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BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTS: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). CONCLUSIONS: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Análise de SobrevidaRESUMO
BACKGROUND: Pembrolizumab plus platinum-based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD-L1 (ie, a tumor proportion score < 1%). METHODS: Individual patient data were pooled from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE-407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab-paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis. RESULTS: Four hundred forty-four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD-L1-negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7-55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50-0.79) and progression-free survival (HR, 0.68; 95% CI, 0.56-0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%-98.4%), and the 3-year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune-mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively. CONCLUSIONS: Pembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD-L1-negative advanced/metastatic NSCLC, and it is a standard-of-care first-line therapy for patients with advanced NSCLC, regardless of PD-L1 expression. LAY SUMMARY: Some tumors produce a protein called programmed death ligand 1 (PD-L1), which interacts with the body's immune system and prevents an immune response against cancer. Antibody therapies such as pembrolizumab block interactions between tumor PD-L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non-small cell lung cancer (NSCLC) tumors that produce PD-L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD-L1 production. This article shows that among patients with NSCLC whose tumors produce no PD-L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort. METHODS: Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants. FINDINGS: As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6·8-40·7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12·0 months [95% CI 3·7 to not reached]); two patients remained on treatment at data cutoff. INTERPRETATION: Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation. FUNDING: Merck.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Artralgia/induzido quimicamente , Antígeno B7-H1/análise , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Mesotelioma/química , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Ensaios Clínicos Controlados não Aleatórios como Assunto , Neoplasias Pleurais/química , Critérios de Avaliação de Resposta em Tumores Sólidos , RetratamentoRESUMO
INTRODUCTION: Lung cancer is the leading cause of cancer-related death worldwide. It is usually diagnosed at advanced stage for which platinum-based chemotherapy had been the standard approach, although with limited clinical benefits. Discovery of oncogenic EGFR mutations in lung cancer have shifted the treatment paradigm with molecularly targeted therapies. AREAS COVERED: EGFR tyrosine kinase inhibitors (TKIs) have become the first-line choice in patients with advanced NSCLC harboring EGFR activating mutations. However, resistance to targeted therapy develops inevitably during the course of treatment. Multiple mechanisms of acquired resistance have been discovered, most commonly the secondary mutation of T790M in exon 20. The second- and third-generation EGFR TKIs are holding promise to overcome T790M-associated acquired resistance and currently being tested in clinical trials. In this article, we focus on the emerging approaches to overcome the different mechanisms of resistance to targeted therapies in patients with EGFR-mutant advanced NSCLC. EXPERT OPINION: It is essential to uncover the complex mechanisms underlying the progression of lung cancer after upfront EGFR TKIs. Next generation, in particular, the third generations of EGFR TKIs have been developed against acquired T790M mutation with promising clinical activity and better toxicity profile. Combination of targeted therapies has also been explored. Further studies are needed to detect the real-time changes of the resistance mechanisms and to develop new therapeutic strategies for lung cancer patients with EGFR mutations.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Introduction: We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials. Methods: This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome. Results: Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38â1.07] and 0.64 [95% CI: 0.42â0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50â1.08 and 0.86 [95% CI: 0.57â1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. Conclusions: These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.
