If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OHUniversity Hospitals Seidman Cancer Center, Cleveland, OH
This systematic literature review included 77 recent papers on relapse SCLC therapy.
•
The full potential of alkylating agents and checkpoint inhibitors remains unclear.
•
There are promising phase 2 data for several tyrosine kinase inhibitors.
•
Phase 2 liposomal irinotecan data were positive.
•
Relapsed SCLC remains an area of high unmet need.
Abstract
Second-line treatment options are limited for patients with small-cell lung cancer (SCLC). We conducted a PRISMA-standard systematic literature review to evaluate the treatment landscape for patients with relapsed SCLC (PROSPERO number: CRD42022299759). Systematic searches of MEDLINE, Embase, and Cochrane Library were performed (October 2022) to identify publications (prior 5 years) from prospective studies of therapies for relapsed SCLC. Publications were screened against predetermined eligibility criteria; data were extracted to standardized fields. Publication quality was assessed using GRADE. The data were analyzed descriptively, grouped by drug class. Overall, 77 publications involving 6349 patients were included. Studies of tyrosine kinase inhibitors (TKIs) with established cancer indications accounted for 24 publications; topoisomerase I inhibitors for 15; checkpoint inhibitors (CPIs) for 11, and alkylating agents for 9 publications. The remaining 18 publications featured chemotherapies, small-molecule inhibitors, investigational TKIs and monoclonal antibodies, and a cancer vaccine. According to GRADE assessment, 69% of the publications reported low-/very-low-quality evidence; quality limitations included lack of randomization and small sample sizes. Only 6 publications/6 trials reported phase 3 data; 5 publications/2 trials reported phase 2/3 results. Overall, the clinical potential of alkylating agents and CPIs remained unclear; investigations of combination approaches and biomarker-directed usage are warranted. Phase 2 data from TKI trials were consistently promising; no phase 3 data were available. Phase 2 data for a liposomal formulation of irinotecan were promising. We confirmed an absence of promising investigational drug/regimens in late-stage development; thus, relapsed SCLC remains an area of high unmet need.
Small-cell lung cancer is a form of lung cancer and gets its name from the way that the cancer looks under a microscope. People with small-cell lung cancer are usually first treated with chemotherapy. If the cancer gets worse despite chemotherapy, they can get another treatment to help control the cancer. This is called a second-line treatment. In this study, we wanted to learn about the second-line treatments that are available for small-cell lung cancer, or that might become available in the future. To do this, we looked at recent studies about how different drugs worked as second-line treatments in people with small-cell lung cancer. Overall, we found 77 such studies of current and potential new second-line treatments. These included 15 studies about chemotherapy drugs called topoisomerase inhibitors, 9 about chemotherapy drugs called alkylating agents, 11 about drugs that help the immune system to fight cancer cells called checkpoint inhibitor drugs, and 24 about drugs that help to reduce tumor growth called tyrosine kinase inhibitors. Only 1 new drug included in these studies has recently become available as a treatment for small-cell lung cancer. This is a chemotherapy drug called lurbinectedin. The other study results suggested that some of the drugs investigated may also help to control small-cell lung cancer as a second-line treatment. Examples included a chemotherapy drug called liposomal irinotecan and tyrosine kinase inhibitors. However, more time and more studies are needed for the researchers to know if these other drugs can be used as second-line treatments in people with small-cell lung cancer.
Introduction
Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer owing to its high metastatic potential and poor prognosis.
Patients with SCLC typically present with extensive-stage disease (ES-SCLC) for which the first-line standard-of-care therapy is etoposide plus a platinum-based agent (eg carboplatin or cisplatin) in combination with checkpoint inhibitor (CPI) therapy (either durvalumab or atezolizumab).
Alternative therapeutic approaches for some patients with ES-SCLC include carboplatin or cisplatin in combination with irinotecan.
Initial response rates to first-line SCLC treatment are generally good, but most patients relapse within 6 to 12 months, and their relapsed SCLC is often resistant to subsequent treatment with platinum-based therapy.
The topoisomerase I inhibitor topotecan, which has approval in the USA and Europe for use in patients with relapsed SCLC, is included as a second- or later-line treatment option for SCLC in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).
In a phase 3 trial of patients with relapsed SCLC, topotecan prolonged survival compared with best supportive care (median survival of 26 weeks vs. 14 weeks, respectively),
Prior to the approval of topotecan, anthracycline-based regimens, such as CAV, were the standard of care for relapsed SCLC, but median on-treatment survival was only 4 to 5 months.
Although topotecan offered benefits over the then standard of care, its clinical utility has been limited by its modest antitumor activity and hematological toxicity profile.
Myelopreservation with Trilaciclib in patients receiving Topotecan for small cell lung Cancer: results from a randomized, double-blind, placebo-controlled Phase II study.
Thus, there remained a pressing unmet need for efficacious second- or later-line treatment options for patients with SCLC. This need was reflected in the decision by the US Food and Drug Administration (FDA) in 2020 to grant accelerated approval to lurbinectedin for the treatment of adults with metastatic SCLC and disease progression on or after platinum-based chemotherapy, on the weight of favorable phase 2 results.
Unfortunately, the antitumor activity reported in the phase 2 trials failed to translate to overall survival (OS) benefit in the phase 3 ATLANTIS trial of lurbinectedin plus doxorubicin vs. physicians’ choice of topotecan or CAV in the second-line setting.
Nevertheless, within the context of the current SCLC treatment landscape and limited number of approved treatment options for relapsed SCLC, lurbinectedin is included in the NCCN Guidelines as a second- or later-line treatment option for patients with SCLC.
Also included in the National Comprehensive Cancer Network (NCCN) recommendations for relapsed SCLC, although not currently approved are: CAV, docetaxel, oral etoposide, gemcitabine, irinotecan, nivolumab, paclitaxel, pembrolizumab, temozolomide, vinorelbine, and bendamustine (category 2B).
Thus, the development of safe and efficacious second- and later-line treatment options for SCLC remains an area of active research, and there is a growing body of evidence from recent and ongoing studies of licensed and investigational drugs.
We conducted a systematic literature review to evaluate all recent data from prospective interventional studies published in patients with SCLC who had relapsed following prior therapy. Our aim was to assess the evidence base for licensed and investigational therapies for relapsed SCLC, with the goal of identifying promising existing/investigational drugs to support current/future clinical decision-making, and to identify remaining challenges and unmet needs.
Methods
Registration
The review protocol was registered with PROSPERO (CRD42022299759)
National Institute for Health Research. International prospective register of systematic reviews. Available at: https://www.crd.york.ac.uk/PROSPERO/ Accessed June 18, 2022.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Transparent reporting of systematic reviews and meta-analyses. Available at: http://www.prisma-statement.org/ Accessed June 18, 2022.
To focus the review on ‘current’ clinical research activities, we included publications from the preceding 5 years that reported the results of prospective interventional studies of licensed or investigational drugs used for the second- and later-line treatment of patients with SCLC.
Systematic literature searches were conducted on October 27, 2021 of the MEDLINE (In-Process & Other Non-Indexed Citations and Ovid MEDLINE [1946–present]) and the Embase (1974–present) bibliographic databases using the Ovid platform. The search strings combined terms for relapsed SCLC and prospective study publications using free text, Medical Subject Headings (MeSH), and Embase subject headings (Emtree). Full search strings are shown in Supplemental Table S1.
