FDA Restricts Approval for Pembrolizumab Plus Trastuzumab and Chemo to Advanced PD-L1+ Gastric/GEJ Cancer

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The FDA has updated the current indication for pembrolizumab plus trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma to those whose tumors express PD-L1 with a CPS of 1 or more.

The FDA has updated the current indication for pembrolizumab (Keytruda) plus trastuzumab (Herceptin), fluoropyrimidine, and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma to those whose tumors express PD-L1 with a combined positive score (CPS) of 1 or more as determined by an FDA-approved test.¹

The regulatory agency also approved the Agilent PD-L1 immunohistochemistry 22C3 pharmDx as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1.

The combination received accelerated approval from the FDA in May 2021 for use in patients with locally advanced unresectable or metastatic HER2-positive gastric/GEJ cancer regardless of PD-L1 expression. The approval was based on findings from an interim analysis of objective response rate (ORR) and duration of response (DOR) from the phase 3 KEYNOTE-811 trial (NCT03615326). Among the first 264 patients who had been randomly assigned to treatment, the ORR was 74% (95% CI, 66%-82%) with pembrolizumab (n = 133) vs 52% (95% CI, 43%-61%) with placebo (n = 131; P <.0001). The median DOR with pembrolizumab and placebo was 10.6 months (range, 1.1+ to 16.5+) and 9.5 months (range: 1.4+ to 15.4+), respectively.²

The multicenter, randomized, double-blind, placebo-controlled trial enrolled patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had not received systemic therapy for metastatic disease. Patients were randomly assigned 1:1 to receive 200 mg of pembrolizumab intravenously or placebo every 2 weeks with trastuzumab and either fluorouracil plus cisplatin or capecitabine (Xeloda) plus oxaliplatin.

The coprimary end points of the trial were overall survival (OS) and progression-free survival (PFS).

In June 2023, Merck announced that the trial had met one of the primary end points of the trial, demonstrating a statistically significant improvement in PFS with the addition of pembrolizumab. However, the benefit was limited to patients with PD-L1–positive tumors.³

Findings from the analysis were simultaneously presented at the 2023 ESMO Congress and published in the Lancet Oncology.^4,5

At the time of the second interim analysis, which was conducted at a median follow-up of 28.3 months (interquartile range [IQR], 19.4-34.3) for the pembrolizumab arm and 28.5 months (IQR, 20.1-34.3) for the placebo arm, the median PFS with pembrolizumab (n = 350) was 10.0 months (95% CI, 8.6-11.7) vs 8.1 months (95% CI, 7.0-8.5) with placebo (n = 348; HR, 0.72; 95% CI, 0.60-0.87; P = .0002). In patients with a PD-L1 CPS of 1 or more, the median PFS was 10.8 months (95% CI, 8.5-12.5) with pembrolizumab (n = 298) vs 7.2 months (95% CI, 6.8-8.4) with placebo (n = 296; HR, 0.70; 95% CI, 0.58-0.85).

Additional findings from the third interim analysis, which had been conducted at a median follow-up 38.4 months (IQR, 29.5-44.4) in the pembrolizumab arm and 38.6 months (IQR, 30.2-44.4) in the placebo arm, indicated that the median PFS was 10.0 months (95% CI, 8.6-12.2) with pembrolizumab vs 8.1 months (95% CI, 7.1-8.6) with placebo in the overall population (HR, 0.73; 95% CI, 0.61-0.87). In patients with a PD-L1 CPS of at least 1, the median PFS was 10.9 months (95% CI, 8.5-12.5) with pembrolizumab vs 7.3 months (95% CI, 6.8-8.5) with placebo (HR, 0.71; 95% CI, 0.59-0.86).

Although not statistically significant, the median OS was longer with pembrolizumab than placebo, at 20.0 months (95% CI, 17.8-22.1) vs 16.8 months (95% CI, 15.0-18.7), respectively (HR, 0.84; 95% CI, 0.70-1.01). In patients with a PD-L1 CPS of 1 or more, the median OS was 20.0 months (95% CI, 17.9-22.7) vs 15.7 months (95% CI, 13.5-18.5) with pembrolizumab and placebo, respectively (HR, 0.81; 95% CI, 0.67-0.98).

Notably, at the time of the third interim analysis, neither PFS nor OS were improved with the addition of pembrolizumab in patients with PD-L1 CPS less than 1 (n = 104), with hazard ratios of 1.03 (95% CI, 0.65-1.64) and 1.41 (95% CI, 0.90-2.20), respectively.

The safety profile of the pembrolizumab regimen was largely consistent with the known safety profiles for trastuzumab plus chemotherapy and pembrolizumab alone.¹

The recommended dose for pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 2 years or until disease progression or unacceptable toxicity. Per the label, pembrolizumab should be administered before trastuzumab and chemotherapy when given on the same day.

References

FDA amends pembrolizumab’s gastric cancer indication. News release. FDA. November 7, 2023. Accessed November 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication
FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. FDA. May 5, 2021. Accessed November 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer
Keytruda (pembrolizumab) plus trastuzumab and chemotherapy met primary endpoint of progression-free survival as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. June 16, 2023. Accessed November 9, 2023. https://www.merck.com/news/keytruda-pembrolizumab-plus-trastuzumab-and-chemotherapy-met-primary-endpoint-of-progression-free-survival-as-first-line-treatment-in-patients-with-her2-positive-advanced-gastric-or-gastroesop/
Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424
Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: survival results from the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Lancet Oncol. Published online October 20, 2023. doi:10.1016/S0140-6736(23)02033-0