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Aim: This study indirectly compared the effectiveness of pembrolizumab monotherapy versus nivolumab + ipilimumab in metastatic non-small-cell lung cancer. Materials and methods: A matching-adjusted indirect comparison was conducted using pooled individual patient data from KEYNOTE-024 and KEYNOTE-042 and published aggregate data from CheckMate 227 Part 1A, with platinum doublet chemotherapy as the anchor. Results: After matching, estimated hazard ratios (95% CI) of pembrolizumab monotherapy versus nivolumab + ipilimumab for overall survival and progression-free survival were 1.07 (0.82, 1.39) and 1.16 (0.93, 1.45), respectively. For objective response rate, the estimated risk ratio (95% CI) was 0.93 (0.71, 1.22) and the risk difference (95% CI) was -2.86%(-11.38, 5.67). Conclusion: Matching-adjusted indirect comparison results demonstrated comparable effectiveness between pembrolizumab monotherapy and nivolumab + ipilimumab as first-line therapies for metastatic non-small-cell lung cancer with PD-L1 tumor-proportion score ≥1%.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/patologia , Nivolumabe/uso terapêuticoRESUMO
Evidence from real-world clinical settings is lacking with regard to first-line immunotherapy plus chemotherapy for the treatment of non-small cell lung cancer (NSCLC). Our aim was to describe outcomes for patients treated with first-line pembrolizumab-combination therapy for metastatic nonsquamous NSCLC in US oncology practices. Using an anonymized, nationwide electronic health record-derived database, we identified patients who initiated pembrolizumab plus pemetrexed-carboplatin in the first-line setting (May 2017 to August 2018) after diagnosis of metastatic nonsquamous NSCLC that tested negative for EGFR and ALK genomic aberrations. Eligible patients had ECOG performance status of 0-1. An enhanced manual chart review was used to collect outcome information. Time-to-event analyses were performed using the Kaplan-Meier method. Of 283 eligible patients, 168 (59%) were male; median age was 66 years (range 33-84); and the proportions of patients with PD-L1 tumor proportion score (TPS) of ≥ 50%, 1-49%, < 1%, and unknown were 28%, 27%, 28%, and 17%, respectively. At data cutoff on August 31, 2019, median patient follow-up was 20.3 months (range 12-28 months), and median real-world times on treatment (rwToT) with pembrolizumab and pemetrexed were 5.6 (95% CI 4.5-6.4) and 2.8 months (95% CI 2.2-3.5), respectively. Median overall survival (OS) was 16.5 months (95% CI 13.2-20.6); estimated 12-month survival was 59.5% (95% CI 53.3-65.0); rwProgression-free survival was 6.4 months (95% CI 5.4-7.8); and rwTumor response rate (complete or partial response) was 56.5% (95% CI 50.5-62.4). Median OS was 20.6, 16.3, 13.2, and 13.7 months for patient cohorts with PD-L1 TPS ≥ 50%, 1-49%, < 1%, and unknown, respectively. These findings demonstrate the effectiveness of pembrolizumab plus pemetrexed-carboplatin by describing clinical outcomes among patients with metastatic nonsquamous NSCLC who were treated at US oncology practices.
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Adenocarcinoma de Pulmão/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Padrões de Prática Médica/estatística & dados numéricos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Estados UnidosRESUMO
OBJECTIVES: Multiple immunotherapy and chemotherapy combinations are approved for the management of advanced NSCLC which have not been directly compared in randomized clinical trials. This study indirectly compared the effectiveness of pembrolizumabâ¯+â¯chemotherapy versus atezolizumabâ¯+â¯chemotherapy+/-bevacizumab for previously untreated non-squamous NSCLC patients without EGFR/ALK aberrations. MATERIALS AND METHODS: A matching-adjusted indirect comparison (MAIC) was conducted using individual patient data (IPD) from KEYNOTE-021 Cohort G (KN021â¯G) (pembrolizumabâ¯+â¯carboplatinâ¯+â¯pemetrexed; Nâ¯=â¯59) and KEYNOTE-189 (KN189) (pembrolizumabâ¯+â¯pemetrexedâ¯+â¯platinum chemotherapy; Nâ¯=â¯410) and published aggregate data from IMpower 130 (atezolizumabâ¯+â¯carboplatinâ¯+â¯nab-paclitaxel; Nâ¯=â¯451) and IMpower 150 (atezolizumabâ¯+â¯carboplatinâ¯+â¯paclitaxelâ¯+â¯bevacizumab; Nâ¯=â¯356). To adjust for cross-trial differences in baseline characteristics, data from patients randomized to pembrolizumabâ¯+â¯chemotherapy in KN021â¯G/KN189 were reweighted to match the baseline characteristics of patients randomized to atezolizumabâ¯+â¯chemotherapy from IMpower 130 or atezolizumabâ¯+â¯chemotherapyâ¯+â¯bevacizumab from IMpower 150. Outcomes included overall survival (OS), blinded independent review-assessed progression-free survival (PFS) and objective response rate (ORR). OS and PFS follow-up were truncated