Complementary searches involved reviewing the bibliographies of relevant publications (retrieved by the systematic searches) to identify additional publications of interest, and manual searches of congress web sites/proceedings identified a priori as being of interest by the authors. Congresses of interest included the American Society of Clinical Oncology (ASCO), Clinical Oncology Society of Australia (COSA), European Society for Medical Oncology (ESMO), ESMO Asia, International Association for the Study of Lung Cancer (IASLC), and World Conference on Lung Cancer (WCLC). Congress handsearching was conducted during January 19 to 25, 2022 and included congress proceedings published between January 1, 2019 and December 31, 2022 on the assumption that data presented at earlier congresses would have since been published in full text and have been identified by the systematic searches.
To identify drugs under investigation for second- or later-line treatment of SCLC without published data at the time of the review, we conducted a manual search of the National Institutes of Health trial registry, ClinicalTrials.gov, on March 15, 2022. Relevant studies were identified using SCLC as the condition/disease of interest. Identified trials were manually screened to identify those evaluating agents under investigation in the second- or later-line setting.
Publication Eligibility
Publications (full text and congress abstracts) were screened for eligibility using criteria prespecified in the protocol (Table 1). Screening was completed by a single reviewer with any uncertainties resolved by a second reviewer and/or the full author group, as required. Relevant congress abstracts were excluded when they were superseded by a full-text publication. The full article text of all short-listed publications was then screened to confirm eligibility for inclusion.
Table 1Eligibility Criteria for Study Selection
Category
Inclusion Criteria
Exclusion Criteria
Population
•
Patients with SCLC who have received at least one line of systemic therapy
•
Patients with no previous systemic therapy
•
Non-human subjects
Interventions
•
Systemic therapy
•
Non-systemic therapy
Comparator
•
Placebo, active comparator or none
•
No exclusions
Outcomes
•
Clinical outcomes: OS, PFS, ORR, DCR (stratified by platinum sensitivity, if data are available)
•
AEs
•
PROs
•
Outcomes not listed in inclusion criteria
Study designs
•
Prospective interventional studies, including single-arm trialsa
•
Systematic reviews
•
Meta-analyses
•
Economic modeling studies
•
Review articles
•
Case studies/series
•
Expert opinion, comment, and letters to editors
Date restrictions
•
Full text: 2016 onwards
•
Congress publications: January 1, 2019 to December 31, 2021
Eligible ongoing trials of licensed/investigational drugs for second- or later-line SCLC treatment were those that were currently active (ie status listed as ‘recruiting’, ‘not yet recruiting’, ‘active’, ‘not recruiting’) and had recent (2021 onwards) or future completion dates. Trials whose status was ‘terminated’, ‘completed’ or ‘unknown’ were deemed to have been published (and so identified by the systematic database searches) or unlikely to provide novel data insights.
Data Abstraction and Analysis
For all eligible publications, standardized data were extracted using data extraction fields preagreed by all authors. Studies and data were grouped by drug, aggregated by drug class, and categorized by status (completed or ongoing) and overall nature of the results (negative or positive).
Quality Assessment
The quality of each included study was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) quality assessment tool. Each publication was given a quality rating (high, moderate, low, very low) according to their level of potential bias, assessed in terms of data quality, consistency, directness, and modifying factors (precision and sparsity of data, and probability of reporting bias).
All studies are included in the Results section, irrespective of their quality rating. Details of the GRADE rating of each publication are included in Table 2 (in summary) and in Supplemental Table S2 (in full).
Table 2Characteristics of Included and Completed Studies
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
Myelopreservation with Trilaciclib in patients receiving Topotecan for small cell lung Cancer: results from a randomized, double-blind, placebo-controlled Phase II study.
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors.
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
Effect of prior thoracic radiotherapy on prognosis in relapsed small cell lung cancer patients treated with anlotinib: a subgroup analysis of the ALTER 1202 trial.
OA03. 02 Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: a subgroup analysis in ALTER 1202 Trial.
Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.
1791P Effect of anlotinib in advanced small cell lung cancer (SCLC) patients with liver metastases: a subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
P2. 12-11 quality of life in ALTER1202 Trial of Anlotinib as third-or further line therapy for advanced small cell lung Cancer (SCLC): a post-hoc analysis.
1787P Effect of anlotinib in advanced small cell lung cancer patients with pleural metastases/pleural effusion: a subgroup analysis from a randomized, double-blind phase II trial (ALTER1202).
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.
Effect of prior thoracic radiotherapy on prognosis in relapsed small cell lung cancer patients treated with anlotinib: a subgroup analysis of the ALTER 1202 trial.
OA03. 02 Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: a subgroup analysis in ALTER 1202 Trial.
1787P Effect of anlotinib in advanced small cell lung cancer patients with pleural metastases/pleural effusion: a subgroup analysis from a randomized, double-blind phase II trial (ALTER1202).
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
1791P Effect of anlotinib in advanced small cell lung cancer (SCLC) patients with liver metastases: a subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
P2. 12-11 quality of life in ALTER1202 Trial of Anlotinib as third-or further line therapy for advanced small cell lung Cancer (SCLC): a post-hoc analysis.
1649P Anlotinib plus oral fluoropyrimidine S1 in treating patients with refractory or relapsed small cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial.
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.
Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.
Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.
Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07).
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: a single-arm phase I study.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors.
A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—preliminary results from the SCLC cohort.
A randomized non-comparative Phase II study of anti-programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as second-line therapy in patients with small cell lung Cancer: results from the IFCT-1603 Trial.
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
MO01.39 liposomal irinotecan in adults with small cell lung Cancer who Progressed on platinum-based therapy: subgroup analyses by platinum sensitivity.
RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—preliminary findings from part 1 dose-defining phase.
MO01.39 liposomal irinotecan in adults with small cell lung Cancer who Progressed on platinum-based therapy: subgroup analyses by platinum sensitivity.
RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—preliminary findings from part 1 dose-defining phase.
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: a single-arm phase I study.
Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).
The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): results from part II of the open-label, randomized, phase II/III distinct study.
Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.
A study in recurrent small cell lung cancer patients, comparing weekly paclitaxel, irinotecan and temozolomide in second-line: a prospective study from a south Indian tertiary cancer hospital.
A phase 2 randomized study of TAS-102 versus topotecan or amrubicin in patients requiring second-line chemotherapy for small cell lung cancer refractory or sensitive to frontline platinum-based chemotherapy.
Efficacy and safety of Rovalpituzumab Tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell Lung Cancer: results from the Phase II TRINITY Study.
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: Results from the phase 2 TRINITY study.
Randomized Phase II study of paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.
Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).
Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer.
Of 1963 publications of potential relevance, 342 were short-listed for full-text review following title/abstract screening, and 65 (38 full-text articles; 27 congress abstracts) confirmed as eligible on full-text review (Figure 1). Manual searches of congress proceedings identified an additional 12 eligible abstracts. Of the 77 included publications (38 full-text articles; 39 congress abstracts), 59 reported phase 2 trials, 6 reported phase 3 trials, 5 phase 2/3 trials, 2 phase 4 trials, and 3 (one each) reported a phase 1b/2a trial, a phase 1b trial, and a real-world study. The study design was not specified for the remaining 2 publications.
