Abstract
Background: The premise that chemotherapy and immunotherapy may provide greater benefit than pembro or chemotherapy alone was supported by KEYNOTE-021 cohort G, in which pembro + pem + ...carboplatin significantly improved ORR and PFS over pem + carboplatin in patients (pts) with advanced nonsquamous NSCLC. We present results of the KEYNOTE-189 study of pembro + pem-platinum vs placebo + pem-platinum as first-line therapy for metastatic nonsquamous NSCLC.
Methods: Pts with previously untreated stage IV nonsquamous NSCLC, no EGFR or ALK alteration, and ECOG PS 0-1 were randomized 2:1 to 4 Q3W cycles of pembro 200 mg or placebo + pem 500 mg/m2 + carboplatin AUC 5 or cisplatin 75 mg/m2 followed by maintenance pembro or placebo + pem. Randomization was stratified by PD-L1 tumor proportion score (TPS; <1% vs ≥1%), platinum agent, and smoking status. Response was assessed by RECIST v1.1 per blinded, independent central review. Pts in the placebo arm with verified PD could crossover to pembro monotherapy if eligible. Primary end points were OS and PFS in the ITT population. Prespecified superiority boundaries at the first interim analysis were one-sided P = .00128 for OS and .00559 for PFS.
Results: 616 pts were randomized: 410 to pembro + pem + platinum (“pembro arm”), 206 to placebo + pem + platinum (“placebo arm”). 76.5% of treated pts in the pembro arm and 66.8% in the placebo arm received ≥5 cycles of pem. 88.1% of enrolled pts were current/former smokers, carboplatin was chosen for 72.2%, and 63.0% had TPS ≥1%. As of Nov 8, 2017, median follow-up was 10.5 mo (range 0.2-20.4), and 33.8% in the pembro arm vs 17.8% in the placebo arm remained on treatment. In the placebo arm, 67 pts crossed over in-study to pembro and 18 received anti-PD-(L)1 therapy outside the study (effective crossover rate: 41.3% in the ITT population, 50.0% when pts still on treatment excluded). Pembro + pem + platinum, improved OS (HR 0.49; 95% CI 0.38-0.64; P < .00001) and PFS (HR 0.52; 95% CI 0.43-0.64; P < .00001) over placebo + pem + platinum. Median OS was not reached with pembro and was 11.3 mo with placebo. Median PFS was 8.8 mo vs 4.9 mo. OS benefit in the pembro arm was observed across subgroups, including all PD-L1 TPS categories (HR 95% CI 0.59 0.38-0.92 for <1%, 0.55 0.34-0.90 for 1-49%, and 0.42 0.26-0.68 for ≥50%). ORR was higher with pembro (47.6% vs 18.9%; P < .00001). Grade ≥3 AEs occurred in 67.2% of pts in the pembro arm vs 65.8% in the placebo arm; AEs led to discontinuation of any treatment in 27.7% vs 14.9%, all treatment in 13.8% vs 7.9%, and death in 6.7% vs 5.9%.
Conclusions: Pembro + pem + platinum provided superior OS, PFS, and ORR compared with placebo + pem + platinum and had a manageable safety profile in pts with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK alterations. These data suggest first-line pembro + pem and platinum may be a new standard of care for this population.
Citation Format: Leena Gandhi, Delvys Rodgríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven Powell, Susanna Yee-Shan Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John J Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M. Catherine Pietanza, Marina C Garassino. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT075.
The development of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) checkpoint inhibitors has changed the landscape of non-small-cell lung cancer (NSCLC) therapy, with 2 approvals from the US ...Food and Drug Administration of PD-1 inhibitors for second-line therapy. However, the rational use of these agents has been limited by the lack of a definitive predictive biomarker.
Tumor PD-L1 expression is associated with an increased likelihood of NSCLC response to these agents, although responses can still occur at a low rate in PD-L1-negative tumors. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited by the multitude of PD-L1 antibodies, assays, scoring systems, and thresholds for positivity currently used. Alternative biomarkers such as tumor neoantigens identified through whole-exome sequencing and clinical parameters (eg, smoking or oncogene driver status) may also have predictive value. Biomarkers that can direct the rational use of PD-1/PD-L1 checkpoint inhibitors are crucial given the risk of life-threatening immune-related complications associated with these therapies and the reality that most patients still do not benefit from their use.
The refinement of existing biomarkers and identification of novel predictive biomarkers will be key to ensuring the effective and safe use of these agents. Since most patients still do not benefit from these agents, it is critical to continue to work to define the select patient population who will derive durable benefit from PD-1/PD-L1 inhibition and identify markers that could have predictive value for combination therapies that could expand the population who benefit.
Telomerase is a eukaryotic reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. We describe here the ...identification of a Tetrahymena telomerase protein with reverse transcriptase motifs, p133. This subunit is associated with the previously identified Tetrahymena telomerase RNA and the telomerase proteins p80 and p95 in immunoprecipitation assays. Therefore, all four known Tetrahymena telomerase components are present in a single complex. Expressed in rabbit reticulocyte lysate, recombinant p133 and telomerase RNA alone catalyze a reverse transcriptase activity with some similarities to and some differences from native Tetrahymena telomerase. These experiments suggest a complexity of telomerase structure and function.
Collagen XXIII is a transmembrane collagen previously shown to be upregulated in metastatic prostate cancer. The purpose of this study was to determine the protein expression of collagen XXIII in ...tumor tissues from a variety of cancers and to assess the utility of collagen XXIII as a biomarker for non-small cell lung cancer (NSCLC).
A multicancer tissue microarray was used for the immunohistochemical examination of collagen XXIII protein expression in a variety of cancers. Subsequently, collagen XXIII expression was analyzed in three separate cohorts using tissue microarrays with representative tumor and control lung tissues from NSCLC patients. In addition, NSCLC patient urine samples were analyzed for the presence of collagen XXIII through Western blot.
Collagen XXIII was present in tissue samples from a variety of cancers. Within lung cancer tissues, collagen XXIII staining was enriched in NSCLC subtypes. Collagen XXIII was present in 294 of 333 (88%) lung adenocarcinomas and 97 of 133 (73%) squamous cell carcinomas. In urine, collagen XXIII was present in 23 of 29 (79%) NSCLC patient samples but only in 15 of 54 (28%) control samples. High collagen XXIII staining intensity correlated with shorter recurrence-free survival in NSCLC patients.
We show the capability of collagen XXIII as a tissue and urinary biomarker for NSCLC, in which positivity in tissue or urine significantly correlates with the presence of NSCLC and high staining intensity is a significant recurrence predictor.
Inclusion of collagen XXIII in a tissue- or urine-based cancer biomarker panel could inform NSCLC patient treatment decisions.
The addition of pembrolizumab to chemotherapy for metastatic lung cancer without
EGFR
or
ALK
mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related ...adverse effects were more common with the combination.
SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic ...profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and ...generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial.
Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle.
Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis.
Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.
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