roche, and Eli Lilly and Company. J.E.G. reports grant from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, G1 Therapeutics, Merch, Novartis, Pfizer and Ludwig Institute of Cancer Research; and a consulting or advisory role for AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Daiichi Sankyo Inc (DSI), EMD Serono – Merck KGaA, Inivata, Janssen Scientific Affairs LLC, Merch and Novartis. A.A. reports grants and personal fees from BMS; and grants from AstraZeneca, Bayer, Eli Lilly and Company, MSD, Roche, and Takeda. N.C. is an employee of and owns stock in Eli Lilly and Company. T.P. is an employee of and owns stock in Eli Lilly and Company. C.G. reports honoraria from Abbvie, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly, Roche; research funding from Novartis and Ipsen; and has been an advisory board member for AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly and Takeda.

      References

        • Planchard D
        • Popat S
        • Kerr K
        • et al.
        Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2018; 29: iv192-iv237
      1. World Health Organization. Cancer - key facts. Accessed from: https://www.who.int/news-room/fact-sheets/detail/cancer. 2018. Accessed at: February 16, 2021.

        • Midha A
        • Dearden S
        • McCormack R
        EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
        Am J Cancer Res. 2015; 5: 2892-2911
        • Graham RP
        • Treece AL
        • Lindeman NI
        • et al.
        Worldwide frequency of commonly detected EGFR mutations.
        Arch Pathol Lab Med. 2018; 142: 163-167
        • Noronha V
        • Patil VM
        • Joshi A
        • et al.
        Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
        J Clin Oncol. 2020; 38: 124-136
        • Sugawara S
        • Oizumi S
        • Minato K
        • et al.
        Randomized Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
        Ann Oncol. 2015; 26: 888-894
        • Cheng Y
        • Murakami H
        • Yang PC
        • et al.
        Randomized Phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations.
        J Clin Oncol. 2016; 34: 3258-3266
        • Hosomi Y
        • Morita S
        • Sugawara S
        • et al.
        Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
        J Clin Oncol. 2020; 38: 115-123
        • Fukuoka M
        • Wu Y-L
        • Thongprasert S
        • et al.
        Biomarker analyses and final overall survival results from a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).
        J Clin Oncol. 2011; 29: 2866-2874
        • Inoue A
        • Kobayashi K
        • Maemondo M
        • et al.
        Updated overall survival results from a randomized Phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
        Ann Oncol. 2013; 24: 54-59
        • Mitsudomi T
        • Morita S
        • Yatabe Y
        • et al.
        Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial.
        Lancet Oncol. 2010; 11: 121-128
        • Zhou C
        • Wu YL
        • Chen G
        • et al.
        Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802).
        Ann Oncol. 2015; 26: 1877-1883
        • Rosell R
        • Carcereny E
        • Gervais R
        • et al.
        Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised Phase 3 trial.
        Lancet Oncol. 2012; 13: 239-246
        • Wu YL
        • Zhou C
        • Liam CK
        • et al.
        First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the Phase III, randomized, open-label, ENSURE study.
        Ann Oncol. 2015; 26: 1883-1889
        • Kato T
        • Yoshioka H
        • Okamoto I
        • et al.
        Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroup analysis of LUX-Lung 3.
        Cancer Science. 2015; 106: 1202-1211
        • Yang JCH
        • Wu YL
        • Schuler M
        • et al.
        Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, Phase 3 trials.
        Lancet Oncol. 2015; 16: 141-151
        • Sequist LV
        • Yang JC
        • Yamamoto N
        • et al.
        Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
        J Clin Oncol. 2013; 31: 3327-3334
        • Park K
        • Tan EH
        • O'Byrne K
        • et al.
        Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial.
        Lancet Oncol. 2016; 17: 577-589
        • Wu YL
        • Zhou C
        • Hu CP
        • et al.
        Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised Phase 3 trial.
        Lancet Oncol. 2014; 15: 213-222
        • Paz-Ares L
        • Tan EH
        • O'Byrne K
        • et al.
        Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the Phase IIb LUX-Lung 7 trial.
        Ann Oncol. 2017; 28: 270-277
        • Wu YL
        • Cheng Y
        • Zhou X
        • et al.
        Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, Phase 3 trial.
        Lancet Oncol. 2017; 18: 1454-1466
        • Zhou C
        • Wu Y-L
        • Chen G
        • et al.
        Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, Phase 3 study.
        Lancet Oncol. 2011; 12: 735-742
        • Sequist LV
        • Wu Y
        • Schuler M
        • et al.
        Subsequent therapies post-afatinib among patients with EGFR mutation-positive (EGFRm+) NSCLC in LUX-Lung 3, 6 and 7: Topic: Medical oncology (Abstract PS02.20).
        J Thorac Oncol. 2017; 12: S1572
        • Mok TS
        • Wu YL
        • Ahn MJ
        • et al.
        Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
        N Engl J Med. 2017; 376: 629-640
        • Hanna N
        • Shepherd FA
        • Fossella FV
        • et al.
        Randomized phase iii trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.
        J Clin Oncol. 2004; 22: 1589-1597
        • Yu H
        • Goldberg S
        • Le X
        • et al.
        ORCHARD: a Phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
        J Thorac Oncol. 2019; 14: S647
        • Remon J
        • Menis J
        • Hasan B
        • et al.
        The APPLE trial: feasibility and activity of AZD9291 (osimertinib) treatment on positive PLasma T790M in EGFR-mutant NSCLC patients. EORTC 1613.
        Clin Lung Cancer. 2017; 18: 583-588
        • Maemondo M
        • Inoue A
        • Kobayashi K
        • et al.
        Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
        N Engl J Med. 2010; 362: 2380-2388
        • Mok TS
        • Wu YL
        • Thongprasert S
        • et al.
        Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
        N Engl J Med. 2009; 361: 947-957
        • Wu YL
        • Sequist LV
        • Tan EH
        • et al.
        Afatinib as first-line treatment of older patients with EGFR mutation-positive non-small-cell lung cancer: subgroup analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 trials.
        Clin Lung Cancer. 2018; 19: e465-e479
        • Yang JCH
        • Sequist LV
        • Geater SL
        • et al.
        Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.
        The Lancet Oncology. 2015; 16: 830-838
        • Soria JC
        • Ohe Y
        • Vansteenkiste J
        • et al.
        Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
        N Engl J Med. 2018; 378: 113-125
        • Ramalingam SS
        • Vansteenkiste J
        • Planchard D
        • et al.
        Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
        N Engl J Med. 2020; 382: 41-50
        • Loong HH
        • Kwan SS
        • Mok TS
        • Lau YM
        Therapeutic strategies in EGFR mutant non-small cell lung cancer.
        Curr Treat Options Oncol. 2018; 19: 58
      2. National Comprehensive Cancer Network. National Comprehensive Cancer Network: NCCN flash updates: NCCN clinical practice guidelines and NCCN compendium updated for Non-Small Cell Lung Cancer (NSCLC) version 2.2020. Accessed from: https://www.nccn.org/professionals/physician_gls/. 2020. Accessed at: March 26, 2021.

