FDA Committee Votes Against PD-L1 as a Predictive Biomarker for Gastric Cancers

The FDA’s Oncologic Advisory Drug Committee (ODAC) voted down the use of PD-L1 as a predictive biomarker for PD-1 inhibitors in the frontline treatment of advanced, HER2-negative microsatellite stable (MSS) gastric or gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 expression of 1 or less.¹

Overall, 10 committee members voted that the risk-benefit assessment was not favorable for the use of PD-1 inhibitors in this population, while 2 voted favorably. Of note, 1 member abstained from voting.

“I just don’t see any overall survival benefit in this group [with a PD-L1 expression of less than 1]. I do think that the [PD-L1 expression] cutoff should be 1 just because of the perceived benefit that I see in that patient population [with PD-L1 expression] between 1 to 10,” Christopher Lieu, MD, associate director for Clinical Research and co-director of Gastrointestinal Medical Oncology at University of Colorado Medicine, said during the meeting while explaining his vote of no.

Although prior reports have demonstrated PD-L1 expression as a predictive biomarker of efficacy in this gastric or GEJ adenocarcinoma population, the ODAC convened to discuss the matter of various clinical trials using different approaches to evaluating PD-L1 expression. Specifically, committee members discussed the value of PD-L1 expression as a predictive biomarker for patient selection, differing risk-benefit evaluations across PD-L1 expression status subgroups, and the adequacy of cumulative data in restricting the approvals of immune checkpoint inhibitors based on PD-L1 expression.

The ODAC reviewed these topics in the context of prior FDA approvals for nivolumab (Opdivo) in April 2021 and pembrolizumab (Keytruda) in November 2023 as frontline therapies for adult patients with locally advanced or unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.^2,3 Additionally, members spoke about an application for tislelizumab (Tevimbra) as a treatment for the same population, which is currently under review by the FDA.

Nivolumab Data

Supporting data for the approval of nivolumab plus fluoropyrimidine- and platinum-based chemotherapy came from the phase 3 CHECKMATE-649 trial (NCT02872116). Investigators randomly assigned 1581 patients to receive nivolumab plus chemotherapy (n = 789) or chemotherapy alone (n = 792). Study treatment consisted of modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with or without nivolumab at 240 mg every 2 weeks or capecitabine plus oxaliplatin with or without nivolumab at 360 mg every 3 weeks.

Among patients with a PD-L1 combined positive score (CPS) of at least 5 (n = 955), the median overall survival (OS) was 14.4 months (95% CI, 13.1-16.2) in the nivolumab arm vs 11.1 months (95% CI, 10.0-12.1) in the chemotherapy alone arm (HR, 0.71; 95% CI, 0.61-0.83; P <.0001). Additionally, data showed a median progression-free survival (PFS) of 7.7 months (95% CI, 7.0-9.2) vs 6.0 months (95% CI, 5.6-6.9), respectively (HR, 0.68; 95% CI, 0.58-0.79; P <.0001).

Frequent adverse effects (AEs) among patients in the nivolumab arm included peripheral neuropathy, nausea, fatigue, diarrhea, and vomiting.

Pembrolizumab Data

Findings from the phase 3 KEYNOTE-859 trial (NCT03675737) supported the FDA approval of pembrolizumab plus fluoropyrimidine- and platinum-containing chemotherapy in gastric or GEJ adenocarcinoma. A total of 1579 patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg or placebo plus investigator’s choice of chemotherapy.

The median OS was 12.9 months (95% CI, 11.9-14.0) with pembrolizumab-based treatment vs 11.5 months (95% CI, 10.6-12.1) with chemotherapy alone (HR, 0.78; 95% CI, 0.70-0.87; P <.0001). Additionally, the median PFS was 6.9 months (95% CI, 6.3-7.2) and 5.6 months (95% CI, 5.5-5.7) in each respective arm (HR, 0.76; 95% CI, 0.67-0.85; P <.0001). Data also showed an objective response rate (ORR) of 51% (95% CI, 48%-55%) vs 42% (95% CI, 38%-45%), respectively (P <.0001); the median duration of response (DOR) was 8 months (95% CI, 7.0-9.7) vs 5.7 months (95% CI, 5.5-6.9) in each arm.

Subgroup analysis data showed that the pembrolizumab combination produced statistically significant improvements in OS, PFS, and ORR among patients with a PD-L1 CPS of at least 1 and a CPS of at least 10.

Tislelizumab Data

In February 2024, the FDA accepted a biologics license application for tislelizumab plus chemotherapy as a first-line therapy for patients with advanced or metastatic gastric or GEJ adenocarcinoma.⁴ The regulatory agency set a Prescription Drug User Fee Act date for December 2024 for its decision on approving this combination.

Supporting data for the application came from the phase 3 RATIONALE-305 trial (NCT03777657). Investigators previously published data from this trial in BMJ.⁵

In the RATIONALE-305 trial, 997 patients were randomly assigned to receive tislelizumab plus chemotherapy (n = 501) or placebo in combination with chemotherapy (n = 496). Patients received tislelizumab at 200 mg intravenously every 3 weeks, and chemotherapy consisted of investigator’s choice of oxaliplatin plus capecitabine or cisplatin plus 5-fluorouracil.

Among patients with a PD-L1 expression status of 5% or higher, the median OS was 17.2 months (95% CI, 13.9-21.3) with tislelizumab/chemotherapy vs 12.6 months (95% CI, 12.0-14.4) with chemotherapy alone (HR, 0.74; 95% CI, 0.59-0.94; P = .006). Data also showed an improvement in investigator-assessed PFS with tislelizumab-based treatment (HR, 0.67; 95% CI, 0.55-0.83; P <.001).

Any-grade treatment-related AEs (TRAEs) occurred in 97% of patients in the tislelizumab/chemotherapy arm and 96% of those in the chemotherapy arm. Additionally, grade 3 or higher TRAEs affected 54% vs 50%, respectively. Common high-grade TRAEs in each arm included neutrophil count decreases (12% vs 12%), platelet count decreases (11% vs 12%), and neutropenia (7% vs 7%).

References

1. September 26, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live September 26, 2024. Accessed September 26, 2024. https://tinyurl.com/mt6276np

2. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. News release. FDA. April 16, 2021. Accessed September 26, 2024. https://tinyurl.com/56f6usfs

3. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. News release. FDA. November 16, 2023. Accessed November 16, 2023. https://shorturl.at/acnQ1

4. BeiGene’s biologics license application for TEVIMBRA® (tislelizumab) for first-line gastric or gastroesophageal junction cancers accepted by FDA. News release. BeiGene, Ltd. February 27, 2024. Accessed September 26, 2024. http://tinyurl.com/ymbdbm58

5. Qiu M-Z, Oh D-Y, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024; 385:e078876. doi:10.1136/bmj-2023-078876