Figure 1PRISMA diagram of included and excluded studies in the systematic literature review
In total, the study publications included 7712 patients receiving second- or later-line treatment for SCLC. The included publications comprised (combination regimen publications are included in each featured drug category): 9 publications on alkylating agents (including 7 featuring lurbinectedin [5 from the phase 2 BASKET trial]); 6 publications on poly-adenosine diphosphate ribose polymerase (PARP) inhibitors; 24 publications on tyrosine kinase inhibitors (TKIs; as single agents, or as part of combination therapy; 13 featured anloitinib, 7 apatinib, 2 pazopanib, 1 amuvatinib, and 1 cediranib); 11 publications on immune CPIs (3 featured nivolumab [1 as monotherapy, 2 as combination therapy], 3 featured pembrolizumab [1 as monotherapy, 2 as combination therapy], and 2 featured durvalumab [both as part of combination therapy]); and 15 publications on topoisomerase I inhibitors (9 featured irinotecan, 4 liposomal irinotecan, 1 topotecan and 1 belotecan). The remaining publications (n = 18) featured the following therapies (alone or as part of combination therapy): platinum-based chemotherapy (5 publications); anthracycline antibiotics (amurubicin, doxorubicin; 4 publications); paclitaxel (3 publications); rovalpituzumab tesirine (Rova-T; an antibody–drug conjugate directed against delta-like protein 3 [DLL3]; 3 publications); small-molecule inhibitors (adavosertib, chiauranib, gedatolisib, linsitinib, and vistusertib; 1 publication each); a monoclonal antibody (mAb) targeting immunoglobulin G4 (IgG4) (1 publication); TAS-102 (a fluoropyrimidine; 1 publication); BI 2536 (an inhibitor of polo-like kinase 1 [Plk-1]; 1 publication); and a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC; 1 publication).
The majority (77%) of the publications included in the review reported results from completed studies (n = 59), 5% from terminated studies (n = 4), and 18% (n =14) reported preliminary data from ongoing studies. Among the completed studies, 78% reported positive results, and of the ongoing studies, 43% described encouraging preliminary data.
The characteristics of all the publications included in the review, including their quality assessment, are presented in Table 2. Only 6% of publications reported high-quality data according to the GRADE appraisal.
Effect of prior thoracic radiotherapy on prognosis in relapsed small cell lung cancer patients treated with anlotinib: a subgroup analysis of the ALTER 1202 trial.
Randomized Phase II study of paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
A randomized non-comparative Phase II study of anti-programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as second-line therapy in patients with small cell lung Cancer: results from the IFCT-1603 Trial.
Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07).
The most common reason for downgrading the quality of publications was methodological limitations, such as small population sizes and/or lack of randomization. Publications reporting moderate-quality evidence accounted for 25% of the included literature, a grading indicative of further research being likely to have an important impact on confidence in the reported results.
Myelopreservation with Trilaciclib in patients receiving Topotecan for small cell lung Cancer: results from a randomized, double-blind, placebo-controlled Phase II study.
Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.
OA03. 02 Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: a subgroup analysis in ALTER 1202 Trial.
Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.
1791P Effect of anlotinib in advanced small cell lung cancer (SCLC) patients with liver metastases: a subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer.
The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): results from part II of the open-label, randomized, phase II/III distinct study.
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
P2. 12-11 quality of life in ALTER1202 Trial of Anlotinib as third-or further line therapy for advanced small cell lung Cancer (SCLC): a post-hoc analysis.
1787P Effect of anlotinib in advanced small cell lung cancer patients with pleural metastases/pleural effusion: a subgroup analysis from a randomized, double-blind phase II trial (ALTER1202).
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients.
Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors.
Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
A phase 2 randomized study of TAS-102 versus topotecan or amrubicin in patients requiring second-line chemotherapy for small cell lung cancer refractory or sensitive to frontline platinum-based chemotherapy.
MO01.39 liposomal irinotecan in adults with small cell lung Cancer who Progressed on platinum-based therapy: subgroup analyses by platinum sensitivity.
Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).
1649P Anlotinib plus oral fluoropyrimidine S1 in treating patients with refractory or relapsed small cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial.
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: a single-arm phase I study.
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: Results from the phase 2 TRINITY study.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—preliminary results from the SCLC cohort.
A study in recurrent small cell lung cancer patients, comparing weekly paclitaxel, irinotecan and temozolomide in second-line: a prospective study from a south Indian tertiary cancer hospital.
Efficacy and safety of Rovalpituzumab Tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell Lung Cancer: results from the Phase II TRINITY Study.
Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).
indicating that further research may change the reported effect estimate and that there is a high degree of potential uncertainty in the reported estimates, respectively (Supplemental Table S2).
Figure 2 illustrates the stage of development and availability of positive, negative, and preliminary data from clinical trials for all investigational agents, as identified from the systematic review. The numbers of patients treated with the different investigational agents in completed clinical trials with positive outcomes are presented in Figure 3. Full results summaries from each publication included in the review are summarized in Supplemental Table S3.
Figure 2Overview of positive/negative study results published since 2015 for drugs investigated for the treatment of second- or later-line SCLC, stratified by monotherapy combination regimens (B)
Figure 3Patients treated with investigational therapies in completed trials of patients with SCLC, stratified by drug class, drug and development phase
Approved Second- and Later-Line Therapies for SCLC
Topotecan
This review was intended to consolidate evidence published in the past 5 years from prospective interventional studies of second- and later-line therapy for patients with SCLC. Within this context, little novel data were expected to be identified for topotecan (as a well-established and approved therapy for relapsed SCLC), but it did feature in 3 of the eligible publications.
Two of the publications featured topotecan as a comparator to combined chemotherapy with cisplatin, etoposide, and irinotecan (1 publication)
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
; both publications are discussed in later sections. A third publication reported the results of a phase 1b/2a study of patients with ES-SCLC (NCT02514447; n = 61; approximately 44% and 56% with sensitive and refractory relapse, respectively) who received treatment with the cyclin-dependent kinase inhibitor trilaciclib vs. placebo prior to topotecan therapy.
Myelopreservation with Trilaciclib in patients receiving Topotecan for small cell lung Cancer: results from a randomized, double-blind, placebo-controlled Phase II study.
Compared with placebo, trilaciclib reduced chemotherapy-induced myelosuppression and was associated with a more favorable safety profile and improved quality of life, without a detrimental effect on the antitumor activity of topotecan.
Lurbinectedin
As previously discussed, the alkylating agent lurbinectedin was granted accelerated approval by the FDA on the basis of favorable phase 2 trial results.
The efficacy and safety of lurbinectedin were investigated in patients with SCLC with only 1 previous chemotherapy-containing treatment in the single-arm, open-label, phase 2 BASKET trial (NCT02454972; n =105), and in 3 subgroup analyses of this trial.
Overall, lurbinectedin was active as second-line therapy, achieving an objective response rate (ORR) of 35.2% (95% confidence interval [CI]: 26.2-45.2) with all patients experiencing partial responses, and with median (95% CI) OS and progression-free survival (PFS) estimates of 9.3 (6.3-11.8) months and 3.5 (2.6-4.3) months, respectively. Durable responses were observed both in patients with a chemotherapy-free interval (CTFI) of ≥ 90 days (ORR, 45%) and in a smaller, but notable, proportion of patients with a CTFI < 90 days (ORR, 22.2%). The safety profile was considered acceptable, with neutropenia being the most common grade 3 to 4 adverse event [AE] (46%). Lurbinectedin was shown to be active in all the subgroups investigated in the phase 2 trial, including: patients with sensitivity or prior resistance to platinum-based chemotherapy; patients with platinum-sensitive relapsed SCLC with CTFI ≥ 90 days and ≥ 180 days (post hoc analysis); and patients with a CTFI of 30 to 89 days.
