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Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced, Unresectable KRAS-mutated Non-Small Cell Lung Cancer

Open AccessPublished:August 07, 2022DOI:https://doi.org/10.1016/j.cllc.2022.08.002

      Highlights

      • Durvalumab benefits patients with KRAS-driven locally advanced, unresectable non-small cell lung cancer
      • TP53 co-mutation in KRAS-driven disease trends towards improved survival
      • Extrathoracic progression may be more common in patients with KRAS-driven disease

      Abstract

      Background

      Consolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes.

      Methods

      We conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression.

      Results

      Of 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015).

      Conclusion

      Patients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.

      Keywords

      Introduction

      Approximately 20% to 35% of patients with NSCLCpresent with stage III disease at diagnosis, with locally advanced disease also occurring in patients who progress following initial therapy for early-stage disease.
      • Casal-Mouriño A
      • Ruano-Ravina A
      • Lorenzo-González M
      • et al.
      Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival.
      Definitive concurrent platinum-based chemoradiation followed by 1-year of anti-PD-L1 consolidation therapy with durvalumab is the standard of care for patients diagnosed with locally advanced, unresectable stage III NSCLC.
      • Antonia SJ
      • Villegas A
      • Daniel D
      • et al.
      Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.
      The phase III PACIFIC trial comparing chemoradiotherapy (CRT) plus placebo to CRT plus durvalumab found that durvalumab consolidation improved median progression-free survival (PFS) from 5.6 months to 16.8 months. Recent updates demonstrate 5-year PFS rate of 33.1% versus 19.0% in the control arm.
      • Antonia SJ
      • Villegas A
      • Daniel D
      • et al.
      Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.
      ,
      • Spigel DR
      • Faivre-Finn C
      • Gray JE
      • et al.
      Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial.
      Median overall survival (OS) was also improved with 5-year OS rates of 42.9% and 33.4% for durvalumab and placebo, respectively.
      • Spigel DR
      • Faivre-Finn C
      • Gray JE
      • et al.
      Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial.
      Despite these significant improvements, up to 25% of patients still progress within 18 months following completion of durvalumab consolidation. To date, patient and/or tumor factors driving early progression remain poorly elucidated. In the era of precision thoracic oncology, little is known regarding the genomic determinants of benefit of immunotherapy.
      KRAS driver mutations are found in approximately 30% of NSCLCs and are associated with worse clinical outcomes to standard chemoradiotherapy for stage III disease.
      • Addeo A
      • Passaro A
      • Malapelle U
      • Luigi Banna G
      • Subbiah V
      • Friedlaender A
      Immunotherapy in non-small cell lung cancer harbouring driver mutations.
      • Hallqvist A
      • Enlund F
      • Andersson C
      • et al.
      Mutated KRAS is an independent negative prognostic factor for survival in NSCLC stage III disease treated with high-dose radiotherapy.
      • Yagishita S
      • Horinouchi H
      • Sunami KS
      • et al.
      Impact of KRAS mutation on response and outcome of patients with stage III non-squamous non-small cell lung cancer.
      -
      • Finn SP
      • Addeo A
      • Dafni U
      • et al.
      Prognostic impact of KRAS G12C mutation in patients with NSCLC: results from the european thoracic oncology platform lungscape project.
      Studies have shown that KRAS-mutated tumors are associated with higher tumor mutational burden and immune-rich microenvironments, and indeed several studies have highlighted the favorable response to immune checkpoint inhibitors (ICIs) in KRAS-mutated tumors.
      • Dong ZY
      • Zhong WZ
      • Zhang XC
      • et al.
      Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
      • Torralvo J
      • Friedlaender A
      • Achard V
      • Addeo A.
      The activity of immune checkpoint inhibition in KRAS mutated non-small cell lung cancer: a single centre experience.
      -
      • Jeanson A
      • Tomasini P
      • Souquet-Bressand M
      • et al.
      Efficacy of immune checkpoint inhibitors in KRAS-Mutant non-small cell lung cancer (NSCLC).
      Yet, co-occurring mutations in several clinically significant, non-targetable genes have been shown to modify the response to immunotherapy in KRAS-mutated NSCLC. Co-mutation in TP53 has been suggested to correlate with better responses to PD-L1 blockade, while co-mutations in STK11 or KEAP1 are associated with poorer responses.
      • Dong ZY
      • Zhong WZ
      • Zhang XC
      • et al.
      Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
      ,
      • Bange E
      • Marmarelis ME
      • Hwang WT
      • et al.
      Impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy among patients with STK11-mutated advanced non-small-cell lung cancer.
      -
      • Skoulidis F
      • Goldberg ME
      • Greenawalt DM
      • et al.
      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      These differences only further highlight the need to better understand the genomic determinants of response and outcomes to immunotherapy so that patients can receive the most appropriate therapies, particularly as novel KRAS-targeted therapies are being developed.
      Additionally, patients with stage III NSCLC whose tumors have KRAS mutations have been found to have greater rates of intracranial relapse as well as lower rates of local thoracic relapse when treated with chemoradiation alone.
      • Yagishita S
      • Horinouchi H
      • Sunami KS
      • et al.
      Impact of KRAS mutation on response and outcome of patients with stage III non-squamous non-small cell lung cancer.
      Understanding patterns of progression is important to optimize systemic disease control of micrometastases and guide surveillance for patients at high-risk for relapse, within the context of the PACIFIC treatment paradigm. However, KRAS mutation status was not reported from PACIFIC, and as such the responses and progression patterns of patients with KRAS-mutated stage III NSCLC with this therapy is currently poorly understood. As there is currently no standard protocol for disease surveillance following durvalumab therapy completion, describing patterns of progression is critically important in guiding decisions regarding surveillance imaging for patients at high-risk for relapse.
      In this single-institution retrospective study, we describe the treatment experiences and outcomes of real-world NSCLC patients with locally advanced disease who received definitive CRT and consolidative durvalumab therapy with a focus on the experiences of patients with KRAS-driven disease. We conduct subgroup analyses by TP53 mutation status and KRAS codon change in patients with KRAS-mutated NSCLC. Finally, we compare patterns of progression in these cohorts of patients stratified by clinical genomic mutational landscape.

