First-Line Pembrolizumab Plus Chemo Wins Canadian Approval for HER2– Advanced Gastric/GEJ Adenocarcinoma

Health Canada has approved pembrolizumab (Keytruda) in combination with fluoropyrimidine- and platinum-containing-chemotherapy for the first-line treatment of adult patients with locally advanced, unresectable, or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The regulatory decision was supported by data from the phase 3 KEYNOTE-859 trial (NCT03675737), which demonstrated that pembrolizumab plus chemotherapy reduced the risk of death by 22% compared with chemotherapy plus placebo (HR, 0.78; 95% CI, 0.70-0.87; P <.0001). Patients in the pembrolizumab arm (n = 790) experienced a median overall survival (OS) of 12.9 months (95% CI, 11.9-14.0) compared with 11.5 months (95% CI, 10.6-12.1) for patients in the placebo arm (n = 789). The 12- and 24-month OS rates for pembrolizumab plus chemotherapy were 52.7% and 28.2%, respectively. Those respective rates were 46.7% and 18.9% for chemotherapy plus placebo.²

“We are proud of the recent expansion of [pembrolizumab’s] indications in gastric cancers, which often go undetected until an advanced stage, at which point patients face a poor prognosis,” André Galarneau, PhD, executive Director and vice president of the Oncology Business Unit at Merck Canada, stated in a news release.¹ “This milestone underscores our commitment to helping improve the lives of patients by offering treatment options that can lead to better health outcomes.”

In November 2023, the FDA approved pembrolizumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced, unresectable, or metastatic, HER2-negative gastric or GEJ adenocarcinoma.³ In December 2023, the European Commission approved the regimen in the same indication, although patients in the European Union are also required to have a PD-L1 combined positive score (CPS) of at least 1.⁴

Those approvals were also supported by findings from KEYNOTE-859, which was a randomized, double-blind study that enrolled patients with histologically or cytologically confirmed, locally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma. No prior treatment was permitted. PD-L1 status was assessed centrally, and patients needed to have HER2-negative disease, which was assessed locally. An ECOG performance status of 0 or 1 was also required.²

Patients were randomly assigned 1:1 to receive 200 mg of intravenous pembrolizumab or placebo once every 3 weeks for up to 35 cycles (approximately 2 years) in combination with chemotherapy, which consisted of 5-fluorouracil at 800 mg/m2 per day on days 1 to 5 every 3 weeks plus cisplatin at 80 mg/m2 once every 3 weeks (FP); or capecitabine (Xeloda) at 1000 mg/m2 twice daily on days 1 to 14 of every 3-week cycle plus oxaliplatin at 130 mg/m2 once every 3 weeks (CAPOX).

Stratification factors included geographic region (Europe/Israel/North America/Australia vs Asia vs rest of the world), PD-L1 CPS (<1 vs ≥1), and chemotherapy choice (FP vs CAPOX).

OS served as the trial’s primary end point, and secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and safety.

Additional data showed patients treated with pembrolizumab plus chemotherapy experienced a median PFS of 6.9 months (95% CI, 6.3-7.2) compared with 5.6 months (95% CI, 5.5-5.7) for placebo plus chemotherapy (HR, 0.76; 95% CI, 0.67-0.85; P <.0001). The 12-month PFS rates were 28.9% for the pembrolizumab arm and 19.3% for the placebo arm. The respective 24-month PFS rates were 17.8% and 9.4%.

Pembrolizumab plus chemotherapy elicited an ORR of 51.3% (95% CI, 47.7%-54.8%), including a complete response (CR) rate of 9.5% and a partial response (PR) rate of 41.8%, compared with an ORR of 42.0% (95% CI, 38.5%-45.5%) for placebo plus chemotherapy (difference, 9.3%; 95% CI, 4.4%-14.1%; P = .00009). The CR and PR rates for the placebo arm were 6.2% and 35.7%, respectively.

The median DOR was 8.0 months (range, 1.2+ to 41.5+) for the pembrolizumab arm vs 5.7 months (range, 1.3+ to 34.7+) for the placebo arm.

The most common any-grade treatment-related adverse effects (TRAEs) for the pembrolizumab arm and the placebo arm, respectively, included nausea (41.4% vs 41.4%), diarrhea (32.1% vs 27.2%), anemia (31.0% vs 26.9%), vomiting (27.4% vs 22.2%), decreased platelet count (25.0% vs 22.5%), decreased neutrophil count (24.6% vs 21.6%), palmar-plantar erythrodysesthesia syndrome (24.1% vs 21.1%), decreased appetite (21.4% vs 21.3%), fatigue (20.0% vs 20.8%), peripheral neuropathy (19.1% vs 20.8%), neutropenia (18.1% vs 17.2%), increased aspartate aminotransferase (17.7% vs 13.0%), and peripheral sensory neuropathy (17.5% vs 16.6%).

Additionally, grade 3 to 5 TRAEs were reported in 59.4% (n = 466) of patients who received pembrolizumab vs 51.1% (n = 402) of those who received placebo. Serious AEs occurred in 23.4% (n = 184) and 18.6% (n = 146) of patients in the pembrolizumab and placebo arms, respectively.

Immune-mediated AEs were more common in the pembrolizumab arm vs the placebo arm (any grade, 27.1%; grade ≥3, 7.9%; vs any grade, 9.3%; grade ≥3, 1.7%). Additionally, TRAEs led to treatment discontinuation in 26.4% of patients who received pembrolizumab vs 20.1% of those who received placebo. TRAEs led to death in 8 patients (1.0%) with pembrolizumab plus chemotherapy vs 16 patients (2.0%) with chemotherapy plus placebo.

References

1. Health Canada approves Keytruda as a first-line treatment for adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy. News release. Merck Canada. April 19, 2024. Accessed April 19, 2024. https://www.merck.ca/en/newsroom/health-canada-approves-keytruda-as-a-first-line-treatment/
2. Rha SY, Wyrwicz LS, Weber Y, et al. Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: phase 3 KEYNOTE-859 study. Ann Oncol. 2023;34(3):319-320. doi:10.1016/j.annonc.2023.01.006
3. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. FDA. November 16, 2023. Accessed April 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-her2-negative-gastric-or-gastroesophageal-junction
4. European Commission approves Merck’s Keytruda (pembrolizumab) plus chemotherapy for new first-line indications in advanced HER2-negative gastric or GEJ adenocarcinoma in tumors expressing PD-L1 (CPS ≥1) and advanced biliary tract cancer. News release. Merck. December 18, 2023. Accessed April 19, 2024. https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-for-new-first-line-indications-in-advanced-her2-negative-gastric-or-gej-adenocarcinoma-in-tumors-expressin/