At a glance: The KEYNOTE lung cancer trials

The PD-1 inhibitor pembrolizumab is being investigated in multiple KEYNOTE trials across different tumor types, either alone or as part of various combinations, leading to a prodigious amount of information. Here we provide a quick guide to the non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) trials sponsored by the drug manufacturer Merck Sharp & Dohme. Where a trial comprises multiple solid tumor cohorts, we focus on just the NSCLC and SCLC cohorts in this guide. NSCLC trials KEYNOTE-001: Completed Phase 1 Patient population: Locally advanced or metastatic melanoma or NSCLC Comparator: None https://clinicaltrials.gov/show/NCT01295827 The results of the NSCLC cohort of the KEYNOTE-001 trial were published in The New England Journal of Medicine in May 2015. They showed that pembrolizumab given at a dose of 2 or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks was well tolerated and had antitumor activity regardless of whether patients had received prior therapy or not. Overall survival (OS) data on the treatment-naïve participants of the same trial, published in the Annals of Oncology in April 2017, showed a median OS time of 22.1 months, with greater benefits for those with a PD-L1 tumor proportion score (TPS) of at least 50%. Three-year results from the trial pointed to a durable effect of the agent on OS, with median OS durations of 22.3 and 10.5 months among treatment-naïve and previously treated participants, respectively. The association between higher PD-L1 levels and better outcomes was also observed in this analysis, which appeared in The Lancet Respiratory Medicine in March 2019. A secondary analysis of the trial – published in The Lancet Oncology in May 2017 – showed significantly better progression-free survival (PFS) and OS for participants who had previously received radiotherapy relative to those who had not. Individuals with versus without prior receipt of thoracic radiation had a higher incidence of any (63 vs 40%) and treatment-related (13 vs 1%) pulmonary toxicity, but the safety profile was considered acceptable by the researchers. The trial investigators reported 5-year results at the 2019 ASCO Annual Meeting, with simultaneous publication in the Journal of Clinical Oncology, showing OS rates at this timepoint of 23.2% and 15.5% for treatment-naïve and previously treated participants, respectively. Pooling data from KEYNOTE-001, 010, 024, and 042, the researchers found that pembrolizumab improved outcomes regardless of brain metastases at baseline. See the KEYNOTE-010 section for the details. KEYNOTE-010: Completed Phase 2/3 Patient population: Previously treated advanced NSCLC with ≥1% PD-L1-positive tumor cells Comparator: Docetaxel https://clinicaltrials.gov/show/NCT01905657 As reported in The Lancet in December 2015, median OS was significantly longer with either the 2 or 10 mg/kg dose of pembrolizumab than with docetaxel 75 mg/m2, all given every 3 weeks (10.4 and 12.7 months, respectively, vs 8.5 months). The survival benefit was even greater among patients with PD-L1 expression on at least 50% of tumor cells. The co-primary endpoint of PFS did not differ significantly between the pembrolizumab and docetaxel arms in the overall study population, but pembrolizumab-treated participants with high (≥50%) PD-L1 expression did derive a significant PFS benefit relative to those given the taxane (5.0 and 5.2 months for 2 and 10 mg/kg, respectively, vs 4.1 months). An updated analysis – conducted at an additional 18 months’ follow-up – showed that the OS benefit afforded by pembrolizumab was maintained not only in the intention-to-treat population, but also in the subgroups of patients with archival or newly collected specimens. These results were published in the Annals of Oncology in January 2019. As reported in the Journal of Thoracic Oncology in January 2019, health-related quality of life (HRQoL) and symptoms did not worsen or improved over the 12-week assessment period with pembrolizumab versus docetaxel. A pooled analysis of data from the KEYNOTE-010, 024, and 042 trials was presented at ELCC 2019 and showed that older (≥75 years) patients with a PD-L1 TPS of at least 50% derive a greater OS benefit from pembrolizumab over chemotherapy than younger patients. These results were subsequently published in Lung Cancer in July 2019. Longer-term analysis of the trial confirmed the OS advantage offered by pembrolizumab over docetaxel was maintained in patients with PD-L1 levels of at least 50% and at least 1% after a median follow-up of 42.6 months and 67.4 months, as reported in the Journal of Clinical