Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial

Summary

Background

Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.

Methods

This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.

Findings

Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.

Interpretation

Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.

Funding

Merck Sharp & Dohme, a subsidiary of Merck & Co.

Introduction

Gastric cancer is the fifth most common cancer and is the third most common cause of cancer mortality worldwide.¹ Chemotherapy with a platinum and fluoropyrimidine is the recommended first-line therapy for patients with advanced or metastatic gastric or gastrooesophageal junction cancer who have good performance status; patients who have human epidermal growth factor 2 (HER2)-positive tumours should also receive trastuzumab.2, 3, 4, 5, 6 In the second-line setting, treatment options include cytotoxic chemotherapy with docetaxel, paclitaxel, or irinotecan and the vascular endothelial growth factor 2 (VEGFR2) monoclonal antibody ramucirumab given as either monotherapy or in combination with paclitaxel.

In recent years, immunotherapy with immune checkpoint inhibitors has revolutionised the treatment of advanced cancer. One such checkpoint is programmed death 1 (PD-1), which is a negative costimulatory receptor expressed mainly on activated T cells.⁷ In tumour cells, inhibition of PD-1 prevents PD-1 from binding to its ligands, PD-1 ligand 1 (PD-L1) and PD-1 ligand 2 (PD-L2), thus restoring antitumour immunity. Overexpression of PD-L1 has been observed in gastric cancer,⁸ making PD-1 pathway inhibition a rational target in patients with gastric or gastro-oesophageal junction cancer.

Research in context

Evidence before this study

We searched PubMed on Feb 10, 2018, with the terms “PD-1 OR PD-L1 OR MK-3475 OR pembrolizumab OR Keytruda OR BMS-936558 OR nivolumab OR Opdivo OR MPDL3280A OR atezolizumab OR Tecentriq OR MEDI4736 OR durvalumab OR Imfinzi OR MSB0010718C OR avelumab OR Bavencio” AND “gastric cancer OR gastroesophageal junction cancer.” No limits were applied to the search. We also searched the abstracts from the 2017 and 2018 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, the 2016 and 2017 American Society of Clinical Oncology Annual Meeting, the 2016 and 2017 World Congress of Gastrointestinal Cancer, and the 2016 and 2017 European Society for Medical Oncology Congress using the same terms to identify results of any clinical trials that were not yet published in the peer-reviewed scientific literature. We identified one randomised phase 3 trial of anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy for advanced gastric or gastro-oesophageal junction cancer, the ATTRACTION-2 study of nivolumab versus placebo as third-line or later therapy. We also identified phase 1 and phase 2 studies of anti-PD-1 or anti-PD-L1 monotherapy for advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-012 and KEYNOTE-059 studies of pembrolizumab and the JAVELIN study of avelumab). In three additional phase 1 and phase 2 studies of anti-PD-1 or anti-PD-L1 combination therapy, pembrolizumab was tested in combination with a platinum and fluoropyrimidine (KEYNOTE-059), ramucirumab (JVDF), or margetuximab, nivolumab was tested in combination with ipilimumab (CheckMate 032), and durvalumab was tested in combination with ramucirumab. We focused on the studies of anti-PD-1 or anti-PD-L1 monotherapy.

Added value of this study

This is the first report of data from a randomised trial of anti-PD-1 or anti-PD-L1 therapy as second-line therapy for advanced gastric cancer and the first report of data from a randomised trial of anti-PD-1 or anti-PD-L1 therapy to include an active comparator. Although the prespecified boundary for detecting a statistically significant improvement in overall survival with pembrolizumab versus paclitaxel in patients with PD-L1-expressing tumours was not reached, the results of the protocol-specified exploratory subgroup analysis suggest that pembrolizumab might have antitumour activity in patients with a good Eastern Cooperative Oncology Group performance status. Data from post-hoc analyses suggest that pembrolizumab also has antitumour activity in patients whose tumours had higher levels of PD-L1 expression or high levels of microsatellite instability. The findings show that pembrolizumab has a favourable safety profile compared with paclitaxel, with patients treated with pembrolizumab having fewer adverse events attributed to study treatment that were high-grade or led to treatment discontinuation.

Implications of all the available evidence

Anti-PD-1 and anti-PD-L1 therapies appear to have antitumour activity in select patients with advanced gastric or gastro-oesophageal cancer, as well as a favourable safety profile. The greatest relative benefit for these therapies, when given as monotherapy, might be in the setting of third-line therapy and beyond in patients with a PD-L1 combined positive score of 1 or higher (approved by the US Food and Drug Administration) and as second-line therapy in patients with good performance status or patients whose tumours show high levels of microsatellite instability or higher levels of PD-L1 expression. These hypothesis-generating results suggest that prospective, controlled assessments of these subgroups are of value. Data from phase 1 and phase 2 studies suggest that combination regimens that include anti-PD-1 and anti-PD-L1 therapies are worthy of further assessment, particularly in early lines of therapy for advanced disease or earlier stages of disease.

Pembrolizumab is a humanised, high-affinity, IgG4-κ monoclonal antibody that binds to PD-1, preventing the interaction of PD-1 with PD-L1 and PD-L2. In the phase 2 KEYNOTE-059 study,⁹ pembrolizumab had antitumour activity and a manageable safety profile in patients with previously treated gastric cancer who received pembrolizumab monotherapy at a fixed dose of 200 mg on day 1 of each 3-week cycle. Patients with advanced gastric cancer that progressed on two or more lines of previous therapy had a response rate of 11·6%; the response rate in patients with a PD-L1 combined positive score (CPS) of 1 or more was 15·5% in those who received pembrolizumab as third-line or later therapy and 22·7% in those who received pembrolizumab as third-line therapy. On the basis of the observed response rate and the durability of response, the US Food and Drug Administration (FDA) granted accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma that expresses PD-L1 (CPS ≥1) and progressed on or after two or more previous lines of therapy including platinum-containing and fluoropyrimidine-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.

Here we present results of the KEYNOTE-061 study of pembrolizumab compared with paclitaxel as second-line therapy in patients with advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma.