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.

Pembrolizumab 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%. This 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. If 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%.

Kogure Y ，Hashimoto H ，Oki M 《-》

Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: A pooled analysis of 3 randomized controlled trials.

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%). 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. 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. 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. 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.

Borghaei H ，Langer CJ ，Paz-Ares L ，Rodríguez-Abreu D ，Halmos B ，Garassino MC ，Houghton B ，Kurata T ，Cheng Y ，Lin J ，Pietanza MC ，Piperdi B ，Gadgeel SM ... -  《-》

Cost-efficiency and budget-neutral expanded access modeling of pembrolizumab versus the novel PD-1 inhibitor toripalimab in locally advanced or metastatic nonsquamous non-small cell lung cancer.

MacDonald K ，Pondel M ，Abraham I 《-》

Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study.

In the global KEYNOTE-042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD-L1)-positive locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE-042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD-L1 tumor proportion score [TPS] ≥50% vs 1%-49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty-two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow-up, 33.0 [range, 25.6-41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD-L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43-0.94]), TPS ≥20% (0.66 [0.47-0.92]) and TPS ≥1% (0.67 [0.50-0.89]). Grade 3 to 5 treatment-related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE-042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD-L1 TPS ≥1%, supporting first-line pembrolizumab monotherapy for PD-L1-positive advanced/metastatic NSCLC in China.

Wu YL ，Zhang L ，Fan Y ，Zhou J ，Zhang L ，Zhou Q ，Li W ，Hu C ，Chen G ，Zhang X ，Zhou C ，Dang T ，Sadowski S ，Kush DA ，Zhou Y ，Li B ，Mok T ... -  《-》

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Shiraishi Y ，Kishimoto J ，Sugawara S ，Mizutani H ，Daga H ，Azuma K ，Matsumoto H ，Hataji O ，Nishino K ，Mori M ，Shukuya T ，Saito H ，Tachihara M ，Hayashi H ，Tsuya A ，Wakuda K ，Yanagitani N ，Sakamoto T ，Miura S ，Hata A ，Okada M ，Kozuki T ，Sato Y ，Harada T ，Takayama K ，Yamamoto N ，Nakagawa K ，Okamoto I ... -  《-》