to the trial with shorter follow-up. Sensitivity analyses were conducted without truncation of follow-up of OS and PFS. RESULTS: After matching for cross-trial differences, the effective sample size of pembrolizumabâ¯+â¯chemotherapy was 428 and 389 for the IMpower 130 and IMpower 150 comparisons, respectively. The estimated HRs (95 % CIs) of pembrolizumabâ¯+â¯chemotherapy versus atezolizumabâ¯+â¯chemotherapy were 0.80 (0.67,0.95) and 0.79 (0.67,0.93) with regard to OS and PFS, respectively. For pembrolizumabâ¯+â¯chemotherapy versus atezolizumabâ¯+â¯chemotherapyâ¯+â¯bevacizumab, the estimated HR (95 % CIs) was 0.86 (0.72,1.03) for OS and 0.81 (0.68,0.96) for PFS. For ORR, the estimated risk ratio (95 % CI) and the risk difference (95 % CI) was 0.9 (0.8,1.1) and -3.5 % (-10.0,3.1) for pembrolizumabâ¯+â¯chemotherapy versus atezolizumabâ¯+â¯chemotherapy, respectively, and 0.8 (0.7,0.9) and -12.2 % (-19.6,-4.8) for pembrolizumabâ¯+â¯chemotherapy versus atezolizumabâ¯+â¯chemotherapyâ¯+â¯bevacizumab, respectively. Findings were consistent across sensitivity analyses for both outcomes. CONCLUSION: MAIC results showed a significantly better OS and PFS for pembrolizumabâ¯+â¯chemotherapy compared with atezolizumabâ¯+â¯chemotherapy and a significantly better PFS for pembrolizumabâ¯+â¯chemotherapy compared with atezolizumabâ¯+â¯chemotherapyâ¯+â¯bevacizumab.
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Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carboplatina/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
PURPOSE: To compare and characterize overall survival (OS) differences between clinical trial data from the KEYNOTE-010 trial and real-world data (RWD) from the Flatiron Health database in patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer (NSCLC) who received second-line pembrolizumab monotherapy. METHODS: Clinical trial data were from the randomized phase II/III KEYNOTE-010 trial that enrolled patients from August 28, 2013, to February 27, 2015. At data cutoff for KEYNOTE-010, the median survival follow-up time for pembrolizumab patients was 11.2 months. RWD were from Flatiron Health advanced NSCLC database and included patients who initiated second-line pembrolizumab from January 26, 2015, to February 28, 2019. At data cutoff for Flatiron, the median survival follow-up time for pembrolizumab-treated patients was 6.1 months. Clinical trial data from KEYNOTE-010 and RWD from Flatiron were analyzed without adjustment, with propensity adjustment, and filtered per the main KEYNOTE-010 eligibility criteria (EC) of histologically/cytologically confirmed PD-L1-positive NSCLC, Eastern Cooperative Oncology Group performance status of 0/1, no prior therapy with docetaxel for NSCLC, and laboratory values indicative of adequate organ function in addition to prior line of therapy requirements. RESULTS: Among 243 patients from KEYNOTE-010 and 782 from Flatiron, median age was 63 v 68 years, and 64% v 54% were male, respectively. OS data from KEYNOTE-010 and Flatiron were similar without any adjustment (n = 782; hazard ratio [HR], 0.96; 95% CI, 0.80 to 1.15) and after both filtering and propensity adjustment (n = 221; HR, 0.99; 95% CI, 0.73 to 1.34). CONCLUSION: Without any adjustment, as well as after applying similar EC and appropriate statistical methods, RWD demonstrated similar effectiveness for pembrolizumab in second-line NSCLC as observed in randomized clinical trials.
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Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking. PATIENTS AND METHODS: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 µm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy. RESULTS: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days. CONCLUSIONS: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Azacitidina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Metilação de DNA , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Recidiva Local de Neoplasia , Resultado do TratamentoRESUMO
INTRODUCTION: We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)-positive non-small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. METHODS: We pooled data for patients with previously treated or untreated PD-L1âpositive (tumor proportion score [TPS], ≥1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases. RESULTS: A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1â43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS ≥50% (0.67 [95% confidence intervals (CI): 0.44â1.02] and 0.66 [95% CI: 0.58â0.76], respectively) and PD-L1 TPS ≥1% (0.83 [95% CI: 0.62â1.10] and 0.78 [95% CI: 0.71â0.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without. CONCLUSIONS: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1âpositive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.