Oncology in February 2020 and the Journal of Thoracic Oncology in May 2021, respectively. Pooling data from KEYNOTE-001, 010, 024, and 042, the researchers found that pembrolizumab improved outcomes relative to chemotherapy regardless of whether patients did or did not have stable brain metastases at intake. For instance, the hazard ratio (HR) for death was 0.67 among those with brain metastases and 0.66 for those without. This analysis was published in JTO Clinical and Research Reports in July 2021. KEYNOTE-024: Completed Phase 3 Patient population: Treatment-naïve metastatic NSCLC with ≥50% PD-L1-positive tumor cells Comparator: Investigator’s choice of five platinum-based chemotherapy regimens https://clinicaltrials.gov/show/NCT02142738 A prespecified interim analysis showed that pembrolizumab, administered at a fixed dose of 200 mg every 3 weeks, significantly extended the primary endpoint of PFS relative to chemotherapy (median 10.3 vs 6.0 months). OS was also significantly longer with pembrolizumab, with 80.2% of patients alive at 6 months, compared with 72.4% of the chemotherapy group. These results were published in The New England Journal of Medicine in November 2016. As seen in KEYNOTE-010, HRQoL was maintained or improved in the pembrolizumab versus chemotherapy groups from baseline to week 15. The article was published in The Lancet Oncology in November 2017. Data published in the Journal of Clinical Oncology in January 2019 showed that pembrolizumab continued to provide an OS advantage over chemotherapy with prolonged follow-up (median 25.2 months) and despite crossover from the chemotherapy to the pembrolizumab arm. A pooled analysis of data from the KEYNOTE-010, 024, and 042 trials showed the particular benefit of pembrolizumab for older patients with high PD-L1 levels. Refer to the KEYNOTE-010 section for the details. The 5-year results, conducted at a median follow-up of 59.9 months and reported in the Journal of Clinical Oncology in April 2021, demonstrated that the OS benefit of pembrolizumab was sustained in the long term, with 31.9% of patients alive at this timepoint compared with 16.3% of those given chemotherapy. And an analysis of the Japanese patients in the trial – published in Cancer Science in September 2021 – showed a significant improvement in both PFS and OS, without an adverse impact on tolerability, in this subset. Pooling data from KEYNOTE-001, 010, 024, and 042, the researchers found that pembrolizumab improved outcomes regardless of brain metastases at baseline. See the KEYNOTE-010 section for the details. KEYNOTE-021: Completed Phase 1/2 Patient population: Locally advanced or metastatic NSCLC Comparator: Various https://clinicaltrials.gov/ct2/show/NCT02039674 This is a multicohort study investigating the addition of pembrolizumab to various chemotherapeutic and immunotherapeutic regimens. The findings for the cohort comparing first-line carboplatin and pemetrexed with or without pembrolizumab (cohort G) were published in The Lancet Oncology in October 2016, and showed a significantly higher objective response rate (ORR; 55 vs 29%) and PFS (median, 13.0 vs 8.9 months) with the addition of pembrolizumab. Additional results from this cohort – published in the Journal of Thoracic Oncology in August 2018 – showed a significant OS improvement with the addition of pembrolizumab at a median follow-up of 24 months (HR for death=0.56). Results from cohorts A–C, comprising treatment-naïve patients, demonstrated the feasibility of adding pembrolizumab 2 or 10 mg/kg every 3 weeks to carboplatin–paclitaxel, either without or with bevacizumab, and to carboplatin–pemetrexed. According to the article appearing in Lung Cancer in August 2018, the ORRs were 48%, 56%, and 75%, respectively. Analysis of cohorts E and F of the trial, which included previously untreated patients with sensitizing EGFR mutations, showed that although the toxicity profile of pembrolizumab–erlotinib was similar to that seen for the individual agents, albeit with no improvement in the ORR versus prior monotherapy studies, the combination of pembrolizumab–gefitinib is not feasible as over two-thirds of patients developed grade 3 or 4 liver toxicity. These results appeared in the Journal of Thoracic Oncology in December 2018. December 2018 also saw the publication in Lung Cancer of data from cohorts D and H showing that the combination of pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg every 3 weeks had antitumor activity in patients who had received one or more prior therapies, “but was associated with meaningful toxicity.” Updated results from cohort G were published in the Journal of