      Methods

      Study Design

      Patients with newly diagnosed or locally recurrent unresectable, locally advanced NSCLC who completed platinum-based CRT between 2015 and 2020 at Johns Hopkins University School of Medicine were identified. Patients who also received durvalumab consolidation therapy at our institution were response evaluable and included in our study cohort. Patients who received durvalumab consolidation elsewhere were excluded. Institutional Review Board approval for study data collection was obtained. Baseline demographic, clinical, and treatment characteristics were obtained from patients’ electronic medical records. NSCLC histology and disease stage were classified by WHO criteria and the American Joint Commission on Cancer and International Union Against Cancer (AJCC, version 8) TNM criteria, respectively.
      • Travis WD
      • Brambilla E
      • Nicholson AG
      • et al.
      The 2015 World Health Organization Classification of Lung Tumors.
      ,
      • Detterbeck FC
      • Boffa DJ
      • Kim AW
      • Tanoue LT.
      The eighth edition lung cancer stage classification.
      Patients with stage IIB or IIIA disease who were deemed to not be surgical candidates by our multidisciplinary team and opted to receive chemoradiation plus durvalumab consolidation instead were also included in our study. PD-L1 tumor proportion score (TPS) was determined from anti-PD-L1 immunohistochemistry conducted with the 22C3 probe or from commercial molecular profiling reports.
      Genomic molecular profiles of patient tumors were determined and recorded from next-generation sequencing (NGS), single-gene sequencing, and FISH cytogenetics from tumor and liquid biopsies performed on CLIA certified panels and obtained prior to immunotherapy. Alterations in actionable genes were defined as fusions, splice site variants, deletion-insertions, and single nucleotide variants occurring in EGFR, ERBB2, ALK, BRAF V600E, MET, RET, or ROS1. Alterations in non-actionable genes included those occurring in KRAS, KEAP1, STK11, and BRAF non-V600E. Distinction between actionable and non-actionable genes was defined by the availability of specific targeted therapies at the start of CRT treatment. Tumors without alterations in KRAS or in the aforementioned actionable genes were defined as non-actionable disease, serving as a clinically relevant comparison to KRAS-driven disease.

      Study Outcomes and Statistical Analysis

      PFS was measured from the date of durvalumab initiation to the date of documented radiographic progression by the Response Evaluation Criteria in Solid Tumors version 1.1
      • Eisenhauer EA
      • Therasse P
      • Bogaerts J
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      or to the date of death from any cause, whichever came first. OS was measured from the date of durvalumab initiation to the date of death from any cause. Patients were censored at the date of last follow-up. Similar to definitions from the PACIFIC trial
      • Raben D
      • Rimner A
      • Senan S
      • et al.
      Patterns of disease progression with durvalumab in stage III non-small cell lung cancer (PACIFIC).
      , thoracic progression was defined as progression in the lung, thoracic lymph nodes, or pleura. Extrathoracic progression was defined as progression in the bone, brain, liver, adrenal glands, or other non-thoracic locations. R studio was used to generate Kaplan-Meier survival curves to examine PFS and OS across patient cohorts, with error margins representing 95% confidence interval for the log-rank survival analysis. Fisher's exact test was used to evaluate differences in patterns of progression. Descriptive statistics were used to describe time from CRT completion durvalumab initiation, time on durvalumab therapy, and the reasons for durvalumab treatment cessation.

      Results

      Patient Characteristics

      In total, 134 patients with locally advanced, unresectable NSCLC who received concurrent CRT between 2015 and 2020 at our institution were identified (Figure 1). Of these patients, 76 received durvalumab consolidation therapy. A total cohort of 74 patients received durvalumab consolidation at our institution, and these response-evaluable patients were therefore included in this retrospective study (Table 1). The mean age at CRT start was 66.5 years (IQR: 59, 75). The majority of patients were male (56.8%). Tumor histology was primarily adenocarcinoma (55.4%) and squamous cell carcinoma (32.4%). Around 12% of patients had other tumor histology including adenosquamous, large cell neuroendocrine, sarcomatoid, and NSCLC not otherwise specified. Tumor stage was primarily IIIA (41.9%) and IIIB (39.2%).
      Figure 1
      Figure 1Retrospective cohort selection of patients who received concurrent chemoradiation and consolidative durvalumab therapy for locally advanced, unresectable non-small cell lung cancer.
      Table 1Patient Cohort Demographics.
      CharacteristicOverall, n = 74Not Tested, n = 35Tested, n = 39P-Value
      Age at start of treatment, years (IQR)67 (59, 75)67 (61, 73)66 (58, 76).9
      Sex.3
      Female32 (43%)13 (37%)19 (49%)
      Male42 (57%)22 (63%)20 (51%)
      ECOG performance status.7
      013 (18%)6 (17%)7 (18%)
      153 (72%)24 (69%)29 (74%)
      28 (11%)5 (14%)3 (7.7%)
      Stage (AJCC8).7
      IIB8 (11%)3 (8.6%)5 (13%)
      IIIA31 (42%)14 (40%)17 (44%)
      IIIB29 (39%)16 (46%)13 (33%)
      IIIC6 (8.1%)2 (5.7)4 (10%)
      Histology<.001
      Adenocarcinoma41 (55%)8 (23%)33 (85%)
      Adenosquamous1 (1.4%)1 (2.9%)0 (0.0%)
      Neuroendocrine2 (2.7%)0 (0.0%)2 (5.1%)
      NOS5 (6/8%)4 (11%)1 (2.6%)
      Sarcomatoid1 (1.4%)0 (0.0%)1 (2.6%)
      Squamous24 (3.2%)22 (63.0%)2 (5.1%)
      PD-L1 status.3
      High (> = 50%)19 (26%)7 (20%)12 (31%)
      Low (1-49%)10 (14%)3 (8.6%)7 (18%)
      Negative (<1%)16 (22%)8 (23%)8 (21%)
      Unknown29 (39%)17 (49%)12 (31%)
      Chemotherapy regimen0.2
      Carboplatin/etoposide1 (1.4%)0 (0.0%)1 (2.6%)
      Carboplatin/paclitaxel40 (54%)23 (66%)17 (44%)
      Carboplatin/pemetrexed17 (23%)5 (14%)12 (31%)
      Cisplatin/etoposide7 (9.5%)4 (11%)3 (7.7%)
      Cisplatin/pemetrexed9 (12%)3 (8.6%)6 (15%)
      Radiotherapy dose, Gy (IQR)63.00