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INTRODUCTION: This exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone. METHODS: We pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain. RESULTS: A total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1â35.1) and 11.0 (0.1â34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32â0.70] and 0.63 [95% CI: 0.53â0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31â0.62] and 0.55 [95% CI: 0.48â0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without. CONCLUSIONS: With or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.
Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Platina/uso terapêutico , Estudos RetrospectivosRESUMO
INTRODUCTION: In 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. METHODS: Patients 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. RESULTS: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0â77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44â0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61â0.80) 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 (â¼5 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. CONCLUSIONS: Pembrolizumab 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.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Docetaxel , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de NeoplasiaRESUMO
PURPOSE: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population. METHODS: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival. RESULTS: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo. CONCLUSION: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Método Duplo-Cego , Feminino , Humanos , Ipilimumab/farmacologia , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: In 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. METHODS: Patients 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. RESULTS: After 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: 0.35â0.83) 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: 0.45â1.12), despite a 70% crossover rate from chemotherapy alone to antiâprogrammed 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. CONCLUSIONS: First-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.
Assuntos
Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/uso terapêuticoRESUMO
INTRODUCTION AND DESIGN: The introduction of the epidermal growth factor receptor inhibitors (EGFR-I) has increased the treatment options available for patients with metastatic colorectal cancer (mCRC). Two EGFR-I agents currently approved for the treatment of mCRC are the fully human monoclonal antibody panitumumab and the mouse-human chimeric monoclonal antibody cetuximab. While these agents have demonstrated activity across multiple lines of therapy, early studies suggested that clinical benefit was confined to a subset of patients treated. Mutation of the KRAS oncogene has emerged as a powerful negative predictive biomarker to identify patients with mCRC who do not benefit from EGFR-I therapy. Multiple retrospective analyses have demonstrated that clinical benefit from treatment with EGFR-I is limited to patients with tumors harboring the wild-type KRAS gene. In this review, the KRAS pathway and studies evaluating KRAS as a prognostic marker in CRC are discussed along with advances in KRAS gene mutation testing. Clinical trials evaluating the role of KRAS status in response to EGFR-I monotherapy or in combination with chemotherapy are also highlighted along with ongoing studies evaluating the role of EGFR-I treatment on curative resections rates. RESULTS AND CONCLUSION: Future studies investigating EGFR-I therapy in mCRC should incorporate KRAS mutation testing into the study protocol in order to more accurately determine the patient population that will obtain clinical benefit from these novel agents.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Ensaios Clínicos como Assunto , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Receptores ErbB/metabolismo , Humanos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/metabolismoRESUMO
BACKGROUND: Recent studies have shown adjuvant therapy improves outcomes from pancreatic cancer (PC). This study investigates receipt and timing of PC treatments, and association with outcomes. METHODS: The analysis cohort consisted of patients with newly-diagnosed PC at a single institution over 5 years. Primary Endpoints were (i) receipt of recommended therapy, and (ii) overall survival (OS). RESULTS: Among 102 patients, 52 underwent resection. Out of 36 localized resected and 16 locally advanced resected (LAR) patients, 26 and 13, respectively, received adjuvant therapy. Six of the latter group received neoadjuvant therapy. Median OS for resected patients was 15.7 months (range 0.6-51.4), compared with 7.7 for unresected patients (range 0.4-32.0) (P < 0.001), and 14.0 months for patients with resection alone (range 0.6-24.4) vs. 16.1 for patients who also received adjuvant therapy (range 3.2-51.4) (P= 0.027). Out of 46 patients undergoing up-front resection, 33 had R0 surgical margins. For the six LAR patients undergoing neoadjuvant therapy, all margins were R0. CONCLUSION: After resection, a substantial proportion of patients do not receive adjuvant therapy, and have worse survival. In this study, neoadjuvant treatment increased both the proportion of patients receiving all components of recommended therapy and the R0 resection rate.