        • Oizumi S
        • Sugawara S
        • Minato K
        • et al.
        Updated survival outcomes of NEJ005/TCOG0902: a randomised Phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations.
        ESMO Open. 2018; 3e000313
        • Roeper J
        • Kurz S
        • Grohé C
        • Griesinger F
        Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC.
        Future Oncol. 2021; 17: 471-486
        • Byers LA
        • Heymach JV
        Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer.
        Clin Lung Cancer. 2007; 8: S79-S85
        • Le X
        • Nilsson M
        • Goldman J
        • et al.
        Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC.
        J Thorac Oncol. 2021; 16: 205-215
        • Seto T
        • Kato T
        • Nishio M
        • et al.
        Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, Phase 2 study.
        Lancet Oncol. 2014; 15: 1236-1244
        • Nakagawa K
        • Garon EB
        • Seto T
        • et al.
        Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, Phase 3 trial.
        Lancet Oncol. 2019; 20: 1655-1669
        • Zhou Q
        • Wu YL
        • Cheng Y
        • et al.
        CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
        Ann Oncol. 2019; 30: v603
        • Saito H
        • Fukuhara T
        • Furuya N
        • et al.
        Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, Phase 3 trial.
        Lancet Oncol. 2019; 20: 625-635
        • Stinchcombe TE
        • Jänne PA
        • Wang X
        • et al.
        Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a Phase 2 randomized clinical trial.
        JAMA Oncology. 2019; 5: 1448-1455
        • Maemondo M
        • Fukuhara T
        • Saito H
        • et al.
        NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
        J Clin Oncol. 2020; 38 (9506-9506)
        • Nakagawa K.
        • Nadal E.
        • Garon E.B.
        • et al.
        RELAY, erlotinib plus ramucirumab or placebo in untreated EGFR-mutated metastatic NSCLC: outcomes by EGFR mutation type (Abstract 1294P).
        Ann Oncol. 2020; 31: S838
        • Yamamoto N
        • Seto T
        • Nishio M
        • et al.
        Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
        J Clin Oncol. 2018; 36 (9007-9007)
        • Zhang L
        • Zhao H
        • Zhang Z
        • et al.
        ACTIVE: Apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled Phase III trial (CTONG1706) (Abstract LBA50).
        Ann Oncol. 2020; 31: S1181
      3. ClinicalTrials.gov. Erlotinib hydrochloride with or without bevacizumab in treating patients with stage IV non-small cell lung cancer with epidermal growth factor receptor mutations. https://clinicaltrials.gov/ct2/show/results/NCT01532089?view=results. 2012. Accessed from: October 6, 2020. Accessed at: May 19, 2021.