      (61.20, 66.00)
      63.00

      (61.20, 65.00)
      63.00

      (61.20, 66.00)
      0.4
      Completed durvalumab consolidation29 (39%)16 (45%)13 (33%)0.3
      Of the 74 patients, 39 patients (84.6% having an adenocarcinoma histology) tumors had received molecular genomic profiling at the time of diagnosis (Figure 2). KRAS mutations were identified in tumors of 18 patients, which defined the KRAS cohort. Fourteen patients had tumors lacking KRAS mutations and lacking mutations in currently targetable genes (EGFR, ERBB2, ALK, BRAF V600E, MET, RET, or ROS1), and these patients were grouped as the non-actionable cohort. Tumors of patients in the non-actionable cohort may have had alterations in other currently non-actionable genes (TP53, STK11, KEAP1, BRAF non-V600E) that have clinical significance in immune checkpoint inhibition response. The cohort defined as the actionable cohort included 7 patients whose tumors had alterations in an actionable gene (EGFR, ERBB2, ALK, BRAF V600E, MET, RET, or ROS1), and thus these patients were excluded from the non-actionable cohort as other therapeutic options were available. The remaining 35 patients, whose tumors were not genomically interrogated, were designated as the not-tested cohort. Patient demographics, cancer characteristics, and treatment details by molecular cohort are listed in the Supplemental Table 1. While tumor histology varied across molecular cohort, other baseline factors such as disease stage and patient demographics did not.
      Figure 2
      Figure 2Oncoplot describing patient tumor genomic testing coverage and mutational profile.
      Molecular testing performed in 39 patients. KRAS mutations were identified in 18 tumors (8 were G12C codons, 10 were non-G12C codons). Pathogenic TP53 mutations were identified in tumors of 16 patients, with 9 patients having KRAS and TP53 co-mutations. 7 patients had tumors with pathogenic alterations in currently targetable driver genes (EGFR, ERBB2, ALK, BRAF V600E, MET, RET, or ROS1). No actionable mutations were identified in the tumors of the remaining 14 patients.
      Of the 18 patients with KRAS-mutated tumors, 8 had KRAS G12C mutations and 10 had KRAS non-G12C mutations. Neither STK11 nor KEAP1 co-mutations were found in tumors with KRAS mutations, however, there was incomplete coverage for STK11 and KEAP1 sequencing in our cohort as earlier standard genome panels did not test for STK11 and KEAP1. Pathogenic TP53 mutations were found in tumors of 16 patients. Of the 18 patients with KRAS-mutated tumors, 17 patients received TP53 testing, and 9 patients had tumors with TP53 co-mutations. The remaining 8 KRAS-mutated tumors did not have TP53 co-mutations. One patient's tumor was found to harbor both a KRAS single nucleotide variant and an EGFR single nucleotide variant. However, this EGFR alteration was determined to be nonpathogenic by Functional Analysis through Hidden Markov Models.
      • Shihab HA
      • Gough J
      • Cooper DN
      • et al.
      Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
      PD-L1 status was available for 45 of 74 patients (60.8%). High PD-L1 TPS (>50%), low PD-L1 TPS (1%-50%), and negative PD-L1 TPS (<1%) were identified in 25.7%, 13.5%, and 21.6% of patient tumors, respectively.