Favorable results were also reported from the first prospective cohort study evaluating lurbinectedin in routine care.
This real-world study included a heavily pretreated SCLC patient cohort (n = 43) receiving lurbinectedin as third- or later-line therapy at a Dutch tertiary referral university medical center. After 12 weeks, the disease control rate (DCR) was 29% and the objective radiological response was 17%. Median (95% CI) PFS and OS were 1.5 (1.4-3.0) months and 7.0 (4.7–not reached) months, respectively. In general, lurbinectedin was well tolerated, albeit with dose reductions used to manage fatigue or hematologic toxicity in some patients.
Yet in the phase 3 ATLANTIS trial (NCT02566993; n = 613) of lurbinectedin plus doxorubicin vs. topotecan or CAV in patients with 1 prior platinum-containing line of therapy, the primary endpoint of improved OS was not met (median OS, 8.6 months vs 7.6 months; hazard ratio [HR]/odds ratio, 0.967; stratified P = .9022).
Despite failure of the primary trial endpoint, secondary endpoints consistently favored lurbinectedin plus doxorubicin (vs. topotecan or CAV) in terms of both safety profile (reduced incidence of grade ≥ 3 and above hematological toxicity) and anticancer activity. Anticancer activity was particularly notable with combination lurbinectedin plus doxorubicin (vs. topotecan or CAV) in patients with a CTFI ≥ 90 days and without central nervous system involvement at baseline. The authors of the trial publication noted that combinations of lurbinectedin and alternative agents were under investigation. Of particular interest to practicing clinicians is the therapeutic potential of lurbinectedin in combination with immunotherapy agents. Investigations of lurbinectedin plus checkpoint inhibitor (CPI) combinations are currently under way, as part of doublet regimens with pembrolizumab (NCT04358237 [phase 1/2 LUPER]; completion date October 2023),
Antonio Calles Blanco, MedSIR, PharmaMar, Merck Sharp & Dohme LLC. Lurbinectedin (PM01183) Combined With Pembrolizumab in Small Cell Lung Cancer. (LUPER). 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04358237 Accessed August 2, 2022.
Mayo Clinic. Durvalumab and Topotecan or Lurbinectedin for the Treatment of Relapsed or Refractory Small Cell Lung Cancer. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04607954 Accessed August 2, 2022.
H. Lee Moffitt Cancer Center and Research Institute, Bristol-Myers Squibb, Jazz Pharmaceuticals. Immune Checkpoint Inhibition With Lurbinectedin Relapsed/Recurrent SCLC. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04610658 Accessed August 2, 2022.
Lurbinectedin (PM01183) Combined With Pembrolizumab in Small Cell Lung Cancer
Pembrolizumab plus lurbinectedin
Checkpoint inhibitor plus alkylating agent
Recruiting
October 2023
NCT02611024
1/2
Pharmacokinetic Study of Lurbinectedin in Combination With Irinotecan in Patients With Selected Solid Tumors
Lurbinectedin plus irinotecan
Alkylating agent plus topoisomerase inhibitor
Recruiting
November 2023
NCT04610658
1/2
Immune Checkpoint Inhibition With Lurbinectedin Relapsed/Recurrent SCLC
Nivolumab-ipilimumab plus lurbinectedin
Checkpoint inhibitor plus alkylating agent
Recruiting
October 2024
NCT04938817
1/2
Safety and Efficacy Study of Pembrolizumab (MK-3475) in Combination With Investigational Agents for the Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC) in Need of Second-Line Therapy (MK-3475-B98/KEYNOTE-B98)
Pembrolizumab/quavonlimab monotherapy or Pembrolizumab/quavonlimab plus lenvatinib or MK-4830
PD-L1 inhibitor plus CTLA-4 inhibitor plus TKI or ILT4 receptor inhibitor
Recruiting
November 2026
NCT03904719
2
CM082 and JS001 in Patients With Advanced Small-cell Lung Cancer (SCLC)
CM082 in combination with JS001
VEGFR inhibitor/anti-PD-1 monoclonal antibody
Recruiting
June 2021
NCT03449901
2
ADI-PEG 20 in Combination With Gemcitabine and Docetaxel for the Treatment of Soft Tissue Sarcoma, Osteosarcoma, Ewing's Sarcoma, and Small Cell Lung Cancer
Pegylated arginine deiminase plus gemcitabine plus docetaxel
Amino acid-degrading enzyme plus antimetabolite plus alkylating agent
Active, not recruiting
May 2022
NCT04727853
2
Study of Irinotecan Liposome Injection as Second-line Regimen in Patients With Small Cell Lung Cancer (SCLC)
Irinotecan liposome injection
Topoisomerase inhibitor
Not yet recruiting
June 2022
NCT04381910
2
Irinotecan Hydrochloride Liposome Injection (LY01610) For Small Cell Lung Cancer
Durvalumab (MEDI4736) and AZD6738 Combination Therapy in Relapsed Small Cell Lung Cancer Subjects
Durvalumab
Anti-PD-1 monoclonal antibody
Enrolling by invitation
May 2023
NCT05060016
2
A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301)
Tarlatamab
Bispecific T-cell engager (BiTE)
Recruiting
June 2023
NCT04607954
2
Durvalumab and Topotecan or Lurbinectedin for the Treatment of Relapsed or Refractory Small Cell Lung Cancer
Durvalumab plus topotecan or lurbinectedin
Anti-PD-1 monoclonal antibody plus topoisomerase inhibitor or alkylating agent
Recruiting
November 2023
NCT04919382
2
Temozolomide and Atezolizumab as Second Line for the Treatment of Metastatic or Recurrent Small Cell Lung Cancer
Atezolizumab plus temozolomide
Monoclonal antibody plus alkylating agent
Recruiting
December 2023
NCT05153239
3
Clinical Trial of Lurbinectedin as Single-agent or in Combination With Irinotecan vs. Topotecan or Irinotecan in Patients With Relapsed Small-cell Lung Cancer (LAGOON)
Lurbinectedin Single-Agent or lurbinectedin plus irinotecan
Alkylating agent or alkylating agent plus topoisomerase inhibitor
Agents Under Investigation for Second- and Later-Line SCLC Therapies
The majority of publications identified by this review reported the results of studies of investigational agents in relapsed SCLC populations. The findings are grouped by drug class and by the nature of the results (positive findings [completed studies], positive preliminary data; negative results). Studies involving more than 1 agent appear in all relevant categories (eg results of the investigational combination olaparib plus cediranib appear in both the PARP inhibitors and TKIs sections). All study results are summarized in Supplemental Table S3 with studies featuring more than 1 investigational agent, again, appearing in all relevant subsections.
Alkylating Agents
Promising preliminary data have been reported from an ongoing, phase 2, single-arm open-label study of the alkylating agent temozolomide plus PARP inhibitor talazoparib as second-line treatment for patients with ES-SCLC (NCT03672773; n = 28).
In a preliminary analysis of 3 patients with evaluable response data to low-dose temozolomide plus talazoparib, 1 patient had a partial response, 1 had stable disease, and 1 had progressive disease. Final results are awaited, with the trial due to complete in October 2023.
Jonsson Comprehensive Cancer Center, Translational Research in Oncology, Pfizer. Talazoparib and low-dose temozolomide in treating participants with relapsed or refractory extensive-stage small cell Lung Cancer. 2018. Available at: https://ClinicalTrials.gov/show/NCT03672773 Accessed June 18, 2022.