Thoracic Oncology in October 2020 and showed the continued benefit of combining pembrolizumab with first-line carboplatin–pemetrexed at a median follow-up of 49.4 months. The ORR was 58% versus 33% and median PFS was 24.5 versus 9.9 months. A pooled analysis of KEYNOTE-021 cohort G, KEYNOTE-189, and KEYNOTE-407 (Journal of Thoracic Oncology, July 2021) pointed to the OS and PFS benefit of add-on pembrolizumab in patients with stable brain metastases (HRs=0.48 and 0.44, respectively) and those without (HRs=0.63 and 0.55), cementing the value of pembrolizumab–chemotherapy as a first-line option for advanced NSCLC. KEYNOTE-042: Completed Phase 3 Patient population: Treatment-naïve advanced NSCLC with PD-L1 TPS ≥1%; no EGFR or ALK alterations Comparator: Carboplatin plus paclitaxel or pemetrexed https://clinicaltrials.gov/ct2/show/NCT02220894 The primary analysis of the trial showed that pembrolizumab monotherapy – given at a dose of 200 mg every 3 weeks for up to 35 cycles – significantly improved OS relative to chemotherapy regardless of PD-L1 levels. However, as reported in The Lancet in April 2019, the magnitude of benefit varied by PD-L1 TPS, with HRs for death of 0.69, 0.77, and 0.81 for scores of at least 50%, 20%, and 1%, respectively. A pooled analysis of data from the KEYNOTE-010, 024, and 042 trials showed the particular benefit of pembrolizumab for older patients with high PD-L1 levels. Refer to the KEYNOTE-010 section for the details. As reported in the Journal of Clinical Oncology in October 2022, OS continued to favor single-agent pembrolizumab over chemotherapy after a median follow-up of 61.1 months; the HRs for death were 0.68, 0.75, and 0.79 in PD-L1 TPS subgroups characterized by at least 50%, 20%, and 1% expression, respectively. Pooling data from KEYNOTE-001, 010, 024, and 042, the researchers found that pembrolizumab improved outcomes regardless of brain metastases at baseline. See the KEYNOTE-010 section for the details. KEYNOTE-189: Completed Phase 3 Patient population: Treatment-naïve metastatic nonsquamous NSCLC lacking EGFR or ALK alterations Comparator: Placebo plus platinum-based agent and pemetrexed https://clinicaltrials.gov/ct2/show/NCT02578680 This trial was initiated in response to the encouraging results of the KEYNOTE-021 study. The primary results – published in The New England Journal of Medicine in April 2018 – showed a significant improvement in OS and PFS with the addition of pembrolizumab 200 mg every 3 weeks to pemetrexed plus either cisplatin or carboplatin, with an HR for death of 0.49 and an HR for progression or death of 0.52 relative to placebo plus chemotherapy. Participants derived a benefit regardless of PD-L1 levels, albeit the PFS benefit did not reach statistical significance among those with a TPS below 1%. HRQoL, as indicated by the global health status score on the EORTC QLQ-C30 questionnaire, was maintained with both add-on pembrolizumab and placebo up to week 12, after which placebo-treated participants experienced greater deterioration up to week 21. These patient-reported outcome (PRO) data were described in The Lancet Oncology in February 2020. Add-on pembrolizumab was further supported by updated analyses, the first of which was conducted at a median follow-up of 23.1 months and published in the Journal of Clinical Oncology in March 2020, the HR for death was a significant 0.56, while that for progression or death was 0.48 in favor of pembrolizumab. Subsequent updates, one at a median of 31.0 months (Annals of Oncology, April 2021) and another at 64.6 months (Journal of Clinical Oncology, February 2023) demonstrated the long-term OS (HRs=0.56 and 0.60, respectively) and PFS (HRs=0.49 and 0.50) benefits of adding pembrolizumab to chemotherapy. A pooled analysis of KEYNOTE-021 cohort G, KEYNOTE-189, and KEYNOTE-407 by baseline brain metastases cemented the value of pembrolizumab–chemotherapy as a first-line option for advanced NSCLC. Details in the KEYNOTE-021 section. Another pooled analysis – this time of participants with a PD-L1 TPS of less than 1% included in the KEYNOTE-189 global and Japan extension studies as well as the KEYNOTE-407 global and China extension studies – showed the continued OS (HR=0.64) and PFS (HR=0.66) benefit of pembrolizumab plus chemotherapy in this patient population after 5 years of follow-up. These results appeared in the Journal of Thoracic Oncology in April 2024. KEYNOTE-407: Completed Phase 3 Patient population: Treatment-naïve metastatic squamous NSCLC Comparator: Carboplatin plus paclitaxel or nab-paclitaxel https://clinicaltrials.gov/ct2/show/NCT02775435 Similar to the results in nonsquamous