      Treatment Characteristics

      The following chemotherapeutic regimens were administered: 7 patients received cisplatin/etoposide, 1 patient received carboplatin/etoposide, 9 patients received cisplatin/pemetrexed, 17 patients received carboplatin/pemetrexed, and 40 patients received weekly carboplatin/paclitaxel. The median total radiotherapy dose was 63 Gy (IQR: 61.2, 66).
      Median time from CRT completion to durvalumab initiation was 28.5 days (IQR: 20, 40) (Supplemental Figure 1A). Median time on durvalumab therapy was 6.6 months (IQR: 2.5, 11.7), with 29 patients (39.2%) completing 1 year of durvalumab consolidation (Supplemental Figure 1B). Durvalumab was discontinued due to progressive disease in 17 patients, severe immune-related adverse event (irAE; including pneumonitis, hepatitis, colitis, rash, sicca, and adrenal insufficiency) in 24 patients, and for other reasons (cerebellar abscess and dyspnea with concern for pneumonitis) in 3 patients. One patient was lost to follow up during durvalumab consolidation therapy (Supplemental Table 2).
      Table 2 details completion or discontinuation status of durvalumab consolidation by genomic cohort. Of the 18 patients with KRAS-mutated NSCLC, 8 patients completed durvalumab consolidation, 5 progressed while on durvalumab consolidation, 3 discontinued durvalumab due to irAE (2 checkpoint induced pneumonitis, 1 checkpoint induced central adrenal insufficiency), and 2 discontinued durvalumab due to other reasons (1 dyspnea with concern/risk for pneumonitis, 1 lost to follow up). Following completion or discontinuation of durvalumab, an additional 5 patients in the KRAS cohort experienced disease progression.
      Table 2Completion or Discontinuation of Durvalumab Consolidation by Genomic Cohort.
      CohortNCompleted DurvalumabDiscontinued Durvalumab Due to Disease ProgressionDiscontinued Durvalumab Due to irAEDiscontinued Durvalumab Due to Other Reasons
      Other reasons included dyspnea with concern/risk for pneumonitis and cerebellar abscess.
      All7429 (39.2%)17 (23.0%)24 (32.4%)4 (5.4%)
      KRAS188 (44.4%)5 (27.8%)3 (16.7%)2 (11.1%)
      Non-actionable144 (28.6%)2 (14.3%)7 (50.0%)1 (7.1%)
      Actionable71 (14.3%)3 (42.9%)3 (42.9%)0 (0.0%)
      Not tested3516 (45.7%)7 (20.0%)11 (31.4%)1 (2.9%)
      low asterisk Other reasons included dyspnea with concern/risk for pneumonitis and cerebellar abscess.

      Progression-Free Survival and Overall Survival

      Median follow-up time from the initiation of durvalumab for the overall cohort was 23.0 months (IQR: 15.4, 28.0). Thirty-seven (50%) patients experienced disease progression following the start of durvalumab consolidation, either during or after therapy completion. Median PFS was 16.1 months, and median OS was 32.4 months for the overall cohort (Figure 3A).
      Figure 3
      Figure 3Kaplan-Meier survival analysis for PFS and OS.
      An event for PFS was defined as radiographic progression or death. Data were censored with loss to follow up. An event for OS was defined as death. Data were censored with loss to follow up. A) Overall cohort PFS and OS. B) KRAS versus non-actionable PFS and OS. C) KRAS G12C versus KRAS non-G12C PFS and OS. D) KRASm/TP53m versus KRASm/TP53wt PFS and OS. Log-rank analysis was used to compare PFS and OS between cohorts. Error margins represent 95% CI.
      To better characterize the overall cohort's survival, we compared PFS and OS by genomic testing status, tumor histology, and actionable gene status. Median PFS was 23.7 months and 12.2 months for patients who had not received genomic profiling compared to those who had. Median OS was 50.8 months versus 31.7 months for the 2 cohorts, respectively. Using log-rank analysis, no statistically significant differences in PFS (P= 0.42) and OS (P= 0.73) were found between patients with and without molecular profiling (Supplemental Figure 2A). Median PFS was 11.9 months and 25.2 months for patients who with tumors with adenocarcinoma histology compared to squamous histology. Median OS was 31.5 months versus 50.8 months for the 2 cohorts, respectively. No statistically significant differences in PFS (P= 0.16) and OS (P= 0.96) were found between patients with adenocarcinoma and squamous cell carcinoma histology (Supplemental Figure 2B). Median PFS was 8.0 months versus 12.5 months for patients whose tumors possessed actionable alterations (EGFR, ERBB2, ALK, BRAF V600E, MET, RET, or ROS1) compared to those without. Median OS was 31.5 months versus 31.7 months for these 2 cohorts, respectively. No statistically significant differences in PFS (P= 0.45) and OS (P = 0.15) were found between patients whose tumors possessed actionable alterations and patients with non-actionable tumors (Supplemental Figure 2C). Worse ECOG performance status was associated with worse OS (P= .0011, Supplemental Figure 2D). Performance status did not vary between genomic cohorts (Supplemental Table 1).
      We next sought to characterize the survival outcomes of patients with KRAS-mutated disease. We compared PFS and OS between the KRAS cohort and the non-actionable cohort. Patients with actionable alterations were excluded from this comparison as they would have had other therapeutic options available at the time of progression. Median PFS was 12.6 months and 12.7 months for patients with KRAS-mutated disease (n = 18) and for patients with non-actionable disease (n = 14), respectively. Median OS was 32.4 months and 32.0 months for the 2 cohorts, respectively. No statistically significant differences in either PFS (P= 0.77) or OS (P= 0.67) were found by log-rank analysis (Figure 3B). The cancer characteristics and postprogression outcomes for the 10 patients with KRAS-mutated NSCLC who experienced disease progression are described in Supplemental Table 3.
      Median PFS was 9.7 months and 12.6 months for patients whose tumors had KRAS G12C and KRAS non-G12C mutations, respectively. Median OS was 20.0 months and 32.4 months for the 2 subgroups, respectively. Log-rank comparisons of PFS (P= 0.44) and OS (P= 0.69) found no statistically significant differences between these 2 KRAS subgroups (Figure 3C).
      Given that 17 of 18 patients with KRAS-driven disease had sequencing for TP53 mutations, we next conducted survival analyses comparing patients with KRAS-mutated, TP53-wildtype (KRAS m/TP53 wt; n = 8) and KRAS-mutated, TP53-mutated tumors (KRAS m/TP53 m; n = 9). Median PFS was 9.3 months for KRAS m/TP53wt patients and 24.0 months for KRAS m/TP53m patients. Median OS was 20.0 months for KRAS m/TP53wt patients and 31.4 months for KRAS m/TP53 m patients. However, these trends towards worse outcomes for KRAS m/TP53wt patients did not reach statistical significance (P= 0.24 for PFS and P= 0.24 for OS) (Figure 3D).
      Co-occurring mutations in STK11 or KEAP1 were not identified in the KRAS cohort. However, 13 of the 18 patients did not receive testing for these genes as these genes were not included in the standard diagnostic sequencing panel at the time of their cancer diagnosis at our institution. STK11 or KEAP1 mutations were identified in tumors of three other patients with non-KRAS-mutated tumors, and their cancer characteristics and clinical outcomes are detailed in Supplemental Table 4.

