Merck's Keytruda in Combination with Herceptin and Chemotherapy Demonstrates Significant Efficacy in First-Line Treatment of HER2-Positive Gastric Cancer

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Recently, Keytruda achieved an early victory in a patient subgroup. According to an abstract presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting: Results from the Phase 3 KEYNOTE-811 study conducted in patients with newly diagnosed HER2-positive gastric or gastroesophageal junction cancer showed that, compared with the standard of care (Herceptin + chemotherapy), the Keytruda + Herceptin + chemotherapy regimen demonstrated highly significant efficacy: a higher overall response rate and a longer duration of response.

Although the study was originally planned to enroll 692 patients, based on interim analysis data from the first 264 patients, the FDA approved Keytruda in combination with Herceptin and chemotherapy in early May this year for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) cancer. With this approval, Keytruda becomes the first anti-PD-1 therapy approved for use in combination with Herceptin and chemotherapy as a first-line treatment for gastric or GEJ cancer.

Below are the detailed results of the Phase III KEYNOTE-811 study presented at the ASCO 2021 conference:

Methods: Herceptin (trastuzumab) in combination with chemotherapy is the standard of care for HER2-positive metastatic gastric and gastroesophageal junction (G/GEJ) cancers. In two Phase II studies, the trastuzumab + chemotherapy + Keytruda combination regimen demonstrated favorable efficacy and a manageable safety profile. The Phase III KEYNOTE-811 study is an ongoing, global, randomized, double-blind, placebo-controlled trial evaluating whether the addition of Keytruda to the standard of care (trastuzumab + chemotherapy) improves efficacy in HER2-positive metastatic G/GEJ cancer compared with SOC alone (NCT03615326).

This study enrolled treatment-naïve patients with unresectable or metastatic HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer, who were randomized in a 1:1 ratio to receive intravenous Keytruda 200 mg or placebo every 3 weeks. All patients received trastuzumab in combination with an investigator’s choice of chemotherapy (5-fluorouracil plus cisplatin, or capecitabine plus oxaliplatin [CAPOX]). Treatment was administered for 2 years or until unacceptable toxicity or disease progression. The trial planned to enroll 692 patients and enrollment has been largely completed. Per protocol, the first interim analysis will be conducted after the first 260 patients are enrolled and followed up for 8.5 months, to evaluate whether the Keytruda + standard of care (SOC) regimen significantly improves the overall response rate (ORR), with a superiority boundary of P=0.002.

Results: Among the first 264 enrolled patients, 133 were randomized to the Keytruda + SOC group and 131 to the placebo + SOC group; 0.8% of patients had microsatellite instability-high (MSI-H) tumors, and the CAPOX chemotherapy selection rate was 87.1%. The median follow-up was 12.0 months (range, 8.5–19.4).

The confirmed ORR was 74.4% (95% CI: 66.2–81.6) in the Keytruda + SOC group and 51.9% (95% CI: 43.0–60.7) in the placebo + SOC group, with an ORR difference of 22.7% (95% CI: 11.2–33.7; P = 0.00006). The complete response (CR) rate was 11.3% in the Keytruda + SOC group versus 3.1% in the placebo + SOC group. The disease control rate (DCR) was 96.2% (95% CI: 91.4–98.8) in the Keytruda + SOC group and 89.3% (95% CI: 82.7–94.0) in the placebo + SOC group.

The median duration of response (DOR) was 10.6 months (range: 1.1+ to 16.5+) in the Keytruda + SOC arm and 9.5 months (range: 1.4+ to 15.4+) in the placebo + SOC arm; the proportions of patients with DOR ≥ 6 months were 70.3% and 61.4%, respectively, and those with DOR ≥ 9 months were 58.4% and 51.1%, respectively.

As of the data cutoff, 433 of 434 enrolled patients had received treatment (217/217 Keytruda + SOC, 216/217 placebo + SOC). In the Keytruda + SOC group, 57.1% of patients experienced Grade 3–5 adverse events, 3.2% died, and 24.4% discontinued treatment; in the placebo + SOC group, 57.4% experienced Grade 3–5 adverse events, 4.6% died, and 25.9% discontinued treatment.

Conclusion: In the first-line treatment of HER2-positive metastatic G/GEJ cancer, compared with the standard of care (trastuzumab + chemotherapy), adding Keytruda to the standard of care significantly improves the ORR, with durable responses and a favorable safety profile. These preliminary data support Keytruda + trastuzumab + chemotherapy as a potential new treatment option for this patient population.

References:

1.ASCO: Merck details Keytruda's Herceptin combo stomach cancer win as its single-agent nod's in danger

2.Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study.