ODAC Votes Against Risk:Benefit Profile of Frontline PD-1 Inhibitors in HER2–, MSS Gastric/GEJ Adenocarcinoma With a PD-L1 Expression Under 1

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 10 to 2 with 1 abstention against the risk:benefit profile of PD-1 inhibitors in the first-line treatment of patients with advanced HER2-negative, microsatellite stable (MSS) gastric/gastroesophageal junction (GEJ) adenocarcinoma with a PD-L1 expression of less than 1.¹

The vote was preceded by discussion of the following question:

DISCUSSION: In patients with HER2-negative microsatellite stable gastric/GEJ adenocarcinoma, does the cumulative data support the use of PD-L1 expression as a predictive biomarker when selecting patients for treatment with PD-1 inhibitors?²

"My vote was no based upon the preponderance of evidence at this time. I think the risk:benefit ratio is not favorable," Katherine Van Loon, MD, MPH, of the University of California, San Francisco, said following the vote.¹

During the meeting, representatives from Bristol Myers Squibb, Merck Sharp & Dohme, and BeiGene presented data from the phase 3 CheckMate 649 (NCT02872116), KEYNOTE-859 (NCT03675737), and RATIONALE-305 (NCT03777657) trials, respectively.

"My vote was no," Daniel Spratt, MD, of Case Western Reserve University, said following the vote. "Yelena Y. Janjigian MD, [of Memorial Sloan Kettering Cancer Center] said [during the ODAC meeting] the average doctor sees 5 of these [patients] a year, and I'm not sure we want to let those doctors make that decision [for including a PD-1 inhibitor for patients with a PD-L1 expression of less than 1] when these hazard ratios [for overall survival (OS) in these subgroups] are approaching 1, and there are financial and toxicity impacts."

CheckMate 649

In April 2021, the FDA approved nivolumab (Opdivo) in combination with chemotherapy for the frontline treatment of patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, based on data from CheckMate 649.³

The study enrolled patients with previously untreated, unresectable, advanced or metastatic gastric/GEJ/esophageal adenocarcinoma who did not have known HER2-positive disease and had an ECOG performance status of 0 or 1.⁴

Patients were randomly assigned 1:1:1 to receive 360 mg of nivolumab plus XELOX once every 3 weeks or 240 mg of nivolumab plus FOLFOX once every 2 weeks; XELOX once every 3 weeks or FOLFOX once every 2 weeks alone; or 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab (Yervoy) once every 3 weeks for 4 cycles, then 240 mg of nivolumab alone once every 2 weeks.

OS and progression-free survival (PFS) in the patient population with a PD-L1 combined positive score (CPS) of at least 5 served as the primary end points. Secondary end points included OS and PFS in the PD-L1 CPS of at least 10, PD-L1 CPS of at least 1, and overall populations; and overall response rate (ORR). Safety and quality of life were exploratory end points.

Statistically significant and clinically meaningful improvements in OS were observed for nivolumab plus chemotherapy vs chemotherapy alone in the population of patients with a PD-L1 CPS of at least 5 (HR, 0.71; 95% CI, 0.59-0.86; P < .0001), the population of patients with a PD-L1 CPS of at least 1 (HR, 0.77; 95% CI, 0.64-0.92; P < .0001), and the overall population (HR, 0.80; 95% CI, 0.68-0.94; P = .0002).

A subgroup analysis showed that among patients with a PD-L1 CPS of less than 1, those treated with nivolumab plus chemotherapy (n = 140) experienced a median OS of 13.08 months vs 12.48 months for those given chemotherapy alone (n = 125; HR, 0.92; 95% CI 0.70-1.23).

The safety profile of nivolumab plus chemotherapy was consistent with the known profiles of each agent, and safety data were similar across PD-L1 subgroups.

KEYNOTE-859

In November 2023, the FDA approved pembrolizumab (Keytruda) in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma, based on data from KEYNOTE-859.⁵

The trial included patients with locally advanced or metastatic stomach or GEJ adenocarcinoma with a known PD-L1 status. Patients were randomly assigned 1:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. One of the stratification factors was PD-L1 CPS (< 1 vs ≥ 1).⁶

OS served as the trial’s primary end point. Secondary end points included PFS, ORR, duration of response (DOR), and safety. The study protocol included alpha control for the overall, PD-L1 CPS of at least 1, and PD-L1 CPS of at least 10 populations.

In the overall population, the median OS was 12.9 months (95% CI, 11.9-14.0) in the pembrolizumab arm (n = 790) vs 11.5 months (95% CI, 10.6-12.1) in the placebo arm (n = 789; HR, 0.78; 95% CI, 0.70-0.87; P < .0001). The median PFS was 6.9 months (95% CI, 6.3-7.2) vs 5.6 months (95% CI, 5.5-5.7), respectively (HR, 0.76; 95% CI, 0.67-0.85; P < .0001).

During the ODAC meeting, Pooja Bhagia, MD, the executive director of Global Clinical Development, Late-Stage Oncology, at Merck Sharp & Dohme said that the magnitude of benefit for the combination increased with higher levels of PD-L1 expression. She added that efficacy trends favoring the combination were seen in the PD-L1 CPS of less than 1 population for OS (HR, 0.92; 95% CI, 0.73-1.17) and PFS (HR, 0.90; 95% CI, 0.70-1.15).

Health-related quality of life was similar between the 2 arms, irrespective of PD-L1 CPS, and the safety profile of the combination was manageable and consistent across PD-L1 subgroups.

RATIONALE-305

In February 2024, the FDA accepted a biologics license application (BLA) seeking the approval of tislelizumab-jsgr (Tevimbra) plus fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, based on findings from RATIONALE-305. The BLA has a target action data of December 2024.⁷

The randomized, double-blind, global study enrolled patients with histologically confirmed, previously untreated, unresectable, locally advanced or metastatic gastric/GEJ cancer who did not have HER2-positive tumors.⁸

Patients were randomly assigned 1:1 to receive 200 mg of tislelizumab once every 3 weeks plus chemotherapy consisting of oxaliplatin plus capecitabine or cisplatin plus 5-fluorouracil; or placebo plus one of the 2 chemotherapy regimens.

The dual primary end points were OS in the intention-to-treat (ITT) and PD-L1 expression of at least 5% populations. PFS, ORR, DOR, and safety were secondary end points.

In patients with a PD-L1 expression of at least 5%, the median OS was 17.2 months (95% CI, 13.9-21.3) in the tislelizumab arm (n = 274) vs 12.6 months (95% CI, 12.0-14.4) in the placebo arm (n = 272; HR, 0.74; 95% CI, 0.59-0.94; P = .0056). In the ITT population, the median OS was 15.0 months (95% CI, 13.6-16.5) for the tislelizumab arm (n = 501) vs 12.9 months (95% CI, 12.1-14.1) for the placebo arm (n = 496; HR, 0.80; 95% CI, 0.70-0.92; P = .0011).

Although an OS benefit was observed across PD-L1 subgroups for the tislelizumab regimen, the benefit was smallest in the population of patients with a PD-L1 expression of less than 1% (HR, 0.98; 95% CI, 0.64-1.50). The safety profile of the tislelizumab combination was consistent across PD-L1 subgroups.

FDA Position

In a presentation on behalf of the FDA, Vaibhav Kumar, MD, MS, a clinical reviewer for gastrointestinal malignancies, said that from the regulatory agency’s perspective, PD-L1 expression appears to be a predictive biomarker for HER2-negative gastric/GEJ adenocarcinoma. He also highlighted that uncertainty surrounds the efficacy of PD-1 inhibitors in patients with a PD-L1 expression of less than 1, and that the use of immune checkpoint inhibitors exposes patients to potential added toxicities.¹

He also explained that under the current National Comprehensive Cancer Network Gastric Cancer Guidelines, nivolumab plus chemotherapy has a category 1 recommendation for patients with HER2-negative disease and a PD-L1 CPS of at least 5; the regimen has a category 2B recommendation for those with a PD-L1 CPS of less than 5, with the regimen useful under certain circumstances.

Additionally, pembrolizumab plus chemotherapy is labeled as a preferred regimen for those with a PD-L1 CPS of at least 1; specifically, it has a category 1 recommendation for those with a PD-L1 CPS of at least 10 and a category 2B recommendation for those with a PD-L1 CPS of 1 to less than 10.

“The safety of the addition of immune checkpoint inhibitors [to chemotherapy] is not known to differ across PD-L1 strata,” Kumar said. “Across the 3 studies, what we know is that the addition of a PD-1 inhibitor to chemotherapy will add anywhere from [a] 3% to 11% increase in the proportion of patients experiencing grade 3/4 treatment-emergent adverse effects [AEs]. The incidence of immune-mediated AEs was approximately 30%, and we know the majority of these are low grade…however, up to 10% of patients will experience grade 3/4 immune-mediated AEs. Unfortunately, there were fatal immune-related AEs, and although the incidence was low, we would not want to expose patients to these risks without the benefit gained of adding an immune checkpoint inhibitor.”

References

1. September 26, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/ELA3JDqtcFw
2. Oncologic Drugs Advisory Committee (ODAC) Meeting. Final questions. Accessed September 26, 2024. https://www.fda.gov/media/182135/download
3. FDA approves first immunotherapy for initial treatment of gastric cancer. FDA. April 16, 2021. Accessed September 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-initial-treatment-gastric-cancer
4. Oncologic Drugs Advisory Committee (ODAC) Meeting. AM BMS presentations. Accessed September 26, 2024. https://www.fda.gov/media/182208/download
5. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. FDA. November 16, 2023. Accessed September 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-her2-negative-gastric-or-gastroesophageal-junction
6. Oncologic Drugs Advisory Committee (ODAC) Meeting. AM Merck presentations. Accessed September 26, 2024. https://www.fda.gov/media/182211/download
7. BeiGene’s biologics license application for Tevimbra (tislelizumab) for first-line gastric or gastroesophageal junction cancers accepted by FDA. News release. BeiGene. February 27, 2024. Accessed September 26, 2024. https://ir.beigene.com/news/beigene-s-biologics-license-application-for-tevimbra-tislelizumab-for-first-line-gastric-or-gastroesophageal-junction-cancers-accepted/4cc83f12-9249-4984-9a2a-c607c8a6e879/
8. Oncologic Drugs Advisory Committee (ODAC) Meeting. AM BeiGene presentations. Accessed September 26, 2024. https://www.fda.gov/media/182209/download