Keytruda Combination Achieves Overall Survival Improvement in HER2-Positive Advanced Gastric or GEJ Adenocarcinoma

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Merck’s Keytruda (pembrolizumab) combined with trastuzumab, plus fluoropyrimidine- and platinum-containing chemotherapy, demonstrated promising improvements in overall survival (OS) in the first-line treatment of patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to data from the Phase III KEYNOTE-811 trial (NCT03615326).¹ The combination produced a statistically significant and clinically meaningful improvement in OS vs. the combination of placebo plus trastuzumab and chemotherapy among the trial’s intention-to-treat (ITT) patient population. The greatest benefit was shown in patients with tumors that express PD-L1 (CPS ≥1), according to the study investigators.

“Patients diagnosed with advanced gastric cancer often face a poor prognosis, underscoring the need for treatment options that have the potential to extend patients’ lives,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in a press release. “These overall survival results from KEYNOTE-811 are encouraging and build on the positive progression-free survival, (PFS) overall response rate (ORR), and duration of response (DoR) data from this study.”¹

Keytruda is an anti-PD-1 therapy that improves the immune system's ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect the tumor and healthy cells.

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.

In November 2023, Keytruda plus fluoropyrimidine- and platinum-containing chemotherapy was approved by the FDA for the first-line treatment of patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma based on findings from the KEYNOTE-859 trial.²

The randomized, double-blind KEYNOTE-811 trial evaluated Keytruda with trastuzumab and chemotherapy in the first-line treatment of 698 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. The trial’s dual primary endpoints are OS and PFS per RECIST v1.1 as assessed by blinded independent central review, with secondary endpoints that included ORR, DoR, and safety.

Patients were randomly assigned to receive Keytruda at a dose of 200 mg every three weeks in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy comprised of investigator’s choice of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin, compared with placebo combined with trastuzumab and chemotherapy.

A pre-specified interim analysis by an independent Data Monitoring Committee showed the Keytruda combination produced statistically significant improvements in PFS vs. the placebo combination in the ITT study population. A pre-specified subgroup analysis by PD-L1 expression showed that the improved PFS in the ITT population was limited to patients with PD-L1 positive tumors. More than 80% of patients enrolled in the trial had PD-L1-positive tumors.³

In terms of safety, the findings in KEYNOTE-811 were consistent with what was reported in prior trials, with no new safety signals identified. Merck stated that the data from the trial will be presented at an upcoming medical meeting and submitted to regulatory authorities.

“[These data] from KEYNOTE-811, demonstrating a significant improvement in progression-free survival, are meaningful and build on the earlier insights from this study that supported the accelerated approval of this Keytruda combination in the U.S. for certain patients with HER2-positive gastric or GEJ adenocarcinoma,” said Scot Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories said in a prior press release. “We look forward to sharing these results with the medical community and regulatory authorities to ensure this Keytruda-based regimen is available to appropriate patients, and we are working with the FDA to update the current indication for Keytruda to those patients whose tumors are PD-L1 positive.”³

References

1. Merck Announces Phase 3 KEYNOTE-811 Trial Met Dual Primary Endpoint of Overall Survival (OS) as First-Line Treatment in Patients With HER2-Positive Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma. News release. Merck. May 1, 2024. Accessed May 1, 2024. https://www.merck.com/news/merck-announces-phase-3-keynote-811-trial-met-dual-primary-endpoint-of-overall-survival-os-as-first-line-treatment-in-patients-with-her2-positive-advanced-gastric-or-gastroesophageal-junction-gej/

2. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy as First-Line Treatment for Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma. Merck. News release. November 16, 2023. Accessed May 1, 2024. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-first-line-treatment-for-locally-advanced-unresectable-or-metastatic-her2-negative-gastric-or-gastroesophageal-junction/

3. 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. June 16, 2023. Accessed May 1, 2024. 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/