NSCLC patients, the addition of pembrolizumab 200 mg every 3 weeks to carboplatin plus paclitaxel or nab-paclitaxel led to a significant improvement in the co-primary endpoints of OS and PFS, with respective HRs of 0.64 and 0.56. The OS and PFS gains with pembrolizumab were observed across all PD-L1 TPS subgroups. These results appeared in The New England Journal of Medicine in September 2018. The use of the PD-1 inhibitor was backed by PRO data reported in the Journal of Clinical Oncology in November 2019, which showed improvements in the EORTC QLQ-C30 global health status scores with the combination relative to chemotherapy alone at weeks 9 and 18. More evidence for adding pembrolizumab to chemotherapy in this setting came from updates conducted at median follow-ups of 14.3 and 56.9 months – published in the Journal of Thoracic Oncology in June 2020 and the Journal of Clinical Oncology in February 2023, respectively – that continued to show gains in OS (identical HRs of 0.71) and PFS (HRs=0.57 and 0.62, respectively) with the combination. A pooled analysis of KEYNOTE-021 cohort G, KEYNOTE-189, and KEYNOTE-407 by baseline brain metastases cemented the value of pembrolizumab–chemotherapy as a first-line option for advanced NSCLC. Details in the KEYNOTE-021 section. Another pooled analysis – this time of the KEYNOTE-189 global and Japan extension studies as well as the KEYNOTE-407 global and China extension studies – showed the long-term benefit of the combination in patients with a PD-L1 TPS of less than 1%. See the KEYNOTE-189 section for details. KEYNOTE-011: Completed Phase 1 Patient population: Advanced solid tumors Comparator: None https://clinicaltrials.gov/ct2/show/NCT01840579 In this multicohort trial, the researchers are evaluating the safety and tolerability of single-agent pembrolizumab given at three different doses – 2 or 10 mg/kg or 200 mg – and also administered in combination with platinum-based chemotherapy or the CTLA-4 inhibitor ipilimumab for advanced NSCLC. The study also includes a cohort of patients with advanced solid tumors and another comprising SCLC patients with extensive disease (see SCLC section). Results from part A – comprising Japanese participants with advanced solid tumors and reported in Investigational New Drugs in March 2016 – demonstrated the tolerability of pembrolizumab 2 and 10 mg/kg given every 2 weeks in this setting. In September 2021, the investigators reported on parts B and C in Cancer Treatment and Research Communications, which showed the feasibility of combining pembrolizumab with first-line chemotherapy in Japanese patients with advanced NSCLC. KEYNOTE-091: Active, not recruiting Phase 3 Patient population: Early-stage resectable NSCLC Comparator: Placebo https://clinicaltrials.gov/ct2/show/NCT02504372 Also known as PEARLS, this trial explored adjuvant treatment with pembrolizumab 200 mg or placebo every 3 weeks in patients with stage IB–IIIA disease who had undergone surgical resection with or without standard adjuvant therapy. The second interim analysis, published in The Lancet Oncology in September 2022, revealed that disease-free survival was significantly longer with pembrolizumab than placebo in the overall study cohort, at medians of 53.6 and 42.0 months, respectively, and an HR for recurrence or death of 0.76, but not in the population with a PD-L1 TPS of at least 50%. The research team believes that adjuvant pembrolizumab “is potentially a new treatment option for stage IB–IIIA NSCLC […] regardless of PD-L1 expression.” A subgroup analysis reported at the 2023 ASCO Annual Meeting showed a consistent DFS benefit of pembrolizumab in patients who received one to four cycles of adjuvant platinum-based chemotherapy. KEYNOTE-598: Completed Phase 3 Patient population: Treatment-naïve metastatic NSCLC with TPS ≥50% Comparator: Pembrolizumab plus placebo https://clinicaltrials.gov/ct2/show/NCT03302234 This trial investigated the effect on OS and PFS of adding either ipilimumab 1 mg/kg every 6 weeks or placebo to pembrolizumab 200 mg every 3 weeks in individuals with stage IV disease and high PD-L1 expression. Results from the study were reported in the Journal of Clinical Oncology in January 2021 and showed no significant benefit in either primary endpoint with the addition of ipilimumab to pembrolizumab; median OS durations were a comparable 21.4 and 21.9 months with add-on ipilimumab and placebo, respectively, and median PFS was 8.2 and 8.4 months. The findings remained similar at the 3-year follow-up (reported at ELCC 2022), with no survival benefit of supplementing pembrolizumab with ipilimumab. The median OS times were a comparable 