      Patterns of Progression

      In the overall cohort, 37 patients (50%) experienced disease progression following initiation of durvalumab. Thoracic-only progression occurred in 17 patients, extrathoracic-only progression occurred in 8 patients, and both thoracic and extrathoracic progression occurred in 12 patients. Progression was observed in the lung (n = 20), thoracic lymph nodes (n = 18), bone (n = 7), brain (n = 6), liver (n = 2), adrenal glands (n = 4), and other locations (n = 6). Table 3 describes patterns of progression by genomic cohort, and Supplemental Table 5 describes specific organs of progression.
      Table 3Patterns of Disease Progression.
      CohortNNo ProgressionIntrathoracic OnlyExtrathoracic OnlyBoth Intrathoracic and Extrathoracic
      All7437 (50.0%)17 (23.0%)8 (10.8%)12 (16.2%)
      KRAS188 (44.4%)2 (11.1%)4 (22.2%)4 (22.2%)
      Non-actionable147 (50.0%)6 (42.9%)1 (7.1%)0 (0.0%)
      Actionable72 (28.6%)3 (42.9%)1 (14.3%)1 (14.3%)
      Not tested3520 (57.1%)6 (17.1%)2 (5.7%)7 (20.0%)
      Intrathoracic progression was defined as progression in the lungs, thoracic lymph nodes, or pleura. Extrathoracic progression was defined as progression in any other location.
      Of the 18 patients with KRAS-driven disease, 10 patients (44%) had progression. Two of these patients had intrathoracic-only progression while the remaining 8 had any extrathoracic progression. In contrast, of the 14 patients in the non-actionable cohort, 7 patients (50%) had progression. Six of these patients had intrathoracic-only progression, and only 1 had any extrathoracic progression. Using Fisher's exact test for count data to compare intrathoracic-only progression against any extrathoracic progression between these 2 cohorts, patients with KRAS-driven disease were found to have a statistically significantly higher rate of any extrathoracic progression (P= 0.015).
      Lastly, we sought to describe patterns of progression for patients with KRAS-mutated tumors (n = 18) by their codon mutation and TP53 status (Supplemental Table 6). KRAS non-G12C (n = 10) patients had higher observed rates of any extrathoracic progression than KRAS G12C (n = 8) patients, as all 7 patients with KRAS G12C-mutated tumors who experienced progression had extrathoracic progression while only one of three patients with KRAS non-G12C-mutated tumors who experienced progression had extrathoracic progression. Greater rates of any extrathoracic progression for KRAS m/TP53 m (n = 9) versus KRAS m/TP53 wt (n = 8) patients were also observed, as all five patients who experienced progression in the TP53m subgroup progressed extrathoracically. In contrast, only two of the four patients who experienced progression in the TP53 wt subgroup progressed extrathoracically. Statistical analysis of these observed differences was not performed as our study was not powered to examine the differences in these small subgroups.

