FDA Limits Pembrolizumab/Nivolumab in PD-L1–Low Gastric Cancer Indications

The manufacturers for both agents will conduct studies supporting validated diagnostic testing for PD-L1 expression in these gastric cancer indications, according to the letters.

The FDA has limited the indications for pembrolizumab (Keytruda) and nivolumab (Opdivo) among patients with select gastric and gastroesophageal cancers with PD-L1 scores of less than 1, according to letters from the agency sent to the developers of these agents.1,2

Additionally, the manufacturers for both agents will conduct studies supporting validated diagnostic testing for PD-L1 expression in these gastric cancer indications, according to the letters.

Furthermore, the current label for frontline nivolumab use in combination with chemotherapy or ipilimumab (Yervoy) to treat patients with advanced or metastatic esophageal squamous cell carcinoma, and gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma, restricts the drug to patients with a PD-L1 combined positive score (CPS) expression of 1 or higher.3 PD-L1 thresholds including CPSs of at least 1 and at least 10 are the restrictions for pembrolizumab’s indications in HER2-negative gastric and GEJ adenocarcinoma, as well as locally advanced or metastatic esophageal/GEJ carcinoma.4

In September 2024, the FDA’s Oncologic Advisory Drug Committee (ODAC) voted against PD-L1 expression as a predictive biomarker in gastric cancers10-to-2, with 1 abstention.5 The members cited the lack of an overall survival (OS) benefit observed in patients with a PD-L1 CPS expression of less than 1 as a reason for rejecting the indication.

Expert Perspective

“I hope we can see how this evolves and how we can get immunotherapies to be effective in this PD-L1-negative population,” Hanna K. Sanoff, MD, MPH, professor of Gastrointestinal Oncology, as well as medical oncologist and clinical researcher, at UNC Lineberger Comprehensive Cancer Center, and ODAC member, said during the September ODAC meeting.5 “Until we do that, I did not see enough evidence that we are helping people and not harming them.”

CHECKMATE-649 Data

Subgroup analysis from the phase 3 CheckMate 649 trial (NCT02872116) evaluating nivolumab plus fluoropyrimidine- and platinum-based chemotherapy or ipilimumab informed the FDA decision for nivolumab.6 Data revealed that the median OS between the nivolumab/chemotherapy and chemotherapy-only PD-L1–low group was 13.1 months vs 12.5 months.

Furthermore, among those with a PD-L1–combined positive score (CPS) of 5 or greater, the median OS was 14.4 months (95% CI, 13.1-16.2) with nivolumab vs 11.1 months (95% CI, 10.0-12.1) with placebo (HR, 0.71; 95% CI, 0.61-0.83; P <.0001). The median progression-free survival (PFS) in respective arms was 7.7 months (95% CI, 7.0-9.2) vs 6.0 months (95% CI, 5.6-6.9; HR, 0.68; 95% CI, 0.58-0.79; P <.0001).

Patients in the phase 3 trial (n = 1581) were randomly assigned to nivolumab/chemotherapy (n = 789) or chemotherapy only (n = 792). Patients received either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with or without nivolumab at 240 mg every 2 weeks or capecitabine/oxaliplatin with or without nivolumab at 360 mg every 3 weeks. The most common adverse effects (AEs) observed with nivolumab included peripheral neuropathy, nausea, fatigue, diarrhea, and vomiting.

KEYNOTE-859 Data

Additionally, subgroup analyses from the phase 3 KEYNOTE-859 trial (NCT03675737) evaluating pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy, which informed the FDA decision for pembrolizumab, showed a respective median OS of 12.7 months with pembrolizumab/chemotherapy vs 12.2 months with chemotherapy alone among the PD-L1–low group.7

Patients in the KEYNOTE-859 trial (n = 1579) were randomly assigned 1:1 to receive chemotherapy and either 200 mg of pembrolizumab or matching placebo. Subgroup analysis data showed that the pembrolizumab regimen exhibited significantly improved OS, PFS, and ORR outcomes among patients with a PD-L1 CPS of at least 1 and a CPS of at least 10.

Treatment discontinuation related to AEs occurred in 15% of patients treated with pembrolizumab. AEs resulting in discontinuation occurring at a frequency of 1% or greater included infections and diarrhea.

References

1. Lemery SJ. BLA 125514/S-182. FDA. May 22, 2025. Accessed June 19, 2025. https://tinyurl.com/5cw8cyvd
2. Lemery SJ. BLA 125554/S-133. FDA. May 23, 2025. Accessed June 19, 2025. https://tinyurl.com/22nap56k
3. Nivolumab. Prescribing information. FDA; 2025. Accessed June 19, 2025. https://tinyurl.com/375rzymm
4. Pembrolizumab. Prescribing information. FDA; 2025. Accessed June 19, 2025. https://tinyurl.com/4h9wmznx
5. September 26, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live September 26, 2024. Accessed June 19, 2025. https://tinyurl.com/mt6276np
6. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. News release. FDA. April 16, 2021. Accessed June 19, 2025. https://tinyurl.com/56f6usfs
7. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. News release. FDA. November 16, 2023. Accessed June 19, 2025. https://tinyurl.com/39uanur8