22.1 and 22.7 months with and without ipilimumab, respectively, while the median PFS times were identical to those in the previous analysis. KEYNOTE-671: Active, not recruiting Phase 3 Patient population: Resectable stage IIB or IIIA NSCLC Comparator: Perioperative placebo plus neoadjuvant chemotherapy https://clinicaltrials.gov/ct2/show/NCT03425643 This study is assessing the efficacy of adding pembrolizumab 200 mg every 3 weeks to four cycles of neoadjuvant platinum-based chemotherapy, followed by surgery and adjuvant pembrolizumab or placebo for up to 13 cycles, in patients with stage II, IIIA, or IIIB disease amenable to resection. The co-primary endpoints are event-free survival (EFS) and OS. At the first interim analysis, conducted at a median follow-up of 25.2 months, EFS was significantly improved in the pembrolizumab versus placebo group, with an HR for progression, recurrence, or death of 0.58 in favor of the PD-1 inhibitor. As reported in The New England Journal of Medicine in June 2023, OS did not differ significantly between the groups at this point. KEYNOTE-789: Completed Phase 3 Patient population: EGFR-mutated, TKI-resistant, metastatic nonsquamous NSCLC Comparator: Pemetrexed, platinum-based chemotherapy, and placebo https://clinicaltrials.gov/ct2/show/NCT03515837 Participants were required to be positive for an activating EGFR mutation (exon 19 deletion or exon 20 L858R point mutation) and resistant to prior tyrosine kinase inhibitor (TKI) treatment; those harboring the T790M mutation should have previously received osimertinib. Patients received either pembrolizumab 200 mg every 3 weeks or placebo together with pemetrexed and carboplatin or cisplatin, and the primary endpoints were PFS and OS. The final analysis of this trial, presented at the 2023 ASCO Annual Meeting, did not show a significant improvement in either outcome with the addition of pembrolizumab to chemotherapy. The median PFS durations were a comparable 5.6 and 5.5 months with pembrolizumab and placebo, respectively, and the median OS durations were 15.9 and 14.7 months. KEYNOTE-799: Completed Phase 2 Patient population: Inoperable locally advanced NSCLC Comparator: None https://clinicaltrials.gov/ct2/show/NCT03631784 The focus here was to evaluate the incidence of grade 3 or worse pneumonitis in stage III NSCLC patients who were given pembrolizumab 200 mg every 3 weeks alongside thoracic radiotherapy and either paclitaxel plus carboplatin (cohort A) or pemetrexed plus cisplatin (cohort B), followed by pembrolizumab monotherapy at the same dose for up to 14 cycles. The investigators also assessed ORR as a co-primary endpoint. According to the publication in JAMA Oncology in June 2021, the combination of pembrolizumab plus concurrent chemoradiotherapy had “promising antitumor activity,” as evidenced by ORRs of 70.5% and 70.6% in cohorts A and B, respectively, and “manageable safety.” Specifically, pneumonitis of at least grade 3 occurred in a corresponding 8.0% and 6.9% of patients, while treatment-related adverse events of this severity were observed in 64.3% and 50.0%. The robust responses elicited by the combination were maintained in the 2-year update, reported at the 2022 ASCO Annual Meeting, with ORRs of 71.4% and 75.5%, respectively. KEYNOTE-867: Active, not recruiting Phase 3 Patient population: Unresectable early-stage NSCLC Comparator: SBRT plus placebo https://clinicaltrials.gov/ct2/show/NCT03924869 Individuals with inoperable stage I or IIA disease will be treated with stereotactic body radiotherapy (SBRT) plus either pembrolizumab 200 mg or placebo every 3 weeks, with a view to evaluating the co-primary endpoints of EFS and OS. KEYNOTE-782: Completed Phase 2 Patient population: Treatment-naïve metastatic nonsquamous NSCLC Comparator: None https://clinicaltrials.gov/ct2/show/NCT03664024 This biomarker study aimed to establish whether the blood tumor mutational burden (TMB), assessed via circulating tumor DNA, can be used to predict response among patients with stage IV nonsquamous NSCLC receiving four cycles of pembrolizumab plus platinum-based doublet chemotherapy, followed by up to 31 cycles of maintenance pembrolizumab and pemetrexed. The researchers reported in Lung Cancer in February 2024 that baseline blood TMB was not associated with either PFS or OS. KEYNOTE-495: Active, not recruiting Phase 2 Patient population: Treatment-naïve metastatic NSCLC Comparator: None https://clinicaltrials.gov/ct2/show/NCT03516981 In this trial, the investigators are evaluating the utility of biomarker-based triage in individuals with stage IV disease, where the biomarker is a combination of a