European Commission Approves New Frontline Indications for Pembrolizumab Plus Chemo in Select GI Cancers

The European Commission has approved pembrolizumab (Keytruda) in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma and a PD-L1 combined positive score (CPS) of at least 1, as well as in combination with gemcitabine/cisplatin for first-line use in patients with locally advanced unresectable or metastatic biliary tract carcinoma.¹

The regulatory decisions are based on overall survival (OS) findings from the phase 3 KEYNOTE-859 (NCT03675737) and KEYNOTE-966 (NCT04003636) trials, respectively.

In the overall KEYNOTE-859 population, the combination of pembrolizumab plus investigator’s choice of 5-fluorouracil (5-FU) and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX; n = 790) resulted in a median OS of 12.9 months (95% CI, 11.9-14.0) vs 11.5 months (95% CI, 10.6-12.1) with placebo plus FP or CAPOX (n = 789), translating to a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.70-0.87; P < .0001).² In the subset of patients with a CPS of at least 1, the median OS with pembrolizumab/chemotherapy (n = 618) was 13.0 months (95% CI, 11.6-14.2) vs 11.4 months (95% CI, 10.5-12.0) with placebo/chemotherapy (n = 617), translating to a 26% reduction in the risk of death (HR, 0.74; 95% CI, 0.65-0.84; P < .0001).

In KEYNOTE-966, pembrolizumab plus gemcitabine and cisplatin (n = 533) resulted in a median OS of 12.7 months (95% CI, 11.5-13.6) vs 10.9 months (95% CI, 9.9-11.6) with placebo plus gemcitabine and cisplatin (n = 536), translating to a 17% reduction in the risk of death (HR, 0.83; 95% CI, 0.72-0.95; 1-sided P = .0034).

“[Pembrolizumab] has shown its potential as an important treatment option in the European Union across a number of gastrointestinal cancers, with 7 indications based on data from our extensive clinical development program,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development at Merck Research Laboratories, stated in a press release.¹ “With these 2 new approvals of [pembrolizumab]-based regimens in advanced HER2-negative gastric and GEJ cancer and advanced biliary tract cancer, Merck continues to demonstrate progress in providing treatment options to patients in Europe.”

KEYNOTE-859: Eligibility Criteria, Treatment, Additional Data

The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic treatment in the metastatic setting.² To participate, they could not have an autoimmune disease in need of systemic therapy within 2 years of treatment nor could they have a medical condition in need of immunosuppression.

Study participants were randomly 1:1 to receive placebo or pembrolizumab at 200 mg plus investigator’s choice of cisplatin at 80 mg/m² and 5-FU at 800 mg/m²/day for 5 days or oxaliplatin at 130 mg/m² and capecitabine at 1000 mg/m² twice daily for 14 days. Key stratification factors included PD-L1 expression (CPS ≥1 vs CPS <1), chemotherapy (FP vs CAPOX), and geographic region (Europe/Israel/North America/Australia vs Asia vs rest of the world).

In addition to OS serving as the major efficacy outcome, secondary outcome measures included progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) per blinded independent central review (BICR) and RECIST v1.1 criteria.

The median patient age was 62 years (range, 21-86), with 39% of patients aged 65 years or older. Most patients were male (68%) and a little more than half were White (55%). In terms of ECOG performance status, 37% had a status of 0, and 63% had a status of 1. The majority had metastatic disease (97%). Seventy-eight percent of patients had a PD-L1 CPS of 1 or higher and 5% had microsatellite instability–high disease. In terms of choice of chemotherapy, 86% received CAPOX.

Additional data showed that in the overall population, the median PFS with pembrolizumab plus chemotherapy was 6.9 months (95% CI, 6.3-7.2) vs 5.6 months (95% CI, 5.5-5.7) with placebo/chemotherapy (HR, 0.76; 95% CI, 0.67-0.85; P < .0001). Those in the pembrolizumab arm experienced an ORR of 51% (95% CI, 48%-55%) vs 42% (95% CI, 38%-45%) in the placebo arm. The median DORs were 8.0 months (95% CI, 7.0-9.7) and 5.7 months (95% CI, 5.5-6.9), respectively.

In the subset of patients with a PD-L1 CPS of 1 or higher, the median PFS in the pembrolizumab and placebo arms was 6.9 months (95% CI, 6.0-7.2) and 5.6 months (95% CI, 5.4-5.7), respectively (HR, 0.72; 95% CI, 0.63-0.82; P < .0001). The ORRs in these groups were 52% (95% CI, 48%-56%) and 43% (95% CI, 39%47%), respectively (P = .0004). The median DOR with pembrolizumab was 8.3 months (95% CI, 7.0-10.9) and 5.6 months (95% CI, 5.4-6.9), respectively.

KEYNOTE-966: Eligibility Criteria, Treatment, Additional Data

The multicenter, double-blind, placebo-controlled trial included a total of 1069 patients with locally advanced unresectable or metastatic biliary tract cancer without previous exposure to systemic treatment for advanced disease. Those with a medical condition requiring immunosuppression were excluded, as were those with autoimmune disease in need of systemic therapy within 2 years of treatment.

Patients were randomly assigned in a 1:1 fashion to placebo or pembrolizumab at 200 mg on day 1 paired with gemcitabine at 1000 mg/m² and cisplatin at 25 mg/m² on days 1 and 8 every 3 weeks. Randomization was stratified by region (Asia vs non-Asia), disease (locally advanced vs metastatic), and site of origin (gallbladder vs intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma).

The major efficacy outcome measure was OS, and key secondary outcome measures comprised PFS, ORR, and DFS by BICR and RECIST v1.1 criteria.

The median patient age was 64 years (range, 23-85), with just under half of patients aged 65 years or older (47%). Fifty-two percent of patients were male and 49% were White. In terms of ECOG performance status, 46% and 54% of patients had a status of 0 and 1, respectively. A history of hepatitis B or C infection was observed in 31% and 3% of patients, respectively.

Additional findings showed that the median PFS with pembrolizumab plus gemcitabine/cisplatin was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 5.1-6.6) with placebo plus gemcitabine/cisplatin (HR, 0.86; 95% CI, 0.75-1.00). The respective ORRs in these arms were 29% (25%-33%) and 29% (95% CI, 25%-33%), respectively. The median DOR with pembrolizumab was 8.3 months (95% CI, 6.9-10.2) vs 6.8 months (95% CI, 5.7-7.1) with placebo.

Safety

The safety of pembrolizumab paired with chemotherapy has been assessed in 4787 patients spanning tumor types. The incidence of grade 3 to 5 adverse effects (AEs) in those with gastric cancer enrolled in KEYNOTE-859 who received pembrolizumab plus chemotherapy was 75%; in those who received chemotherapy alone, this rate was 70%. The incidence of grade 3 to 5 AEs in those with biliary tract cancer enrolled in KEYNOTE-966 who received the pembrolizumab combination was 85% vs 84% in those given chemotherapy alone.

References

1. 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 December 20, 2023. 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/
2. Pembrolizumab (Keytruda). Prescribing information; Merck Sharp & Dohme LLC. Accessed December 20, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s143lbl.pdf