These preliminary positive data for low-dose temozolomide in combination with talazoparib follow earlier negative results of the alkylating agent in combination with the PARP inhibitor veliparib in patients with relapsed SCLC (NCT01638546; n = 104; 41% platinum-sensitive, 59% refractory).
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
Yet no differences in 4-month PFS (primary endpoint) or median OS were seen between groups, despite significantly higher ORR with temozolomide plus veliparib. Reflecting on the antitumor efficacy results, the authors conclude that further studies of combination temozolomide plus PARP inhibitor treatment are potentially warranted.
Only 1 other publication featuring an alkylating agent was identified: a terminated phase 2 trial of ifosfamide (UMIN000002465; n = 12).
The trial investigated ifosfamide in combination with recommended supportive care in patients with refractory relapse of SCLC who had received 1 to 3 prior lines of therapy.
The trial was stopped at the interim analysis owing to futility: no objective response was observed in any patients, and the authors concluded that ifosfamide monotherapy should not be used or investigated further in this indication.
PARP Inhibitors
Three publications reported positive results from completed trials of PARP inhibitors in patients with relapsed SCLC: the phase 2 SUKES-B (NCT03009682) and SUKES N-2 (NCT03428607) trials of olaparib,
SUKES-B and SUKES N-2 investigated olaparib alone (n = 15) and in combination with ceralasertib (n = 26), respectively. In these studies, olaparib demonstrated efficacy and an acceptable tolerability profile in patients with relapsed SCLC.
The phase 1b study of fluzoparib evaluated the PARP inhibitor in combination with an investigational human IgG4 antibody (SHR-1316) blocking programmed death-ligand 1 (PD-L1) in patients with relapsed SCLC (n = 23); moderate efficacy and a manageable toxicity profile were reported.
An ongoing phase 2 trial of olaparib (in combination with the TKI cediranib) for patients with relapsed SCLC (NCT02551432; n = 25; 80% platinum-sensitive disease) has also reported promising initial results.
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors.
In biomarker-unselected platinum-pretreated SCLC, ORR was 28%; antihypertensive treatment was required but overall AEs were considered manageable. The trial is expected to be completed in December 2022.
National Cancer Institute and AstraZeneca. A Phase 2 study of Cediranib in combination with Olaparib in advanced solid tumors. 2016. Available at: https://ClinicalTrials.gov/show/NCT02498613 Accessed June 18, 2022.
However, not all trials of olaparib, and the PARP inhibitors class, for relapsed SCLC have reported positive results. A phase 2 trial of olaparib in combination with the PD-L1 inhibitor durvalumab (NCT02484404; n = 20) failed to meet its primary endpoint in patients with relapsed SCLC (40% platinum-sensitive; 60% platinum-refractory); the ORR for the combination was 10.5%, which is below the preset threshold of 35%.
In addition, the earlier discussed trial of veliparib plus temozolomide vs. placebo plus temozolomide (NCT01638546; n = 104) reported no significant survival benefit with the addition of veliparib, despite a higher ORR in the veliparib plus temozolomide arm.
Randomized, double-blind, Phase II Study of Temozolomide in combination with either Veliparib or Placebo in patients with relapsed-sensitive or refractory small-cell lung Cancer.
Almost one-third of the publications (23/77; 16 separate studies) identified by this review reported the results of TKI trials in relapsed SCLC populations; 11 publications (from 4 studies) featured anlotinib, 7 apatinib, 2 pazopanib, and 1 (each) chiauranib, cediranib, and amuvatinib.
The publications featuring anlotinib included 9 publications from the phase 2 ALTER 1202 trial of anlotinib vs. placebo as third- or later-line therapy in patients with SCLC (NCT03059797; n = 120).
Effect of prior thoracic radiotherapy on prognosis in relapsed small cell lung cancer patients treated with anlotinib: a subgroup analysis of the ALTER 1202 trial.
OA03. 02 Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: a subgroup analysis in ALTER 1202 Trial.
Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.
1791P Effect of anlotinib in advanced small cell lung cancer (SCLC) patients with liver metastases: a subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
P2. 12-11 quality of life in ALTER1202 Trial of Anlotinib as third-or further line therapy for advanced small cell lung Cancer (SCLC): a post-hoc analysis.
1787P Effect of anlotinib in advanced small cell lung cancer patients with pleural metastases/pleural effusion: a subgroup analysis from a randomized, double-blind phase II trial (ALTER1202).
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
Hangzhou FPsHo. A Single-arm, Phase Ⅱ Clinical Trial of anlotinib hydrochloride combined with irinotecan or docetaxel for second line treatment of nonsensitive relapsed small-cell lung Cancer: Available at: https://ClinicalTrials.gov/show/NCT04757779; 2019.
Median PFS (primary endpoint) and OS were significantly longer with anlotinib than with placebo (4.1 months vs. 0.7 months [HR, 0.19; P < .0001] and 7.3 months vs. 4.9 months [HR, 0.53; P = .0029], respectively), and the investigators deemed the safety profile of anlotinib to be favorable.
Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised, double-blind, placebo-controlled Phase 2 study.
The benefits of anlotinib vs. placebo were consistently demonstrated across subgroups of interest, including patients who had/had not received previous thoracic radiotherapy, patients with brain metastases, patients with liver metastases, patients with pleural metastases/pleural effusion, patients who relapsed within 3 months after second-line treatment, and patients previously treated with chemoradiotherapy.
Effect of prior thoracic radiotherapy on prognosis in relapsed small cell lung cancer patients treated with anlotinib: a subgroup analysis of the ALTER 1202 trial.
OA03. 02 Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: a subgroup analysis in ALTER 1202 Trial.
1791P Effect of anlotinib in advanced small cell lung cancer (SCLC) patients with liver metastases: a subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
1787P Effect of anlotinib in advanced small cell lung cancer patients with pleural metastases/pleural effusion: a subgroup analysis from a randomized, double-blind phase II trial (ALTER1202).
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
P2. 12-11 quality of life in ALTER1202 Trial of Anlotinib as third-or further line therapy for advanced small cell lung Cancer (SCLC): a post-hoc analysis.
These results from the ALTER 1202 trial build on positive results from 2 phase 2 trials of anlotinib as second- or later-line therapy in patients with SCLC, which suggested that the drug warranted further investigation. The first of these phase 2 trials, the SALTER trial, investigated anlotinib in combination with oral fluoropyrimidine S-1 (NCT03823118; n = 52) as second- or later-line therapy, and reported antitumor activity (ORR, 43.8%; median OS and PFS, 178 days and 134 days, respectively) and a manageable safety profile.
1649P Anlotinib plus oral fluoropyrimidine S1 in treating patients with refractory or relapsed small cell lung cancer (SALTER TRIAL): an open-label, multicenter, single-arm, phase II trial.
The second phase 2 trial, an evaluation of anlotinib in combination with the programmed death protein-1 (PD-1) mAb penpulimab (NCT04203719; n = 20) as second-line therapy, also reported promising antitumor activity (ORR, 50%; 1 complete response and 9 partial responses; median PFS, 4.7 months) and a favorable safety profile.
Positive results have also been reported for the vascular endothelial growth factor receptor (VEGFR)-2-targeting TKI apatinib, both as monotherapy (2 phase 2 trials [NCT02995187; n = 22 and NCT02945852; n = 40] and 1 phase 4 trial [ChiCTR-OPC-17013964; n = 52])
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.
and as part of combination therapy with irinotecan or docetaxel (phase 2, NCT03547804; n = 31), etoposide (phase 2, NCT03389087; n = 53), irinotecan (phase 2, ChiCTR1800018642; n = 17) or camrelizumab (phase 2, NCT03417895 [PASSION]; N = 59).
Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.
The phase 2 monotherapy trials evaluated apatinib as third- or later-line SCLC therapy. The first monotherapy trial, published by Xu et al. (n = 40), reported an ORR (primary endpoint) of 17.5% and median OS and PFS estimates of 5.8 months and 3.0 months, respectively.
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.
From the second monotherapy trial, Liu et al. reported median PFS (primary endpoint) and OS estimates of 5.4 months and 10 months, respectively, in patients (n = 22) with ES-SCLC.
The phase 4 study of apatinib monotherapy reported a median PFS of 6.2 months and an ORR of 19.4% in patients receiving second- and later-line therapy for ES-SCLC (n = 52); AEs were considered to be tolerable.
In the phase 2 trials of apatinib as part of combination therapy, He et al. reported promising efficacy data and a manageable toxicity profile when used as a third- or further-line therapy for patients with ES-SCLC in combination with etoposide (n = 53),
Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.
Positive results were also reported for apatinib when used in combination with irinotecan in patients with relapsed SCLC despite 1 prior systemic therapy (n = 17),
Further positive data for TKI therapy were reported from 2 phase 2 trials of pazopanib vs. no comparator (n = 58) or vs. placebo (NCT01797874; n = 97) in the second-line setting,
Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07).
Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.
and from 1 phase 2 trial of chiauranib (CS2164) (NCT03216343; n = 28), a novel investigational multi-kinase inhibitor with targets including Aurora kinase B, VEGFR, platelet-derived growth factor receptor, c-Kit and colony stimulating factor 1 receptor.
In the placebo-controlled pazopanib trial, active therapy significantly prolonged PFS vs. placebo (3.7 months vs. 1.8 months; HR, 0.44; P < .0001); however, on the basis of the toxicity profile (grade 3 AEs with pazopanib included thrombocytopenia [10.4%] and liver enzyme elevation [10.4%]), the authors recommended further work be undertaken to identify biomarkers that would help to inform more targeted patient selection.
Pazopanib maintenance after first-line etoposide and platinum chemotherapy in patients with extensive disease small-cell lung cancer: a multicentre, randomised, placebo-controlled Phase II study (KCSG-LU12-07).
In the non-placebo-controlled trial of pazopanib in patients with platinum-sensitive (67.2% of patients) or platinum-refractory (32.8%) relapse, median OS and PFS were 6.0 months and 2.5 months, respectively; 14% (8/58) of patients had a partial response and 34% (20/58) of patients had stable disease.
Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.
In the single-arm phase 2 trial of chiauranib, the investigational TKI was well tolerated and demonstrated antitumor activity in patients who had progressive SCLC after a platinum-based regimen and at least one other chemotherapy.
The overall response and DCR were 17.9% and 64.3%, respectively, and median PFS, OS and duration of response were 3.6 months, 8.4 months and 8.2 months, respectively.
Further to these completed trials of TKI agents in patients with relapsed SCLC, positive preliminary data have also been reported from an ongoing phase 2 trial (NCT04757779) of anlotinib in combination with irinotecan or docetaxel in patients with SCLC who relapsed within 6 months of initiating first-line therapy.
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: a single-arm phase I study.
In an interim analysis of 24 patients with analyzable efficacy data, ORR was 47.6% and the median OS and PFS were 7.5 months and 4.0 months, respectively.
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
Hangzhou FPsHo. A Single-arm, Phase Ⅱ Clinical Trial of anlotinib hydrochloride combined with irinotecan or docetaxel for second line treatment of nonsensitive relapsed small-cell lung Cancer: Available at: https://ClinicalTrials.gov/show/NCT04757779; 2019.
The combination of cediranib with olaparib is also being investigated in an ongoing trial (due to conclude in December 2022), as previously discussed in the overview of PARP inhibitor studies (NCT02498613).
Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: a phase II study of cediranib in combination with olaparib in advanced solid tumors.
National Cancer Institute and AstraZeneca. A Phase 2 study of Cediranib in combination with Olaparib in advanced solid tumors. 2016. Available at: https://ClinicalTrials.gov/show/NCT02498613 Accessed June 18, 2022.
Although the results of completed and ongoing trials of TKI agents in relapsed SCLC populations have been (so far) generally positive, a study of amuvatinib (a multi-targeted kinase inhibitor with potent activity against c-Kit) in combination with platinum etoposide chemotherapy failed to meet the primary endpoint of at least 3 confirmed responses in stage 1.
A phase 2, open-label, multi-center study of amuvatinib in combination with platinum etoposide chemotherapy in platinum-refractory small cell lung cancer patients.
The study included 23 patients with platinum-refractory SCLC after 1 or more lines of prior therapy; ORR was 17.4% and median OS and PFS were 119 days and 68 days, respectively. High c-Kit expression was observed in 2 patients with durable disease control, however, indicating possible further investigation of amuvatinib in this patient subgroup with high c-Kit expression.
CPIs
Immune CPIs have changed the treatment paradigm for several responsive tumor types in recent years, and so their potential for the treatment of relapsed SCLC has been an area of active research. To date, promising results have been reported for some CPIs, but the results have not been consistent at the class level.
As described earlier (see TKI section), treatment with the CPI camrelizumab in combination with apatinib demonstrated potential antitumor activity in a phase 2 trial of patients treated after 1 or more prior lines of therapy (NCT03417895 [PASSION]; N = 59),
and the CPI penpulimab also showed favorable antitumor activity when used in combination with anlotinib in patients receiving second-line treatment for SCLC (NCT04203719; n = 20).
In a further 2 phase 2 trials, pembrolizumab in combination with either amrubicin (NCT03253068; n = 25; patients with at least one previous line of therapy; 3 patients platinum-sensitive/22 patients platinum-refractory on relapse) or paclitaxel (NCT02551432; n = 26; patients with 1 previous line of therapy) was shown to be effective with an acceptable tolerability profile.
The ongoing phase 2 KEYNOTE-158 trial (NCT02628067; N = 1066) of pembrolizumab in patients with incurable solid tumors, including SCLC, with progression on or intolerance to 1 or more standard lines of therapy, is further investigating the clinical potential of pembrolizumab.
Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
In a prespecified analysis (n = 790), high tissue tumor mutational burden was identified as a potential biomarker for identifying patients who may have a robust and durable response to pembrolizumab.
Merck Sharp, Dohme Corp. Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158). 2015. Available at: https://ClinicalTrials.gov/show/NCT02628067 Accessed June 18, 2022.
However, preliminary data from the ongoing BIOLUMA study of nivolumab plus ipilimumab in patients with relapsed SCLC (NCT03083691; n =18) are less promising for CPI therapy as a doublet regimen.
BIOLUMA: A phase II trial of nivolumab in combination with ipilimumab to evaluate efficacy and safety in lung cancer and to evaluate biomarkers predictive for response—preliminary results from the SCLC cohort.
Although there was an ORR to combination therapy of 38.8%, toxicity rates were high and there were 2 treatment-related deaths. Only patients with a high tumor mutation burden are now being included to improve the benefit to risk ratio. The trial is estimated to complete in September 2023.
Lung Cancer Group Cologne, Bristol-Myers Squibb. BIOLUMA: Biomarkers for Nivolumab and Ipilimumab and Evaluation of the Combination in Lung Cancer. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT03083691 Accessed June 18, 2022.