T-cell-inflamed (TcellinfGEP) gene expression profile and TMB. All participants are receiving pembrolizumab plus either lenvatinib or the anti-LAG3 monoclonal antibodies MK-4280 (favezelimab) or MK-1308 (quavonlimab). The primary endpoint of the study is ORR. An interim analysis presented at the SITC 36th Annual Meeting in 2021 (and published subsequently in Nature Medicine in July 2023) demonstrated the feasibility of using this combination biomarker to assess the clinical activity of pembrolizumab-based dual therapies in this setting. Of the four biomarker-defined subgroups, ORRs tended to be highest for the TcellinfGEPhighTMBhigh subgroup for each of the combination therapies, at 39–60%, but the researchers cautioned that the “sample sizes were small.” Updated efficacy data continued to show the promising antitumor activity of each of the pembrolizumab-based combinations in the TcellinfGEPnon-lowTMBhigh subgroup. These findings were reported at the SITC 37th Annual Meeting in 2022. Country-specific trials KEYNOTE-032: Completed Phase 1 Patient population: Locally advanced or metastatic NSCLC; Chinese Comparator: None https://clinicaltrials.gov/ct2/show/NCT02835690 Here the focus was on evaluating the safety, tolerability, and pharmacokinetics of three doses of pembrolizumab (2 or 10 mg/kg or 200 mg every 3 weeks) in Chinese patients. Efficacy, as indicated by the ORR, duration of response, PFS, and OS, was investigated as the secondary endpoint. As reported in The Oncologist in March 2020, pembrolizumab had a similar safety and pharmacokinetic profile to that seen in international studies, and the antitumor activity was “encouraging,” with an ORR of 14.3%, median PFS of 2.1 months, and an unreached median OS. KEYNOTE-042 China Extension Study: Completed Phase 3 Patient population: Treatment-naïve, PD-L1-positive advanced NSCLC; Chinese Comparator: Carboplatin plus paclitaxel or pemetrexed https://clinicaltrials.gov/ct2/show/NCT03850444 The first results from this extension study (median follow-up 11.3 months) were in line with those of the global trial, demonstrating an OS gain with the use of up to 35 cycles of pembrolizumab 200 mg every 3 weeks alongside six cycles of chemotherapy. As reported at the IASLC 2019 World Conference on Lung Cancer, the HRs for death in the population with a PD-L1 TPS of at least 1% and 20% were a significant 0.65 and 0.62, respectively, while the HR of 0.62 in the population with a PD-L1 TPS of at least 50% was borderline significant. The findings were similar in an updated analysis conducted at a median of 33.0 months, the only difference being that the HRs for death were statistically significant in all populations delineated by PD-L1 TPS, at 0.67, 0.66, and 0.63 for those with at least 1%, 20%, and 50% expression, respectively. These data were published in the International Journal of Cancer in November 2020. A further update, at a median follow-up of 47.2 months, showed the continued survival benefit of pembrolizumab in this population, with corresponding HRs for death of 0.67, 0.68, and 0.66. The researchers presented these results at the AACR Annual Meeting 2022. KEYNOTE-407 China Extension Study: Completed Phase 3 Patient population: Treatment-naïve metastatic squamous NSCLC; Chinese Comparator: Carboplatin plus paclitaxel or nab-paclitaxel https://clinicaltrials.gov/ct2/show/NCT03875092 Initial data from the China Extension study (median follow-up 10.4 months) were presented at the ESMO Asia Congress 2019 and were consistent with those from the global study. The addition of up to 35 cycles of pembrolizumab 200 mg every 3 weeks to four cycles of chemotherapy significantly prolonged the dual primary endpoints of OS and PFS relative to chemotherapy alone, at medians of 17.3 versus 12.6 months and 8.3 versus 4.2 months, respectively, and corresponding HRs of 0.44 and 0.32. The protocol-specified final analysis, at a median follow-up of 28.1 months, showed the long-term benefit of add-on pembrolizumab in this patient population, at HRs for OS and PFS of 0.44 and 0.35, respectively. The findings were published in JTO Clinical and Research Reports in September 2021. Another pooled analysis – this time of the KEYNOTE-189 global and Japan extension studies as well as the KEYNOTE-407 global and China extension studies – showed the long-term benefit of the combination in patients with a PD-L1 TPS of less than 1%. See the KEYNOTE-189 section for details. KEYNOTE-025: Completed Phase 1b Patient population: Platinum-treated advanced NSCLC with PD-L1 TPS ≥1%; Japanese Comparator: None https://clinicaltrials.gov/ct2/show/NCT02007070 The results of this study in