Pembrolizumab Combo Yields Significant OS in HER2+ Gastric/GEJ Cancer

Developers previously announced that the pembrolizumab-based combination had produced a statistically significant PFS improvement vs trastuzumab and chemotherapy alone in June 2023.

Treatment with pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy produced a clinically meaningful and statistically significant overall survival (OS) improvement compared with placebo plus trastuzumab and chemotherapy in patients with HER2-positive advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a press release on findings from the phase 3 KEYNOTE-811 trial (NCT03615326).¹

Results from the final analysis of the trial highlighted that the OS improvement observed in the pembrolizumab arm reached the dual primary end point. Additionally, the highest OS benefit occurred among patients with PD-L1–positive tumors, specifically those with a combined positive score (CPS) of 1 or higher.

The safety profile of pembrolizumab was comparable with prior reports of the agent, and investigators reported no new safety signals. Developers will present data at a future medical meeting and share their findings with regulatory health authorities across the world.

“Patients diagnosed with advanced gastric cancer often [have] a poor prognosis, underscoring the need for treatment options that have the potential to extend patients’ lives,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, said in the press release.¹ “These [OS] 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.”

As part of the double-blind phase 3 KEYNOTE-811 trial, 698 patients were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks or a matched placebo plus trastuzumab and investigator’s choice of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin.

The trial’s dual primary end points were PFS per blinded independent central review based on RECIST v1.1 guidelines and OS. Secondary end points included ORR, DOR, and safety.

Developers previously announced that the pembrolizumab-based combination had produced a statistically significant PFS improvement vs trastuzumab and chemotherapy alone in June 2023.² Additionally, further findings from the KEYNOTE-811 trial were presented at the 2023 European Society for Medical Oncology Congress (ESMO).

Data presented at ESMO highlighted that the pembrolizumab regimen reduced the risk of disease progression or death by 28% across the intent-to-treat population (HR, 0.72; 95% CI, 0.60-0.87; P = .0002).³ A significant PFS improvement in the pembrolizumab arm was also reported in patients with a PD-L1 CPS of 1 or higher, as the experimental combination elicited a 30% reduction in the risk of disease progression or death (HR, 0.70; 95% CI, 0.58-0.85).

Based on an interim analysis with a median follow-up of 38.5 months, the median OS among patients with a PD-L1 CPS of 1 or higher was 20.0 months (95% CI, 17.9-22.7) for patients in the pembrolizumab arm vs 15.7 months (95% CI, 13.5-18.5) for those who received trastuzumab and chemotherapy alone (HR, 0.81; 95% CI, 0.67-0.98). These OS outcomes were not statistically significant at the time of the analysis.

“The majority of patients with gastroesophageal cancer are diagnosed at an advanced stage, at which point, historically, they’ve [had] extremely poor outcomes,” principal investigator Yelena Y. Janjigian, MD, chief attending physician of Gastrointestinal Oncology at Memorial Sloan Kettering Cancer Center, said in a press release on the data presented at ESMO.³ “The results from the KEYNOTE-811 trial further demonstrate the clinical benefit of pembrolizumab with trastuzumab and chemotherapy, which reduced the risk of disease progression or death for patients with advanced HER2-positive disease expressing PD-L1 with a CPS [of 1 or higher].”

The FDA granted accelerated approval to pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or GEJ adenocarcinoma in May 2021 based on findings from the KEYNOTE-811 trial.⁴ In November 2023, the FDA updated the indication for this pembrolizumab combination.⁵ As part of the updated indication, only patients with a PD-L1 CPS of 1 or higher as detected with an FDA-approved test are eligible to undergo treatment with this regimen.

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 2, 2024. https://tinyurl.com/54d5yrmc
2. 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. News release. June 16, 2023. Accessed May 2, 2024. bit.ly/3p903iB
3. KEYTRUDA® (pembrolizumab) plus trastuzumab and chemotherapy significantly improved progression-free survival (PFS) versus trastuzumab and chemotherapy in first-line HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Merck. October 20, 2023. Accessed May 2, 2024. https://tinyurl.com/y6m8ubj7
4. FDA approves Merck’s KEYTRUDA® (pembrolizumab) combined with trastuzumab and chemotherapy as first-line treatment in locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. News release. Merck. May 5, 2021. Accessed May 2, 2024. https://tinyurl.com/yv4yacn8
5. FDA amends pembrolizumab’s gastric cancer indication. News release. FDA. November 7, 2023. Accessed November 9, 2023. https://tinyurl.com/5baeauyy