      Discussion

      In this study, we describe the clinical survival outcomes and the patterns of progression for patients with locally advanced, unresectable NSCLC treated with standard chemoradiation therapy plus durvalumab consolidation, focusing on patients with KRAS-driven disease. Patients with KRAS-mutated tumors were found to have similar PFS and OS compared to the non-actionable cohort, but KRAS patients who experienced disease progression had statistically higher rates of extrathoracic progression compared to non-actionable patients who experienced disease progression. As KRAS mutation status was not recorded in the PACIFIC trial, our study adds to the currently limited understanding of how genomic alterations may affect response to consolidation immunotherapy in the non-metastatic treatment setting.
      With the recent greatly anticipated approval of sotorasib and with several other KRAS-specificsmall molecule inhibitors in the pipeline, treatment for patients with KRAS-driven stage III NSCLC will become more complex. It remains to be seen whether KRAS inhibitors will provide greater benefit for patients than durvalumab consolidation following standard concurrent chemoradiation, whether combination consolidation therapy can be tolerated, and whether sequential post-progression therapy is successful due to novel resistance mechanisms to KRAS inhibitors.
      • Dunnett-Kane V
      • Nicola P
      • Blackhall F
      • Lindsay C
      Mechanisms of resistance to KRASG12C inhibitors.
      With these new drugs however, both increased utilization of comprehensive molecular profiling and greater understanding of how KRAS-driven disease impacts immunotherapy response and resistance are imperative to ensure that patients receive the most optimal first-line therapy from our rapidly expanding armamentarium.
      As several studies have highlighted how KRAS-mutated tumors tend to have immune-rich microenvironments, our results add to the growing body of literature suggesting that KRAS-mutation can be one predictor of response to checkpoint inhibition.
      • Dong ZY
      • Zhong WZ
      • Zhang XC
      • et al.
      Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
      -
      • Jeanson A
      • Tomasini P
      • Souquet-Bressand M
      • et al.
      Efficacy of immune checkpoint inhibitors in KRAS-Mutant non-small cell lung cancer (NSCLC).
      Yet in contrast, findings presented at ASCO 2021 from a retrospective review of 134 patients treated with durvalumab consolidation at MD Anderson showed that patients whose tumors possess any driver mutation had poorer PFS compared to patients whose tumors lacked driver mutations (8.9 months vs. 26.6 months, P< .001).
      • Liu Y
      • Zhang Z
      • Rinsurongkawong W
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      Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.
      Further findings from this study were recently published in June 2022, suggesting that patients with KRAS-mutated disease (n = 22) had worse PFS compared to patients without driver mutations (n = 61) (P< .001), with median PFS of 8.0 months and 40.1 months, respectively.
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      • Zhang Z
      • Rinsurongkawong W
      • et al.
      Association of driver oncogene variations with outcomes in patients with locally advanced non–small cell lung cancer treated with chemoradiation and consolidative durvalumab.
      With a median follow-up of 23.6 months, no significant differences for overall survival based on driver mutation profile were identified.
      • Liu Y
      • Zhang Z
      • Rinsurongkawong W
      • et al.
      Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.
      ,
      • Liu Y
      • Zhang Z
      • Rinsurongkawong W
      • et al.
      Association of driver oncogene variations with outcomes in patients with locally advanced non–small cell lung cancer treated with chemoradiation and consolidative durvalumab.
      In contrast, median PFS for our KRAS cohort was numerically higher at 12.6 months, and we identified no difference in outcomes between patients with KRAS-mutated NSCLC and patients with non-actionable tumors. These differences may be attributable to small cohort sizes or co-mutation patterns which were not reported. Larger, multi-institutional studies and greater utilization of comprehensive genomic profiling are needed to better clarify these findings.
      Indeed, it has been increasingly identified that certain co-mutations in KRAS-mutated tumors can modulate the immune microenvironment and enhance or ablate responses to ICI. Co-mutations are estimated to occur in approximately 50% of KRAS-mutated tumors, most commonly occurring in TP53 (40%), STK11 (20%), and KEAP1 (13%).
      • Scheffler M
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      • Hein R
      • et al.
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      ,
      • Singhi EK
      • Gay CM.
      Narrative review of the emerging role of molecular biomarkers in guiding the definitive management of unresectable non-small cell lung cancer.
      TP53 co-mutation has been shown to be associated with an increased PD-L1 expression and abundant tumor infiltrating lymphocytes, suggestive of increased response to ICI.
      • Dong ZY
      • Zhong WZ
      • Zhang XC
      • et al.
      Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.
      ,
      • Bange E
      • Marmarelis ME
      • Hwang WT
      • et al.
      Impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy among patients with STK11-mutated advanced non-small-cell lung cancer.
      ,
      • Skoulidis F
      • Byers LA
      • Diao L
      • et al.
      Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
      ,
      • Skoulidis F
      • Goldberg ME
      • Greenawalt DM
      • et al.
      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      ,
      • Friedlaender A
      • Drilon A
      • Weiss GJ
      • Banna GL
      • Addeo A.
      KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures.
      ,
      • Padda SK
      • Aredo JV
      • Vali S
      • et al.
      Computational biological modeling identifies PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRAS-mutated Non-small-cell lung cancer.
      In our cohort of patients receiving durvalumab consolidation, patients with KRAS m/TP53 m co-mutated tumors had numerically higher median PFS (24.0 vs. 9.3 months) and median OS (32.4 vs. 20.0 months) compared to patients with KRASm/TP53wt tumors, but these differences were not statistically significant, potentially limited by the small cohort sizes. Further investigation with larger cohorts is needed to determine if this observed difference in survival outcomes for patients whose tumors harbor TP53 co-mutations will be similar to the metastatic setting.
      • Skoulidis F
      • Goldberg ME
      • Greenawalt DM
      • et al.
      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      KRAS codon mutation has also been associated with both tumor biology differences and cancer outcomes. KRAS G12C is the most common codon change, found in 41% of KRAS-mutated NSCLC, and is more commonly found in patients with a history of smoking.
      • Friedlaender A
      • Drilon A
      • Weiss GJ
      • Banna GL
      • Addeo A.
      KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures.
      Evidence surrounding the impact of KRAS G12C codon on outcomes is conflicting.
      • Lei L
      • Wang WX
      • Yu ZY
      • et al.
      A real-world study in advanced non-small cell lung cancer with KRAS mutations.
      • Izar B
      • Zhou H
      • Heist RS
      • et al.
      The prognostic impact of KRAS, its codon and amino acid specific mutations, on survival in resected stage I lung adenocarcinoma.
      • Nadal E
      • Chen G
      • Prensner JR
      • et al.
      KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma.
      -
      • Park S
      • Kim JY
      • Lee SH
      • et al.
      KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer.
      In our study, we found no significant differences in PFS and OS between patients with stage III KRAS G12C- versus KRAS non-G12C-mutated tumors when treated with durvalumab consolidation. A recent study highlighted that positive PD-L1 expression prognosticates worse outcomes for patients with KRAS G12C-mutated tumors.
      • Tao L
      • Miao R
      • Mekhail T
      • et al.
      Prognostic value of KRAS mutation subtypes and PD-L1 expression in patients with lung adenocarcinoma.
      PD-L1 expression was unknown for 5 out of 18 patients with KRAS-mutated NSCLC in our cohort, and so small sample sizes precluded subgroup analysis by PD-L1 expression. As recent studies have highlighted how gene expression profile and immunophenotype varies by specific KRAS codon change,
      • Ricciuti B
      • Son J
      • Okoro JJ
      • et al.
      Comparative analysis and isoform-specific therapeutic vulnerabilities of KRAS mutations in non-small cell lung cancer.
      ,
      • Hofmann MH
      • Gerlach D
      • Misale S
      • Petronczki M
      • Kraut N.
      Expanding the reach of precision oncology by drugging All KRAS mutants.
      future studies with larger cohorts may shed insight into how the interplay between PD-L1 expression and KRAS codon substitution modulates response to durvalumab.