Japanese patients were consistent with those of the phase 3 KEYNOTE-010 trial. Treatment with pembrolizumab at a dose of 10 mg/kg every 3 weeks for up to 2 years led to an ORR of 27% among patients with a PD-L1 TPS of at least 50% and of 22% among those with a TPS of at least 1%. These data were published in Cancer Science in January 2019. KEYNOTE-189 Japan Extension Study: Completed Phase 3 Patient population: Treatment-naïve metastatic nonsquamous NSCLC lacking EGFR or ALK alterations; Japanese Comparator: Placebo plus platinum-based agent and pemetrexed https://clinicaltrials.gov/ct2/show/NCT03950674 As reported in Cancer Science in May 2021, similar to in the global trial population, the addition of up to 35 cycles of pembrolizumab 200 mg every 3 weeks to four cycles of chemotherapy improved the OS and PFS of Japanese patients, albeit without reaching statistical significance; the HRs were 0.29 and 0.62, respectively. The research team believes these data support the first-line use of pembrolizumab plus chemotherapy in this setting. Another pooled analysis – this time of the KEYNOTE-189 global and Japan extension studies as well as the KEYNOTE-407 global and China extension studies – showed the long-term benefit of the combination in patients with a PD-L1 TPS of less than 1%. See the KEYNOTE-189 section for details. KEYNOTE-593: Active, not recruiting Phase 4 Patient population: Platinum-naïve (PD-L1 ≥50%) or treated (PD-L1 ≥1%) advanced NSCLC; Indian Comparator: None https://clinicaltrials.gov/ct2/show/NCT03715205 This trial will assess the safety of pembrolizumab 200 mg administered every 3 weeks for up to 35 cycles in Indian patients with NSCLC. Those receiving the PD-1 inhibitor in the first line are required to have stage IV disease and high PD-L1 expression (≥50%), whereas previously treated participants can be of stage IIIB, IIIC, or IV and have PD-L1 expression of 1% or greater. SCLC trials KEYNOTE-028: Completed Phase 1b Patient population: Advanced solid cancer that has progressed on or is unsuitable for standard therapy Comparator: None https://clinicaltrials.gov/ct2/show/NCT02054806 Data from the SCLC cohort of this multicohort study pointed to encouraging antitumor activity and manageable safety of treatment with pembrolizumab 10 mg/kg every 2 weeks in patients with extensive-stage disease that was positive for PD-L1 expression (≥1%). As reported in the Journal of Clinical Oncology in August 2017, the ORR was 33% and two patients had adverse events of grade 3–5 that were considered related to treatment. A pooled analysis of this and KEYNOTE-158 focusing on participants who had received two or more prior lines of therapy for SCLC signaled the benefit of the PD-1 inhibitor in this patient population. The ORR was 19.3%, and 61.0% of responders had responses that lasted for at least 18 months, according to the December 2019 publication in Journal of Thoracic Oncology. KEYNOTE-011: Completed Phase 1 Patient population: Advanced solid tumors Comparator: None https://clinicaltrials.gov/ct2/show/NCT01840579 Findings from part E of the trial, which consisted of Japanese patients with previously untreated extensive-stage SCLC, showed the antitumor activity and manageable toxicity of pembrolizumab given alongside cisplatin or carboplatin plus etoposide. These results appeared in Investigational New Drugs in February 2024. KEYNOTE-158: Recruiting Phase 2 Patient population: Advanced solid cancer that has progressed on standard therapy Comparator: None https://clinicaltrials.gov/ct2/show/NCT02628067 This is an ongoing multicohort trial investigating up to 2 years of treatment with pembrolizumab 200 mg every 3 weeks across various solid tumors. Treatment with pembrolizumab 200 mg every 3 weeks achieved an ORR of 18.7% in the overall SCLC cohort, with rates of 35.7% and 6.0% in patients with PD-L1-positive and negative tumors, respectively. Presenting the findings at the 2018 ASCO Annual Meeting, the investigators described the efficacy of pembrolizumab as “promising,” especially in the setting of PD-L1 positivity. Researchers pooled data from the subset of participants in this study and KEYNOTE-028 who had received at least two prior lines of SCLC therapy – see the KEYNOTE-028 section above for the details. KEYNOTE-604: Completed Phase 3 Patient population: Untreated extensive-stage SCLC Comparator: Etoposide, platinum-based chemotherapy, and placebo https://clinicaltrials.gov/ct2/show/NCT03066778 This trial – in patients with a new diagnosis of extensive-stage SCLC – is assessing the impact on PFS and OS of adding either pembrolizumab 200 mg every 3 weeks or placebo to the standard