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Pembrolizumab Misses Endpoints in Phase III Gastric Cancer Trial

Jason M. Broderick @jasoncology
Published: Friday, Dec 15, 2017

Dr. Roy Baynes
Roy Baynes, MD, PhD
Pembrolizumab (Keytruda) did not improve survival as a second-line treatment for PD-L1–positive patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from the phase III KEYNOTE-061 trial.

PD-L1–positivity was defined as a combined positive score ≥1.The hazard ratio for overall survival (OS) was 0.82 (95% CI, 0.66-1.03; one sided P = .042). Pembrolizumab also failed to demonstrate a statistically significant improvement in progression-free survival (PFS), according to Merck, the developer of the PD-1 inhibitor. 

The FDA granted pembrolizumab an accelerated approval in September 2017 for the treatment of patients with PD-L1–positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy. In a press release, Merck noted that at the current time, this approved indication “remains unchanged.”

“We want to thank the patients and investigators for their participation in this study and we look forward to sharing the full results from KEYNOTE-061, which will provide the medical community with important information about how patients with gastric cancer whose tumors express PD-L1 respond to treatment,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in the press release. 

The randomized, open-label phase III KEYNOTE-061 trial (NCT02370498) accrued 592 patients with advanced gastric or GEJ adenocarcinoma whose disease progressed after first-line treatment with platinum and fluoropyrimidine doublet therapy. Patients were randomized to single-agent pembrolizumab (200 mg fixed dose every 3 weeks) or paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle).

The primary endpoints were OS and PFS in PD-L1–positive patients. Secondary outcome measures included OS, PFS, and overall response rate (ORR) regardless of PD-L1 expression. In the press release, Merck noted that there were no new safety signals reported. 

The accelerated approval of pembrolizumab in gastric/GEJ adenocarcinoma was based on findings from the phase II KEYNOTE-059 study. In the study, 143 of 259 patients had PD–L1-positive tumors (combined positive score ≥1) and microsatellite stable tumor status or undetermined microsatellite instability or mismatch repair status. The ORR in these patients was 13.3% (95% CI, 8.2-20.0), including a complete response (CR) rate of 1.4% and a partial response (PR) rate of 11.9%.1

The duration of response among the 19 responding patients ranged from 2.8+ to 19.4+ months. Responses were 6 months or longer in 11 (58%) patients and 12 months or longer in 5 (26%) patients.

Full results from the KEYNOTE-059 trial were presented at the 2017 ASCO Annual Meeting.2 All 259 patients received pembrolizumab at a flat 200 mg dose every 3 weeks. The median age of patients was 62 years and 76.4% were male. The ECOG performance status for patients was primarily 0 (41.3%) and 1 (58.3%). Overall, 51.7% of patients had received 2 prior lines of therapy, and 29% and 19.3% had received 3 or ≥4 prior lines of therapy, respectively.

Across the entire study population, the ORR with pembrolizumab was 11.6%. In those who specifically received 2 prior lines of therapy, the ORR was 16.4%. The median PFS was 2.0 months and the median OS was 5.6 months, with a 12-month OS rate of 23.4%.

After a median follow-up of 5.8 months, 2.3% of patients had a CR and 9.3% had a PR. When including stable disease, the disease control rate was 27%. The median duration of response was 8.4 months.

Those treated in the third-line setting had a 3% CR rate and a 13.4% partial response rate. In the fourth-line and beyond, the ORR dropped to 6.4%, with a 1.6% CR rate. For those with PD-L1–positive tumors in the third-line setting (n = 75), the ORR was 22.7% with a 2.7% CR rate. In patients with PD-L1–negative tumors treated with third-line pembrolizumab (n = 58), the ORR was 8.6% with a 3.4% CR rate.

Among 7 patients with microsatellite instability-high (MSI-H) tumors, the ORR with pembrolizumab was 57.1% and the CR rate was 14.3%. The disease control rate was 71.4%. In those with non–MSI-H tumors (n = 167), the ORR was 9% and the CR rate was 2.4%. The disease control rate was 22.2%.

The most frequently occurring treatment-related adverse events (AEs) of all grades were fatigue (18.9%), pruritus (8.9%), rash (8.5%), hypothyroidism (7.7%), decreased appetite (7.3%), anemia (6.9%), nausea (6.9%), diarrhea (6.6%), and arthralgia (5.8%). There were 2 treatment-related grade 5 AEs (acute kidney injury and pleural effusion).

The accelerated approval of pembrolizumab for this indication is contingent on the results of a confirmatory trial. The ongoing phase III KEYNOTE-062 trial is evaluating pembrolizumab alone and in combination with chemotherapy in the frontline setting for PD-L1–positive advanced gastric or GEJ cancer, and the phase III KEYNOTE-585 trial is studying the combination of pembrolizumab and chemotherapy in the neoadjuvant and adjuvant settings.


  1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1). Merck. Accessed September 22, 2017.
  2. Fuchs CS, Doi T, Jang RW-J, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol. 2017;35 (suppl; abstr 4003).


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