A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.     

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC

IntroductionIn cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study.MethodsPatients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m² plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsAfter the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35?0.83) remained improved with pembrolizumab combination (n = 60) versus chemotherapy (n = 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45?1.12), despite a 70% crossover rate from chemotherapy alone to anti?programmed death (ligand) 1 therapy. Among the 12 patients who completed 2 years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy.ConclusionsFirst-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.     

Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non–small-cell lung cancer: KEYNOTE-189 Japan Study

Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.     

Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated,Programmed Death-Ligand 1–Positive Advanced NSCLC

IntroductionIn the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.MethodsPatients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m² once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.ResultsA total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.ConclusionsPembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up.MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.     

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial

IntroductionEMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53–0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results.MethodsPatients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates.ResultsAfter 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9–23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6–15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51–0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4–9.0) versus 5.5 months (95% CI: 4.3–6.2) (HR = 0.55, 95% CI: 0.44–0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone.ConclusionsAt protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.     

Efficacy,Safety, and Health-Related Quality of Life With Camrelizumab Plus Pemetrexed and Carboplatin as First-Line Treatment for Advanced Nonsquamous NSCLC With Brain Metastases (CAP-BRAIN): A Multicenter,Open-Label,Single-Arm,Phase 2 Study

IntroductionSystemic treatment options for NSCLC with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in patients with advanced nonsquamous NSCLC with BMs.MethodsThis was a multicenter, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients had treatment-naive metastatic nonsquamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mg/m²) and carboplatin (area under the curve 5) intravenously on day 1 of each 21-day cycle for four cycles, followed by maintenance with camrelizumab (200 mg) and pemetrexed (500 mg/m²) every 21 days until disease progression, unacceptable toxicity, or death. The primary end point was confirmed intracranial objective response rate according to modified Response Evaluation Criteria in Solid Tumors version 1.1, which was primarily analyzed in the efficacy analysis set (EAS).ResultsA total of 45 patients were enrolled and treated (full analysis set), with 40 patients having at least one post-baseline tumor assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% confidence interval [CI]: 9.2–17.3). The confirmed intracranial objective response rate was 52.5% (95% CI: 36.1–68.5) in EAS and 46.7% (95% CI: 31.7–62.1) in full analysis set. The extracranial objective response rate was 47.5% (95% CI: 31.5–63.9) and 42.2% (95% CI: 27.7–57.8), respectively. Median intracranial progression-free survival was 7.6 months (95% CI: 4.6–not reached [NR]), median overall progression-free survival was 7.4 months (95% CI: 4.4–NR), and median overall survival was 21.0 months (95% CI: 15.9–NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decrease (six [13.3%]) and anemia (four [8.9%]). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy—Lung scores (p = 0.025, p < 0.001).ConclusionsCamrelizumab plus pemetrexed and carboplatin was found to have an activity with manageable toxicity and to improve cognitive function and quality of life for patients with nonsquamous NSCLC with BMs in the first-line setting.     

First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations

IntroductionIn the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses.MethodsAdults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC.ResultsWith a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals.ConclusionsWith a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC.     

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized,Double-Blind,Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11)

IntroductionSintilimab, an anti–programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).MethodsA total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.ResultsAs of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362–0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%–58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%–38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.ConclusionsIn Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.     

A Randomized Phase III Study of Pembrolizumab Versus Pembrolizumab-Carboplatin-Pemetrexed for Locally Advanced or Metastatic Nonsquamous Non-small-cell Lung Cancer with PD-L1 50% or more (LAPLACE-50): Study Protocol

BackgroundPembrolizumab monotherapy or immune checkpoint inhibitor with platinum and pemetrexed combination chemotherapy are the standard therapies for patients with nonsquamous non–small-cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥ 50%. However, there are no data on the comparative effectiveness of the 2 regimens in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%.Patients and MethodsThis randomized, multicenter, phase III trial (LAPLACE-50, jRCTs031200078) was designed to compare the efficacy and safety of pembrolizumab with pembrolizumab-carboplatin-pemetrexed combination in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%. Patients are eligible for enrollment if they are at least 20 years old; have pathologically confirmed locally advanced/metastatic nonsquamous NSCLC without sensitizing epidermal growth factor receptor or anaplastic lymphoma kinase mutations; have not received previous systemic therapy for metastatic disease; have an Eastern Cooperative Oncology Group performance status of 0 or 1; and have at least 1 measurable lesion. Patients will be excluded if they have symptomatic central nervous system metastases, interstitial pneumonitis, active autoimmune disease, or are on systemic immunosuppressive treatment. The patients will be randomized 1:1 to pembrolizumab (200 mg) or pembrolizumab (200 mg) plus carboplatin (area under the curve 5) plus pemetrexed (500 mg/m²) on day 1 of each 21-day treatment cycle. The primary endpoint is progression-free survival. The recruitment phase began in August 2020 and will enroll 290 patients.ConclusionIf the primary endpoint is achieved, pembrolizumab could be the first choice for first-line treatment in patients with nonsquamous NSCLC with PD-L1 TPS ≥ 50%.     

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048

Background

Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab–chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Methods

Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67).

Results

At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09–0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25–1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31–1.41]). Pembrolizumab–chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23–2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55–2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55–2.22]). Median PFS was similar for pembrolizumab and pembrolizumab–chemotherapy versus EXTREME in all subgroups. Grades 3–5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab–chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab–chemotherapy died because of treatment-related pneumonitis.

Conclusion

These results support the use of first-line pembrolizumab and pembrolizumab–chemotherapy for Japanese patients with R/M HNSCC.

Clinical trial registry ClinicalTrials.gov, NCT02358031.

     

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction

Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42?1.91). Herein, we present an updated analysis.

First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non–small-cell Lung Cancer: A Systematic Review and Network Meta-analysis

BackgroundThis study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non–small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.Materials and MethodsA search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.ResultsA total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.ConclusionsFor patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.     

Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC

IntroductionFor patients with NSCLC receiving immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) has been validated as a predictive biomarker for improved overall survival (OS). Nevertheless, its histology-specific predictive value in patients with advanced squamous versus nonsquamous cancers remains unclear. To evaluate the differential value of PD-L1 TPS as a predictive biomarker for OS after first-line pembrolizumab in patients with squamous versus nonsquamous NSCLC.MethodsRetrospective, observational study of patients diagnosed with having advanced NSCLC who were treated between October 2015 and April 2019 at community oncology clinics and academic medical centers in a deidentified electronic health record–derived database. Included patients were diagnosed with having advanced or metastatic NSCLC, received treatment with first-line, single-agent pembrolizumab, and had documentation of PD-L1 testing with a numeric result. Exclusion criteria included alterations in EGFR, ALK, and ROS1. The primary end point was OS from start of first-line pembrolizumab therapy by squamous or nonsquamous histology and PD-1 expression level measured by TPS (low, <50% or high, ≥50%).ResultsThe cohort of 1460 patients with NSCLC who received pembrolizumab as a first-line therapy had a mean age of 72 years. Histology was 28% squamous and 72% nonsquamous. PD-L1 expression was low in 13% and high in 87%. No meaningful differences in age, sex, or smoking history were observed by PD-L1 TPS or histology type. A generalized gamma model adjusting for sex and stage at diagnosis found that for patients with nonsquamous histology, high PD-L1 TPS was significantly associated with improved OS by a median OS difference of 8.4 months (p < 0.001). In contrast, for patients with squamous histology, there was no evidence of association between PD-L1 expression level and OS (p = 0.283). PD-L1–related incremental differences in median OS between the patients with squamous and nonsquamous tumors were significantly different (p = 0.034).ConclusionsAmong patients with NSCLC treated with first-line pembrolizumab, high PD-L1 TPS is associated with OS among patients with nonsquamous NSCLC, but not among patients with squamous NSCLC.     

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial

BackgroundPembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy.Patients and methodsIn the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS).ResultsBetween 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths.ConclusionsPembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.Clinical trial name and numberKEYNOTE-001 (ClinicalTrials.gov, NCT01295827).     

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain

IntroductionFinal overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP).MethodsOverall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients.ResultsAt data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31–1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38–1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45–1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57–1.74; previous TKI: HR = 1.22; 95% CI: 0.68–2.22) or liver metastases (HR = 1.01; 95% CI: 0.68–1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39–1.19).ConclusionsThis final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.