of care, namely, etoposide plus investigator’s choice of carboplatin or cisplatin. In the second interim analysis – conducted at a median of 13.5 months and reported in the Journal of Clinical Oncology in May 2020 – combination treatment with pembrolizumab plus chemotherapy significantly reduced the risk for progression or death, by 25% relative to chemotherapy alone. The risk for death was also lower, albeit without reaching statistical significance, in the pembrolizumab than control group (HR=0.80). An updated analysis at a follow-up of around 3.5 years was presented at the IASLC World Conference on Lung Cancer 2022 and gave identical HRs to those in the previous analysis for PFS and OS, leading the researchers to state that the findings “support continued exploration of pembrolizumab-based combinations” in SCLC. PRO data from the trial – reported in JTO Clinical and Research Reports in September 2023 – showed that pembrolizumab plus etoposide–platinum maintained HRQoL, further supporting the benefit of pembrolizumab. Summary of approvals - FDA Pembrolizumab was initially approved in October 2015 by the US FDA for the treatment of advanced NSCLC patients with PD-L1-positive disease that had progressed after other treatments. A companion PD-L1 test received simultaneous approval. A year later, in October 2016, the FDA approved pembrolizumab in the first-line metastatic NSCLC setting, with use restricted to patients with a PD-L1 TPS of at least 50%. In May 2017, the FDA modified the indication for pembrolizumab to include all patients with nonsquamous metastatic NSCLC, regardless of PD-L1 expression. The PD-1 inhibitor is to be given alongside pemetrexed and carboplatin in the first line. The FDA approved pembrolizumab in combination with pemetrexed and platinum-based chemotherapy for treatment-naïve individuals with nonsquamous metastatic NSCLC lacking EGFR or ALK aberrations in August 2018. This was shortly followed – in October – by a positive decision for pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel for those with squamous disease. April 2019 saw the approval of pembrolizumab for the first-line treatment of stage III NSCLC that is not amenable to resection or chemoradiotherapy, lacks EGFR or ALK alterations, and has a PD-L1 TPS of 1% or higher. In June 2019, the indication of pembrolizumab was further expanded to include patients with metastatic SCLC who have received platinum-based chemotherapy and at least one other systemic regimen. The FDA approved pembrolizumab in the adjuvant NSCLC setting in January 2023. The PD-1 inhibitor is indicated for patients with stage IB (T2a ≥4 cm), II, or IIIA disease that has been treated with surgery and platinum-based chemotherapy. Later in the same year (October), pembrolizumab was approved by the FDA for use in patients with operable NSCLC, to be given alongside platinum-based chemotherapy in the neoadjuvant setting and then as monotherapy in the adjuvant setting. Summary of approvals - EMA In June 2016, the EMA adopted a positive opinion regarding the marketing authorization of pembrolizumab for patients with locally advanced or metastatic NSCLC expressing PD-L1 who have received at least one prior chemotherapy regimen. The decision also required patients with EGFR or ALK mutations to have received appropriate therapy for these mutations prior to initiation of the PD-1 inhibitor. Later in the same year, the EMA adopted a new indication such that single-agent pembrolizumab could be given in the first line to metastatic NSCLC patients with a TPS of at least 50% and no EGFR mutations or ALK alterations. In July 2018, the EMA gave the nod to first-line pembrolizumab together with pemetrexed and platinum chemotherapy for metastatic nonsquamous NSCLC patients who are negative for EGFR and ALK alterations. The positive decision for those with squamous NSCLC came in January 2019, allowing the use of pembrolizumab, carboplatin and paclitaxel or nab-paclitaxel in previously untreated individuals. The EMA extended the indication of pembrolizumab in September 2023 to include the adjuvant treatment of patients at high risk for recurrence after complete resection and platinum-based chemotherapy. And in February 2024, the EMA allowed the use of pembrolizumab, in combination with platinum-containing chemotherapy, as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment, for the treatment of resectable NSCLC at high risk for recurrence. medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

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At a glance: The KEYNOTE lung cancer trials

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