      4. ClinicalTrials.gov. Bevacizumab plus EGFR-TKIs in Chinese patients with EGFR-mutant NSCLC: a real-world study (BELLA). Accessed from: https://clinicaltrials.gov/ct2/show/NCT04575415. 2020. Accessed at: February 16, 2020.

      5. ClinicalTrials.gov. AZD9291 (osimertinib) with or without bevacizumab as initial treatment for patients with EGFR-mutant lung cancer. Accessed from: https://clinicaltrials.gov/ct2/show/NCT04181060. 2019. Accessed at: February 16, 2020.

      6. ClinicalTrials.gov. Osimertinib with or without bevacizumab in treating patients with EGFR positive non-small cell lung cancer and brain metastases. Accessed from: https://clinicaltrials.gov/ct2/show/NCT02971501. 2016. Accessed at: April 20, 2021.

      7. UMIN-CTR Clinical Trial. Randomized Phase II study of osimertinib plus bevacizumab and osimertinib for chemotherapy-naive patients with nonsquamous non-small cell lung cancer harboring EGFR mutations (investigator-initiated multicenter clinical trial, WJOG9717L). Accessed from: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034306. 2017. Accessed at: April 20, 2021.

        • Yu HA
        • Schoenfeld AJ
        • Makhnin A
        • et al.
        Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a Phase 1/2 single-group open-label trial.
        JAMA Oncol. 2020; 6: 1048-1054
        • Haratake N
        • Toshihiro M
        • Takeharu Y
        • T S
        Optimizing sequential treatment with EGFR tyrosine kinase inhibitor with a simulation of the T790M mutation rate in EGFR–mutated lung cancer.
        JTO Clinical and Research Reports. 2020; 1100085
        • Wu YL
        • Ahn MJ
        • Garassino MC
        • et al.
        CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3).
        J Clin Oncol. 2018; 36: 2702-2709
        • Eide IJZ
        • Helland Å
        • Ekman S
        • et al.
        Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study).
        Lung Cancer. 2020; 143: 27-35
        • Akamatsu H
        • Toi Y
        • Hayashi H
        • et al.
        Efficacy of osimertinib plus bevacizumab vs osimertinib in patients with EGFR T790M-mutated non-small cell lung cancer previously treated with epidermal growth factor receptor-tyrosine kinase inhibitor: West Japan oncology group 8715L Phase 2 randomized clinical trial.
        JAMA Oncol. 2021; 7: 386-394
        • Green JA
        Osimertinib-first or second line for epidermal growth factor (EGFR) mutation-positive non-small cell lung cancer?.
        J Thor Dis. 2018; 10: S3837-S3839
        • Le T
        • Gerber DE
        Newer-generation EGFR inhibitors in lung cancer: how are they best used?.
        Cancers (Basel). 2019; 11: 366
        • Tamiya M
        • Tamiya A
        • Suzuki H
        • et al