      To the best of our knowledge, our study is the first to identify greater rate of extrathoracic progression for patients with KRAS-driven stage III NSCLC compared to patients with non-actionable NSCLC. As our analysis is limited by small cohort sizes in the subgroup of patients with disease progression, future studies are needed to further evaluate this finding. Nevertheless, patterns of progression in KRAS-mutated NSCLC may have implications for monitoring of patients following therapy completion. Currently, there are no standardized screening recommendations for brain metastases, which were the most common location of extrathoracic progression in the PACIFIC study.
      • Raben D
      • Rimner A
      • Senan S
      • et al.
      Patterns of disease progression with durvalumab in stage III non-small cell lung cancer (PACIFIC).
      In our study, bone and brain metastases were the first and second most common locations of extrathoracic progression, respectively, both in the overall and in the KRAS cohort. Our data highlight the need for practicing clinicians to have greater suspicion for extrathoracic progression in patients with KRAS-driven NSCLC and to tailor imaging surveillance appropriately.
      Interestingly, of the 8 patients with KRAS-driven NSCLC who progressed with extrathoracic progression, 4 patients experienced progression within 3 months of starting durvalumab consolidation and 2 patients experienced progression within 2 months of durvalumab completion. The remaining 2 patients experienced progression four and 12 months after durvalumab discontinuation (Supplemental Figure 3). Given that 50% of these patients experienced extrathoracic progression shortly after starting durvalumab and 25% experienced extrathoracic progression shortly after durvalumab completion, the question of the mechanism by which durvalumab mediates systemic micrometastatic control for KRAS-driven disease is raised. As our results and other studies suggest that patients with KRAS-driven NSCLC have higher rates of extrathoracic progression,
      • Yagishita S
      • Horinouchi H
      • Sunami KS
      • et al.
      Impact of KRAS mutation on response and outcome of patients with stage III non-squamous non-small cell lung cancer.
      more translational studies elucidating the mechanisms behind KRAS-mediated metastatic seeding and ICI-mediated control of micrometastases are needed.
      The administration of checkpoint inhibitors is not without its own risks.
      • Conroy M
      • Naidoo J.
      Immune-related adverse events and the balancing act of immunotherapy.
      Grade 3 or 4 irAEs occurred in 30% of patients enrolled in PACIFIC, and 15% of patients in PACIFIC required durvalumab cessation due to adverse events.
      • Antonia SJ
      • Villegas A
      • Daniel D
      • et al.
      Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.
      Our KRAS cohort had a similar rate of durvalumab discontinuation due to irAEs in 3 out of 18 patients (16%), with an additional patient discontinuing therapy due to risk for checkpoint inhibitor pneumonitis after episodes of dyspnea (Table 2). A recent study examining the efficacy of durvalumab for patients with EGFR-mutated NSCLC found that 6 of 13 patients (46.2%) experienced severe irAEs, and 1 patient experienced severe pneumonitis after initiating osimertinib following durvalumab discontinuation. The authors suggested that checkpoint inhibition may have primed the patient's immune system for overactivation upon administration of osimertinib.
      • Aredo JV
      • Mambetsariev I
      • Hellyer JA
      • et al.
      Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy.
      They also showed that patients with EGFR-mutated NSCLC derived less benefit from durvalumab, suggesting that for some patients, alternative consolidation therapies with TKI may provide greater benefit.
      • Aredo JV
      • Mambetsariev I
      • Hellyer JA
      • et al.
      Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy.
      ,
      • Hellyer JA
      • Aredo JV
      • Das M
      • et al.
      Role of consolidation durvalumab in patients with EGFR- and HER2-mutant unresectable stage III NSCLC.
      With the recent promising development of KRAS G12C inhibitors such as sotorasib and adagrasib,
      • Hong DS
      • Fakih MG
      • Strickler JH
      • et al.
      KRASG12C inhibition with sotorasib in advanced solid tumors.
      • Riely GJ
      • Ou SHI
      • Rybkin I
      • et al.
      99O_PR KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non–small cell lung cancer (NSCLC) harboring KRASG12C mutation.
      -
      • Skoulidis F
      • Li BT
      • Dy GK
      • et al.
      Sotorasib for lung cancers with KRAS p.G12C mutation.
      it will be interesting to see if postprogression treatment following durvalumab failure with these KRAS-specific inhibitors has similar potential to cause synergistic adverse events. More data is needed to provide greater understanding regarding the specific risks and toxicities for patients receiving sequential therapy.
      Taken together, these studies and the novel drug developments highlight a growing need to provide comprehensive genomic profiling for patients with stage III disease such that the most appropriate targeted therapies and surveillance methods are applied. While the use and the coverage of comprehensive genomic sequencing has increased significantly in recent years, molecular profiling for stage III NSCLC is not universally utilized and has been primarily limited to patients with adenocarcinoma histology. The lack of guidelines regarding use of mutational profiling in early-stage lung cancer leads to variability in evaluating for actionable molecular changes. Currently, testing is more frequently offered for patients with factors known to be associated with driver mutations in metastatic disease, such as tumors with adenocarcinoma histology.
      • Zhu QG
      • Zhang SM
      • Ding XX
      • He B
      • Zhang HQ.
      Driver genes in non-small cell lung cancer: characteristics, detection methods, and targeted therapies.
      Indeed, in our real-world cohort of patients receiving durvalumab for stage III NSCLC at Johns Hopkins, only 53% of patients, primarily those with adenocarcinoma histology, had clinical genomic profiling, and furthermore, 20% of the tumors with adenocarcinoma histology were not sequenced. Yet, it has been acknowledged that certain clinically significant mutations, such as KRAS, STK11, KEAP1, and TP53, are found in squamous cell carcinomas.
      • Heist RS
      • Sequist LV
      • Engelman JA.
      Genetic changes in squamous cell lung cancer: a review.
      • Friedlaender A
      • Banna G
      • Malapelle U
      • Pisapia P
      • Addeo A.
      Next generation sequencing and genetic alterations in squamous cell lung carcinoma: where are we today?.
      -
      • Acker F
      • Stratmann J
      • Aspacher L
      • et al.
      KRAS mutations in squamous cell carcinomas of the lung.
      In the era of precision oncology, standardization of comprehensive molecular profiling with next-generation sequencing for actionable genes as well as clinically meaningful non-actionable genes in stage III disease is needed to guide appropriate treatments. Considering financial and access limitations, comprehensive genomic profiling should be offered to all patients with stage III NSCLC not only to guide treatment decisions for consolidation with durvalumab, but also to inform decisions regarding the next lines of therapy and characterize how immunotherapy may select for resistance by comparing to post-progression sequencing.
      Our study is not without limitations. In addition to the inherent limitations of retrospective study, our study is limited by its single-institutional nature, its small cohort sizes, and the real-world nature of available molecular data. PD-L1 expression was unknown for 40% of our patients. Moreover, some patients in our cohort also had incomplete molecular profiling, potentially skewing results as unidentified co-mutations may have had impacts of durvalumab efficacy. Despite these limitations, our findings still corroborate recent preclinical and clinical studies suggesting that KRAS-driven NSCLC is responsive to immune checkpoint inhibition and highlight that sequential therapeutics with G12C directed small molecule inhibitors may be more nuanced than in other driver subsets where durvalumab therapy has not been found to provide similar benefit.
      • Aredo JV
      • Mambetsariev I
      • Hellyer JA
      • et al.
      Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy.
      Nevertheless, further analysis with larger, potentially multi-institutional cohorts with more comprehensive genomic profiling are eagerly awaited to provide greater insight into how mutation profile impacts response to durvalumab consolidation. Likewise, utilization of whole exome sequencing, analysis of tumor mutational burden, and comparisons of tumor mutation signatures at diagnosis and recurrence may better identify clinically significant molecular profiles associated with the resistance to durvalumab immunotherapy and highlight potential areas for the development of future targeted therapies.