Disappointing results were also reported from a phase 2 trial of nivolumab in combination with gemcitabine as second- or later-line treatment (NCT03662074; n =14).
The trial was stopped after completion of the first stage because only 1 response was observed and 2 had been required to progress to the next stage; the combination did not demonstrate a benefit on the radiographic response rate compared with a historical control. PFS and OS were also not prolonged with the combination. In addition, the phase 3 CheckMate 331 trial (NCT02481830; n = 569) of nivolumab for the second-line treatment of relapsed SCLC (57% platinum-sensitive; 43% platinum-refractory) failed to show benefit over established chemotherapy agents (topotecan or amrubicin).
Nivolumab did not increase median OS vs. chemotherapy (7.5 months vs. 8.4 months; HR, 0.86; P = .11), although it did have a more favorable safety profile than chemotherapy. Further, exploratory analyses reported an association between some baseline characteristics and improved survival with nivolumab, suggesting that further biomarker-focused investigation may help to identify patients most likely to benefit from nivolumab.
Lack of treatment benefit was also reported for the PD-L1 inhibitor atezolizumab vs. topotecan or rechallenge with initial chemotherapy in a phase 2 trial (NCT03059667; n = 73) in patients who had received 1 previous line of therapy (64.4% platinum-sensitive; 35.6% platinum-refractory). The ORR was 2.3% and median PFS was 1.4 months, precluding initiation of a phase 3 trial.
A randomized non-comparative Phase II study of anti-programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as second-line therapy in patients with small cell lung Cancer: results from the IFCT-1603 Trial.
as discussed in the section ‘PARP inhibitors’, or in a phase 2 trial of durvalumab (anti-PD-L1) in combination with tremelimumab (an inhibitor of cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4]) without/with stereotactic body radiation therapy (SBRT) (arms A/B, respectively).
The doublet CPI regimen failed to show a clear efficacy signal (ORR, 0% [arm A] and 28.6% [arm B]; median PFS, 2.1 months [arm A] and 3.3 months [arm B]) in patients who had received 1 or 2 prior lines of SCLC therapy (n = 18). Despite the lack of clear efficacy signal, the authors concluded that the question of adding SBRT to combination immune CPI therapy in patients with relapsed SCLC remains relevant for future studies.
Topoisomerase I Inhibitors
Two phase 2 trials of topoisomerase I inhibitor monotherapy in second- or later-line treatment of SCLC have reported positive results.
The first, a single-arm study of irinotecan in patients who had received at least one prior line of systemic treatment (n = 30; 18 patients platinum-sensitive/12 patients platinum-refractory on relapse), reported an ORR to irinotecan of 41.3%, a median OS of 10.4 months, and a tolerable safety profile.
The second trial was a larger comparison study of belotecan vs. topotecan as monotherapy for the second-line treatment of platinum-sensitive-relapsed SCLC (NCT01497873; n = 161). Belotecan consistently achieved better outcomes than topotecan (ORR [primary endpoint]: 33% vs. 21%, P = .09; DCR: 85% vs. 70%, P = .030; median OS: 13.2 months vs. 8.2 months, HR [95% CI]: 0.69 [0.48-0.99]). The signal for prolonged OS with belotecan (vs. topotecan) was particularly notable in patients younger than 65 years of age.
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
In the phase 3 trial (UMIN000000828; n =180), the combination of irinotecan with cisplatin and etoposide was compared with topotecan alone as second-line treatment of patients with sensitive-relapsed SCLC.
Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.
Median OS (primary endpoint) and PFS were significantly longer with the combination vs. topotecan (18.2 months vs. 12.5 months [P = .0079] and 5.7 months vs. 3.6 months [P < .0001]), and the combination was associated with a significantly higher ORR (84% vs. 27%; risk ratio, 0.32; P < .0001). Severe AEs were more common with the combination than with topotecan (10% vs. 4%), as were grade 3 or 4 febrile neutropenia and thrombocytopenia (febrile neutropenia: 31% vs. 7%, respectively; thrombocytopenia: 41% vs. 28%, respectively). These AEs, however, were generally managed with irinotecan dose modifications, and the authors concluded that the combination could be considered as a standard second-line treatment option for selected patients with sensitive-relapsed SCLC.
The first phase 2 trial of irinotecan in combination with other agents investigated a formulation of hyaluronic acid and irinotecan in combination with carboplatin as second-line treatment for patients with refractory ES-SCLC (n = 13); median OS and PFS were 28.5 weeks and 14.2 weeks, respectively, and ORR was 22%.
The second phase 2 trial (NCT01941316; N = 62) evaluated irinotecan in combination with carfilzomib as second-line therapy for patients with platinum-sensitive (n = 37) and platinum-refractory (n = 25) SCLC.
In patients with sensitive and refractory relapse, respectively, median OS was 6.9 months and 6.8 months, median PFS was 3.6 months and 3.3 months, and ORR was 21.6% and 12.0%. Based on these results, the author considered combination therapy with irinotecan and carfilzomib efficacious in both platinum-sensitive and platinum-refractory patients. However, grade 5 toxicity was 4.8%, leading the authors to suggest that consideration of the combination regimen be limited to potential use in patients with Performance Status 0 to 1; particularly those with platinum-refractory disease relapse and those who cannot receive immunotherapy. The third phase 2 trial of irinotecan-based combination therapy (ChiCTR1800018642; n = 17) was described in section ‘TKIs’; it investigated the combination of irinotecan with apatinib in patients with 1 prior systemic therapy, and reported promising efficacy data and a manageable AE profile.
Positive results for a liposomal formulation of irinotecan have been reported in 4 publications from phase 2 (part 1) of the phase 2/3 RESILIENT trial (NCT03088813).
RESILIENT part 1 (N = 30) was a single-arm, open-label, phase 2, dose-finding and expansion study of liposomal irinotecan in adults with advanced SCLC who had progressed with first-line platinum-based therapy.
RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—preliminary findings from part 1 dose-defining phase.
Ipsen. Study of Irinotecan Liposome Injection (ONIVYDE®) in Patients With Small Cell Lung Cancer (RESILIENT). 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT03088813 Accessed June 18, 2022.
Promising antitumor activity with liposomal irinotecan was reported at the recommended dose of 70 mg/m2 (n = 25), with an ORR of 44% (complete response, 4%; partial response, 40%; stable disease, 28%; progressive disease, 20%; non-evaluable, 8%), a best overall response of 72% and a DCR at 12 weeks (DCR12wks) of 48%. Median PFS and OS were 3.98 months and 8.08 months, respectively, and the safety profile was aligned with the known safety profile of irinotecan; treatment was generally well tolerated. A subgroup analysis also reported antitumor activity in patients with both platinum-sensitive and platinum-resistant disease, although ORR and DCR12wks were numerically higher in patients with platinum-sensitive disease (ORR 53.3% vs. 30% and DCR12wks 60% vs. 30%).
MO01.39 liposomal irinotecan in adults with small cell lung Cancer who Progressed on platinum-based therapy: subgroup analyses by platinum sensitivity.
The secondary OS and PFS data were immature at the time of the subgroup analysis. Part 2 of the RESILIENT trial, the phase 3 evaluation of liposomal irinotecan vs. topotecan in 450 patents who have relapsed SCLC despite first-line platinum-based therapy, is ongoing and will provide further data regarding the efficacy and safety of the liposomal formulation of irinotecan. Preliminary findings from the primary analysis, indicated that the primary endpoint of OS was not met.
