NICE Recommends Pembrolizumab Plus Chemo for Untreated HER2– Advanced Gastric/GEJ Adenocarcinoma

The National Institute for Health and Care Excellence has recommended the marketing authorization of pembrolizumab (Keytruda) paired with platinum- and fluoropyrimidine-based chemotherapy for the treatment of patients with untreated locally advanced unresectable for metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors have a PD-L1 combined positive score (CPS) of at least 1.¹

The recommendation is based on findings from the phase 3 KEYNOTE-859 trial (NCT03675737), in which the addition of the immunotherapy to chemotherapy (n = 790) significantly extended overall survival (OS) vs chemotherapy alone (n = 789), at 12.9 months (95% CI, 11.9-14.0) vs 11.5 months (95% CI, 10.6-12.1), translating to a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.70-0.87; P < .0001).²

In those with a PD-L1 CPS of 1 or higher, those who received pembrolizumab plus chemotherapy (n = 618) experienced a median OS of 13.0 months (95% CI, 11.6-14.2) vs 11.4 months (95% CI, 10.5-12.0) with chemotherapy alone (n = 617; HR, 0.74; 95% CI, 0.65-0.84; P < .0001). In those with a PD-L1 CPS of 10 or higher, the median OS with pembrolizumab (n = 279) was 15.7 months (95% CI, 13.8-19.3) vs 11.8 months (95% CI, 10.3-12.7) without (n = 272; HR, 0.65; 95% CI, 0.53-0.79; P < .0001).

The addition of pembrolizumab to chemotherapy also resulted in a significantly longer progression-free survival (PFS) vs chemotherapy alone, at a median of 6.9 months (95% CI, 6.3-7.2) and 5.6 months (95% CI, 5.5-5.7), respectively (HR, 0.76; 95% CI, 0.67-0.85; P < .0001). In those with a CPS of 1 or higher, the median PFS with pembrolizumab was 6.9 months (95% CI, 6.0-7.2) vs 5.6 months (95% CI, 5.4-5.7) without (HR, 0.72; 95% CI, 0.63-0.82; P < .0001). In those with a PD-L1 CPS of 10 or higher, the median PFS with pembrolizumab was 8.1 months (95% CI, 6.8-8.5) vs 5.6 months (95% CI, 5.4-6.7) without (HR, 0.62; 95% CI, 0.51-0.76; P < .0001).

“We are pleased that access to an additional treatment option will be made available for some people living with stomach cancer and gastroesophageal junction cancer,” Katie Noon, interim chief executive officer at Guts UK, stated in a news release.¹ “For eligible patients, this news will be warmly welcomed as it may give people more choice and alternatives when it comes to suitable treatments.”

The double-blind, randomized, phase 3 study enrolled patients with histologically or cytologically confirmed adenocarcinoma of the stomach or GEJ that was locally advanced but unresectable or metastatic.² Patients were at least 18 years of age, had tumors that were HER2 negative, had measurable disease by RECIST 1.1 criteria and had not received prior treatment. They were required to have an ECOG performance status of 0 or 1 and had acceptable organ function.

If patients had squamous cell or undifferentiated gastric cancer, known history of hepatitis C infection, immunodeficiency or history of receiving chronic systemic immunosuppressive therapy, or a known history of human immunodeficiency virus, they were excluded. Patients also could not have active autoimmune disease in need of treatment or active central nervous system metastases.

Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo on day 1 of each 3-week cycle for up to 35 cycles. Chemotherapy regimens were selected by investigators and included fluorouracil at 800 mg/m² daily given continuously on days 1 to 5 of each 3-week cycle plus cisplatin at 80 mg/m² on day 1 of each 3-week cycle or capecitabine at 1000 mg/m² given twice daily on days 1 to 14 of each 3-week cycle plus oxaliplatin at 130 mg/m² on day 1 of each 3-week cycle.

The trial’s primary end point was OS and secondary end points included PFS, objective response rate, DOR, and safety.

Stratification factors included geographical region (western Europe, Israel, North America, and Australia vs Asia vs rest of the world), PD-L1 CPS (<1 vs ≥1), and investigator’s choice of chemotherapy (fluorouracil plus cisplatin vs capecitabine plus oxaliplatin).

Additional data showed that in the intention-to-treat (ITT) population, 51.3% of those who received pembrolizumab plus chemotherapy achieved an objective response vs 42.0% of those who received chemotherapy alone (P = .0001). In this population, the median duration of response (DOR) was 8.0 months (95% CI, 7.0-9.7) in the pembrolizumab arm vs 5.7 months (95% CI, 5.5-6.9) in the chemotherapy-alone arm. In those with a PD-L1 CPS or 1 or higher, 52% vs 43% of patients achieved an objective response; the median DORs were 8.3 months (95% CI, 7.0-10.9) and 5.6 months (95% CI, 5.4-6.9). In those with a PD-L1 CPS of 10 or higher, 61% and 43% of patients, respectively, achieved an objective response; the median DORs were 10.9 months (95% CI, 8.0-13.8) and 5.8 months (95% CI, 5.3-7.0).

Regarding safety, no new safety signals were observed. Treatment-related toxicities that were grade 3 to 5 occurred in 59% of patients in the pembrolizumab arm (n = 785) vs 51% of those in the chemotherapy-alone arm (n = 787). The most common grade 3 to 5 adverse effects of any cause were anemia (12% vs 10%) and decreased neutrophil count (10% vs 8%). Immune-mediated AEs were reported in 27.0% vs 9.0% of patients, respectively. AEs led to death for 1.0% vs 2.0% of patients.¹

References

1. NICE recommends MSD’s KEYTRUDA (pembrolizumab) with platinum- and fluoropyrimidine-based chemotherapy for untreated HER2-negative advanced gastric or gastro-oesophageal junction adenocarcinoma. News release. MSD. July 26, 2024. Accessed July 26, 2024.
2. Rha SY, Oh D-Y, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(11):P1181-P1195. doi:10.1016/S1470-2045(23)00515-6