Pembrolizumab/Chemo Combo Misses OS Endpoint in Advanced Gastric/GEJ Cancer

The combination of pembrolizumab (Keytruda) and chemotherapy did not improve overall survival (OS) or progression-free survival (PFS) compared with standard chemotherapy alone for the frontline treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to topline findings of the phase III KEYNOTE-062 trial.¹

The lack of survival benefit was observed in patients with PD-L1 (combined positive score [CPS] ≥1 or ≥10).

However, in an arm evaluating pembrolizumab monotherapy, the PD-1 inhibitor met the primary endpoint of OS in the entire intent-to-treat (ITT) population of patients whose tumors express PD-L1 (CPS ≥1) compared with chemotherapy, which consisted of cisplatin and either 5-fluorouracil or capecitabine.

Additionally, Merck, the manufacturer of pembrolizumab, noted in a press release that the safety profile of the PD-1 inhibitor was consistent with what has been previously observed in gastric cancer. Full findings of the study will be presented at the 2019 ASCO Annual Meeting and will be discussed with regulatory agencies.

“Gastric cancer is historically difficult to treat, and unfortunately continues to be associated with high mortality rates in many countries, particularly in the metastatic stage,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Keytruda monotherapy did show noninferior overall survival in the total patient population, though the study did not meet all of its primary endpoints. We sincerely thank the patients and investigators for their involvement in KEYNOTE-062 and look forward to sharing detailed study results with the medical community.”

KEYNOTE-062 is the confirmatory trial for the FDA’s accelerated approval of pembrolizumab in September 2017 as a third-line treatment for previously treated patients with recurrent locally advanced or metastatic gastric/GEJ cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after ≥2 prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

The approval was based on findings from the phase II KEYNOTE-059 study. In the study, 143 of 259 patients had PD—L1-positive tumors (CPS ≥1) and microsatellite stable tumor status or undetermined microsatellite instability (MSI) or mismatch repair status. Results showed that the overall response rate (ORR) in this subgroup was 13.3% (95% CI, 8.2-20.0), which included a complete response (CR) rate of 1.4% and a partial response (PR) rate of 11.9%.²

The duration of response among the 19 responding patients ranged from 2.8+ to 19.4+ months; however, responses were ≥6 months in 11 (58%) patients and ≥12 months in 5 (26%) patients.

Full results from the KEYNOTE-059 study were presented at the 2017 ASCO Annual Meeting.³ 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%, and was 16.4% on those who specifically received 2 prior lines of therapy. 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%. Also, the median duration of response was 8.4 months.

Patients who were treated in the third-line setting had a 3% CR rate and a 13.4% PR rate. In the fourth-line setting and beyond, the ORR was 6.4% and the CR rate was 1.6%. 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 MSI-high (MSI-H) tumors, the ORR with pembrolizumab was 57.1%, the CR rate was 14.3%, and the disease control rate was 71.4%. In those with non—MSI-H tumors (n = 167), the ORR was 9%, the CR rate was 2.4%, and the disease control rate was 22.2%.

Regarding safety, the most frequently occurring, all-grade treatment-related adverse events (AEs) 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%). Two treatment-related grade 5 AEs (acute kidney injury and pleural effusion) occurred.

Pembrolizumab is being evaluated in the first-line setting of gastric cancer in other ongoing clinical trials, including KEYNOTE-811 (NCT03615326), KEYNOTE-859 (NCT03675737), and KEYNOTE-585 (NCT03221426).

References

1. Merck Provides Update on Phase 3 KEYNOTE-062 Trial Evaluating KEYTRUDA (pembrolizumab) as Monotherapy and in Combination with Chemotherapy for First-Line Treatment of Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. Merck. Published April 25, 2019. https://bit.ly/2IXZtwG. Accessed April 25, 2019.
2. 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. http://bit.ly/2wberGs. Accessed September 22, 2017.
3. 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).