However, patients who received liposomal irinotecan experienced a doubling of ORR compared to those who received topotecan. Initial data suggest that no new safety concerns emerged during the phase 2 part of the study.
Ipsen. Study of Irinotecan Liposome Injection (ONIVYDE®) in Patients With Small Cell Lung Cancer (RESILIENT). 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT03088813 Accessed June 18, 2022.
The only other ongoing trial of topoisomerase I inhibitors with preliminary data is the phase 2 trial investigating the combination of irinotecan or docetaxel with anlotinib in patients with SCLC who relapsed within 6 months of initiating first-line therapy (NCT04757779; estimated completion December 2024) discussed in ‘TKIs’, which reported positive preliminary results in 24 patients.
1657P Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: updated results from a single-arm phase II study.
The effect and safety of anlotinib combined with irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: a single-arm phase I study.
Hangzhou FPsHo. A Single-arm, Phase Ⅱ Clinical Trial of anlotinib hydrochloride combined with irinotecan or docetaxel for second line treatment of nonsensitive relapsed small-cell lung Cancer: Available at: https://ClinicalTrials.gov/show/NCT04757779; 2019.
Although the identified literature relating to topoisomerase I inhibitor therapy was broadly positive, 2 trials (1 phase 2 [UMIN000013882; n =14]; 1 phase 2/3 [NCT03098030; n = 471]) of irinotecan-based therapy failed to demonstrate benefit over the comparator group. In the phase 2 trial, there was no statistical difference in PFS in patients who received irinotecan as maintenance therapy after first-line induction therapy for ES-SCLC vs. amrubicin.
Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).
The study was ultimately terminated early owing to slow accrual. The authors concluded that maintenance therapy with irinotecan or amrubicin after induction therapy might be effective in some patients. In the phase 2/3 trial, the combination of irinotecan with the anti-disialoglioside antibody dinutuximab was not found to be more effective than irinotecan alone or topotecan alone for the second-line treatment of patients with relapsed/refractory SCLC in a phase 2/3 trial (n = 471).
The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): results from part II of the open-label, randomized, phase II/III distinct study.
Other Chemotherapy Drugs/Regimens not Currently Licensed for Relapsed SCLC
Two publications identified by the searches reported the results of studies of the anthracycline glycoside amrubicin in patients with relapsed or refractory SCLC.
One publication (from 2016) reported the results of a large, multicenter open-label study conducted in China that recorded a response rate with amrubicin of 39%, and a manageable AE profile, in patients (n = 95) with refractory SCLC.
More recently, however, a single-arm phase 2 trial of weekly amrubicin in patients with refractory or relapsed SCLC (UMIN000009440; n = 21) was terminated early owing to a lack of efficacy.
The efficacy of doublet treatment with carboplatin plus etoposide vs. the approved second-line SCLC treatment option, topotecan, was investigated in an open-label phase 3 trial (NCT02738346; n = 164) conducted across 38 centers in France.
Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.
Eligible patients had relapsed or progressive SCLC despite prior platinum plus etoposide treatment. Median PFS (primary endpoint) was significantly longer in the combination chemotherapy group than in the topotecan group (4.7 months vs. 2.7 months; stratified HR, 0.57; 90% CI: 0.41-0.73; P = .0041). Rates of grade 3/4 AEs were similar between treatment groups. The authors concluded that carboplatin plus etoposide rechallenge is a reasonable second-line chemotherapy option for patients with sensitive-relapsed SCLC.
A single phase 4 trial (ChiCTR-ONC-13003470; N = 1211) reported the results of lobaplatin-based treatment for patients with SCLC managed in routine care in China; 36% (n = 431) of the cohort had relapsed SCLC despite prior lobaplatin-based therapy alone (22%) or in combination with etoposide (46%) or irinotecan (31%).
In the relapsed SCLC subgroup, ORR was 33%, DCR 71%, and median PFS and OS were 4.0 months and 9.2 months, respectively. Treatment tolerability was reported for the overall cohort (treatment-naive and relapsed SCLC), for which the most common grade 3/4 AEs were leukopenia (24%), neutropenia (36%), thrombopenia (15%), and anemia (12%). The authors concluded that lobaplatin-based regimens are effective and tolerable in Chinese patients with SCLC.
Two publications reported studies of paclitaxel: a phase 2 trial of nab-paclitaxel in patients with refractory or sensitive-relapsed SCLC (NCT03219762 [NABSTER; n = 68]),
A study in recurrent small cell lung cancer patients, comparing weekly paclitaxel, irinotecan and temozolomide in second-line: a prospective study from a south Indian tertiary cancer hospital.
In the phase 2 trial, nab-paclitaxel demonstrated some modest antitumor activity in relapsed SCLC (partial response, median OS and PFS of 8%, 1.8 months and 3.6 months in patients with refractory disease, and 14%, 1.9 months and 6.6 months in patients with sensitive disease, respectively) and a favorable toxicity profile, but failed to meet the primary endpoint (objective tumor response).
The phase 4, real-world study of paclitaxel in the second-line setting reported a favorable toxicity profile and a response rate comparable to irinotecan or temozolomide.
A study in recurrent small cell lung cancer patients, comparing weekly paclitaxel, irinotecan and temozolomide in second-line: a prospective study from a south Indian tertiary cancer hospital.
The final chemotherapy publication identified by the review featured TAS-102, a novel antimetabolite combination chemotherapy agent. It reported the results of a randomized phase 2 trial of TAS-102 compared with a control group of topotecan or amrubicin in patients with relapsed SCLC who had received 1 prior line of therapy (NCT01904253; n = 18).
A phase 2 randomized study of TAS-102 versus topotecan or amrubicin in patients requiring second-line chemotherapy for small cell lung cancer refractory or sensitive to frontline platinum-based chemotherapy.
At the interim analysis, TAS-102 showed no evidence of activity and the study was terminated early on the basis of interim futility.
Other Investigational Therapies
Targeted treatments
The potential of Rova-T, an antibody–drug conjugate directed against DLL3, for the second- or later-line treatment of SCLC has been investigated in 2 trials (reported in 3 publications).
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: Results from the phase 2 TRINITY study.
Efficacy and safety of Rovalpituzumab Tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell Lung Cancer: results from the Phase II TRINITY Study.
Promising phase 2 data were reported from the TRINITY trial (NCT02674568; n = 339) in patients with DLL3-expressing SCLC who had received ≥ 2 prior regimens.
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: Results from the phase 2 TRINITY study.
Efficacy and safety of Rovalpituzumab Tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell Lung Cancer: results from the Phase II TRINITY Study.
The ORR to Rova-T, mainly in the third-line setting (77% of patients), was 12.4% and the median OS was 5.6 months. The most commonly reported AEs were fatigue, photosensitivity reaction, and pleural effusion; grade 3 to 5 AEs were seen in 63% of patients. The investigators concluded that Rova-T demonstrated modest antitumor activity with associated side effects. However, when evaluated against topotecan in patients with SCLC who had received 1 prior line of therapy in the phase 3 TAHOE trial (NCT03061812; n = 444), OS with Rova-T was inferior to that for topotecan. Rates of serosal effusions, photosensitivity reaction, and peripheral edema were also higher with Rova-T than with topotecan.
Randomized Phase II study of paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.
00017-7&id=gr1.jpg){kind=link}
00017-7&id=gr2.jpg){kind=link}
00017-7&id=gr3.jpg){kind=link}