Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled
Pembrolizumab plus pemetrexed-platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed-platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189.
In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1-5, every three cycles thereafter during year 1, and every four cycles during years 2-3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680.
Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2-20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed-platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed-platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed-platinum group and 180 (90%) of 200 in the placebo plus pemetrexed-platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1·0 point [95% CI -1·3 to 3·2] increase) and placebo plus pemetrexed-platinum (-2·6 points [-5·8 to 0·5] decrease; between-group difference: 3·6 points [-0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1·3 points [95% CI -1·2 to 3·6] increase) than with placebo plus pemetrexed-platinum (-4·0 points [-7·7 to -0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed-platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed-platinum (hazard ratio 0·81 [95% CI 0·60-1·09], p=0·16).
The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed-platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer.
Merck Sharp & Dohme.
Garassino MC
，Gadgeel S
，Esteban E
，Felip E
，Speranza G
，Domine M
，Hochmair MJ
，Powell S
，Cheng SY
，Bischoff HG
，Peled N
，Reck M
，Hui R
，Garon EB
，Boyer M
，Wei Z
，Burke T
，Pietanza MC
，Rodríguez-Abreu D
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Pembrolizumab Plus Chemotherapy for Metastatic NSCLC With Programmed Cell Death Ligand 1 Tumor Proportion Score Less Than 1%: Pooled Analysis of Outcomes After Five Years of Follow-Up.
We report long-term outcomes from a pooled analysis of patients with previously untreated metastatic NSCLC with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) less than 1% enrolled in phase III studies of pembrolizumab plus chemotherapy versus placebo plus chemotherapy.
This exploratory pooled analysis included individual patient data from the KEYNOTE-189 global (NCT02578680) and Japan extension (NCT03950674) studies of metastatic nonsquamous NSCLC without EGFR or ALK alterations and the KEYNOTE-407 global (NCT02775435) and People's Republic of China extension (NCT03875092) studies of metastatic squamous NSCLC. Patients received pembrolizumab or placebo plus pemetrexed and cisplatin or carboplatin in KEYNOTE-189 and pembrolizumab or placebo plus carboplatin and paclitaxel or nab-paclitaxel in KEYNOTE-407. PD-L1 TPS was centrally assessed using PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA).
Overall, 442 patients were included in this analysis (pembrolizumab plus chemotherapy, n = 255; chemotherapy, n = 187). The median follow-up was 60.7 (range, 49.9‒72.0) months. Pembrolizumab plus chemotherapy improved overall survival (hazard ratio, 0.64; 95% confidence interval [CI]: 0.51‒0.79) and progression-free survival (hazard ratio, 0.66; 95% CI: 0.54‒0.81) versus chemotherapy. The 5-year overall survival rates (95% CI) were 12.5% (8.6%‒17.3%) versus 9.3% (5.6%‒14.1%). Grades 3 to 5 treatment-related adverse events occurred in 59.1% of patients for pembrolizumab plus chemotherapy and 61.3% for chemotherapy.
With approximately 5 years of follow-up, pembrolizumab plus chemotherapy provided clinically meaningful and durable improvements in survival outcomes versus chemotherapy alone in patients with previously untreated metastatic NSCLC with PD-L1 TPS less than 1%. These results continue to support pembrolizumab plus chemotherapy as a standard of care in this patient population.
gov, NCT02578680 (KEYNOTE-189 global), NCT03950674 (KEYNOTE-189 Japan extension), NCT02775435 (KEYNOTE-407 global), NCT03875092 (KEYNOTE-407 People's Republic of China extension).
Gadgeel SM
，Rodríguez-Abreu D
，Halmos B
，Garassino MC
，Kurata T
，Cheng Y
，Jensen E
，Shamoun M
，Rajagopalan K
，Paz-Ares L
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ResearchGate
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