      Conclusion

      In summary, patients with stage III KRAS-mutated NSCLC may derive similar PFS and OS benefit from durvalumab consolidation compared to patients with stage III NSCLC who are not found to have clinically actionable molecular alterations on NGS testing. However, our study cohort found that patients with KRAS-mutated NSCLC who experience disease progression may be more likely to have extrathoracic progression, which may speak to molecularly specific considerations for surveillance following therapy completion. As the medicine cabinet targeting KRAS and other clinically significant genes expands, molecular characterization of tumors by comprehensive genomic profiling is needed to better understand the clinical impact of co-mutations in modulating the response to immunotherapy in unresectable stage III NSCLC.

      Acknowledgments

      The authors thank Dr. Chen Hu and Dr. Meredith Atkinson for helpful discussions on this manuscript.

      Disclosures

      MZG has no financial or non-financial disclosures. JCM disclosures consulting: MJH Life Sciences, Johnson & Johnson and Stock: Doximity. PG has no financial or non-financial disclosures. KRV disclosures Honoraria: Physicians’ Education Resource, LLC, American Society of Clinical Oncology; Consulting: AstraZeneca; Research support: Lung Cancer Research Foundation, Canon, Radiation Oncology Institute; Travel: prIME Oncology Young Investigators Forum in NSCLC (2018.3). RKH disclosures Advisory board: BMS; Honoraria: Physicians’ Education Resources; Research funding: Genentech. DE disclosures Panel Chair: NCCN NSCLC Guideline Panel. VL disclosures Consultant/Advisory role: Takeda, Seattle Genetics, Bristol-Myers Squibb, AstraZeneca, Guardant Health; Research Funding: GlaxoSmithKline, Bristol-Myers Squibb, Merck, Seattle Genetics. CH disclosures Consultant/Advisory role: AbbVie, Amgen, AstraZeneca, BMS, Genentech/Roche, Janssen, GlaxoSmithKline; Grant Research funding: AbbVie, Amgen, AstraZeneca, BMS, GlaxoSmithKline. PF disclosures Grants/contracts: AstraZeneca, Array, BMS, Corvus, Kyowa, BioNTech, Novartis, Regeneron; Consultant: AbbVie, Amgen, AstraZeneca, BMS, Novartis, Genentech, G1 Therapeutics, Surface Oncology, Sanofi, Merck, Iteos, Jansse, F-Star, Daiichi; Data safety monitoring board member: Flame Biosciences, Polaris. JB disclosures Advisory Boards/Consulting Agreements: Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi, Regeneron; Grant Research Funding: AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Inc., Revolution Medicines; Data and Safety Monitoring Board/Committees: GlaxoSmithKline, Sanofi, Janssen. BPL disclosures Research funding: Eli Lilly, Genentech, BMS, AstraZeneca, Turning Point Therapeutics, Takeda, Jansse, Daiichi Sankyo, Pfizer, Mirati, Novartis, Amgen; Advisory Boards: Eli Lilly, Genentech, AstraZeneca, Celgene, Pfizer, Merck, Novartis, Takeda. JLF disclosures Consulting/Advisory role: Merck, BMS, Genentech, AstraZeneca, Takeda, Regeneron, Eli Lilly; Research funding: Pfizer, AstraZeneca, BMS. KAM disclosures Consulting, AstraZeneca, Janssen, Mirati, Amgen; Grant Funding, BMS, Mirati.

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