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Terapia Neoadjuvante , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Cetuximab , Quimioterapia Adjuvante , Estudos de Coortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Complicações Pós-Operatórias , Radioterapia Adjuvante , GencitabinaRESUMO
BACKGROUND: Immune checkpoint inhibitors have been rapidly adopted for therapy of advanced non-small-cell lung cancer (aNSCLC) based on clinical trial findings. Our aim was to examine outcomes in United States oncology practice settings for patients prescribed pembrolizumab monotherapy for previously treated, programmed death ligand-1 (PD-L1)-expressing aNSCLC, thus clinically similar to patients in the KEYNOTE-010 trial. PATIENTS AND METHODS: This retrospective observational study used a nationally representative database to identify adult patients with histologically confirmed aNSCLC and PD-L1 tumor proportion score (TPS) ≥ 1% previously treated with platinum-containing chemotherapy (and appropriate tyrosine kinase inhibitor if nonsquamous aNSCLC with EGFR/ALK genomic tumor aberration). Eligible patients initiated pembrolizumab monotherapy from January 1, 2016, to November 29, 2018; data cutoff was May 31, 2019. The Kaplan-Meier method was used to estimate real-world time on treatment (rwToT) and overall survival (OS). RESULTS: The 349 eligible patients included 199 (57%) men; the median age was 68 years (range, 37-84 years); 70 (25%) of 278 patients with known performance status had Eastern Cooperative Oncology Group score ≥ 2. The median patient follow-up was 8.1 months (range, 1 day to 39.2 months). The median rwToT was 4.9 months (95% confidence interval [CI], 3.7-5.8 months) overall and 5.8 months (95% CI, 4.2-6.6 months) for the TPS ≥ 50% cohort (n = 218). The median OS was 13.8 months (95% CI, 11.0-16.5 months) and 16.5 months (95% CI, 13.7-22.0 months) overall and for TPS ≥ 50%, respectively; 12-month survival rates were 54% and 60%, respectively. CONCLUSION: Patients treated at oncology practices with pembrolizumab monotherapy for previously treated PD-L1-expressing aNSCLC experienced rwToT and OS similar to treatment duration and OS in phase III clinical trial settings.
Assuntos
Adenocarcinoma de Pulmão/mortalidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Terapia de Salvação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: In the absence of head-to-head trials, this study indirectly compared the effectiveness of pembrolizumab + chemotherapy vs nivolumab + ipilimumab for the first-line treatment of metastatic stage IV NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1%. METHODS: An anchored matching-adjusted indirect comparison (MAIC) was conducted using pooled individual patient data (IPD) from the ITT population in KEYNOTE-021G, KEYNOTE-189 and KEYNOTE-407 (n = 816) and published aggregate data of nivolumab + ipilimumab from CheckMate 227 Part 1A (n = 793). To adjust for cross-trial differences in baseline characteristics, data from KEYNOTE-021G/KEYNOTE-189/KEYNOTE-407 were re-weighted to match the baseline characteristics of CheckMate 227 Part 1A. Outcomes included OS, PFS and ORR. Base case analyses were restricted to patients with PD-L1 TPS ≥1%, with sub-group analyses in PD-L1 TPS ≥50% and 1-49%. RESULTS: The estimated HR (95% CI) of pembrolizumab + chemotherapy vs nivolumab + ipilimumab was 0.80 (0.59,1.09) and 0.53 (0.41,0.68) for OS and PFS, respectively. For ORR, the estimated risk ratio was 1.8 (1.3,2.4) for pembrolizumab + chemotherapy vs nivolumab + ipilimumab and the risk difference was 25.5% (15.0,36.0). PD-L1 TPS ≥50% and 1-49% sub-groups showed an OS HR of 0.89 (0.58,1.36) and 0.68 (0.46,1.01), respectively. CONCLUSION: These MAIC results suggest that pembrolizumab + chemotherapy leads to a greater clinical benefit vs nivolumab + ipilimumab in patients with PD-L1 TPS ≥1% across multiple endpoints.
RESUMO
PURPOSE: In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non-small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407. METHODS: Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided. RESULTS: A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125). CONCLUSION: Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.