FDA Accepts sBLA for Pembrolizumab Plus Chemotherapy in Advanced Gastric/GEJ Adenocarcinoma

The FDA has accepted for review a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) plus fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The sBLA is based on data from the phase 3 KEYNOTE-859 trial (NCT03675737), in which pembrolizumab plus chemotherapy led to a statistically significant improvement in overall survival (OS) vs chemotherapy alone, irrespective of PD-L1 expression, in patients with HER2-negative locally advanced or metastatic gastric/GEJ cancer.^2,3

At a median follow-up of 31.0 months (range, 15.3-46.3), the combination elicited median OS of 12.9 months (95% CI, 11.9-14.0) vs 11.5 months (95% CI, 10.6-12.1) with chemotherapy alone (HR, 0.78; 95% CI, 0.70-0.87; P < .0001). The 12- and 24-month OS rates with the combination were 52.7% and 28.2% vs 46.7% and 18.9% with chemotherapy alone, respectively.

The FDA is scheduled to decide on the application by December 16, 2023, per the Prescription Drug User Fee Act target action date.

“The 5-year survival rate for patients diagnosed with metastatic gastric cancer is estimated to be only 6%, and 80% of patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma have HER2-negative disease,” Scot Ebbinghaus, MD, vice president, Global Clinical Development, Merck Research Laboratories, said in a press release. “We are committed to working closely with the FDA to bring [pembrolizumab] to more patients with gastric and GEJ cancer who are in need of additional treatment options that may help them live longer.”

In November 2022, Merck announced that the trial met its primary end point of OS and demonstrated statistically significant improvements in progression-free survival (PFS) and overall response rate (ORR) in the all-randomized population.²

Findings from the trial were presented by Sun Young Rha, MD, during the 2023 ESMO Virtual Plenary series in February.³ Rha is a professor of medical oncology in the Department of Internal Medicine and director of the Songdang Institute for Cancer Research at Yonsei University College of Medicine, Yonsei University Health System, in Seoul, South Korea.

To be eligible for enrollment, patients had to have histologically or cytologically confirmed adenocarcinoma of the stomach or GEJ; locally advanced or metastatic disease; no prior treatment; known PD-L1 status; HER2 negativity; and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to 200 mg of intravenous (IV) pembrolizumab plus 800 mg/m² of 5-flourouracil per day on days 1 through 5 and 80 mg/m² of cisplatin every 3 weeks, or 1000 mg/m² of oral capecitabine twice daily on days 1 through 14 plus 130 mg/m² of IV oxaliplatin every 3 weeks; or placebo plus chemotherapy. Pembrolizumab and placebo were administered for up to 35 cycles, equating to approximately 2 years.

OS served as the primary end point, with secondary end points consisting of PFS, ORR, duration of response (DOR), and safety.

Additional findings indicated that median PFS was 6.9 months (95% CI, 6.3-7.2) with the combination vs 5.6 months (95% CI, 5.5-5.7) with chemotherapy alone (HR, 0.76; 95% CI, 0.67-0.85; P < .0001). The 12- and 24-month PFS rates with the combination were 28.9% and 17.8% vs 19.3% and 9.4% with chemotherapy, respectively.

Notably, OS and PFS benefit was similar across subgroups, including those for the stratification factors of geographic region, PD-L1 expression, and choice of chemotherapy.

The ORR was 51.3% (95% CI, 47.7%-54.8%) with the combination (complete response [CR], 9.5%; partial response [PR], 41.8%) vs 42.0% (95% CI, 38.5%-45.5%) with chemotherapy alone (CR, 6.2%; PR, 35.7%), reflecting an absolute difference of 9.3% (95% CI, 4.4%-14.1%) favoring the addition of pembrolizumab (P = .00009). The median DOR was 8.0 months (range, 1.2+ to 41.5+) with the combination vs 5.7 months (range, 1.3+ to 34.7+) with chemotherapy alone.

Regarding safety, common any-grade treatment-related adverse effects (TRAEs) with pembrolizumab and chemotherapy alone, 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%).

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

Immune-mediated AEs occurred more commonly in the pembrolizumab arm than in the chemotherapy alone arm, respectively (any grade, 27.1%; grade ≥3, 7.9% vs any grade, 9.3%; grade ≥3, 1.7%). One death each was reported in both arms, owing to pneumonitis.

Treatment discontinuation occurred in 26.4% (n = 207) of patients who received pembrolizumab vs 20.1% (n = 158) of those who received chemotherapy alone.

Fatalities were reported in 8 patients (1.0%) with pembrolizumab vs 16 (2.0%) with chemotherapy alone.

The authors concluded, “Data support pembrolizumab plus chemotherapy as a new treatment option for patients with locally advanced or metastatic, HER2-negative gastric or GEJ adenocarcinoma.”

Pembrolizumab also received accelerated approval from the FDA in May 2021 for use in combination with trastuzumab (Herceptin), fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.⁴ The approval was based on response rate and durability of response data from the phase 3 KEYNOTE-811 study (NCT03615326).

References

1. FDA accepts application for Merck’s Keytruda (pembrolizumab) plus chemotherapy as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. News release. Merck. April 13, 2023. Accessed April 13, 2023. https://www.merck.com/news/
2. Merck announces phase 3 KEYNOTE-859 trial met primary endpoint of overall survival in patients with HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. November 22, 2022. Accessed April 13, 2023. https://www.merck.com/news/
3. 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. Presented at: ESMO Virtual Plenary Series; February 16-17, 2023. doi:10.1016/j.annonc.2023.01.006
4. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed April 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/