Frontline Pembrolizumab Plus Trastuzumab/Chemo Improves PFS in HER2+ Advanced Gastric or GEJ Adenocarcinoma

The addition of pembrolizumab (Keytruda) to trastuzumab (Herceptin) and chemotherapy improved progression-free survival (PFS) over trastuzumab and chemotherapy alone when used as a frontline regimen in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, meeting one of the dual primary end points of the phase 3 KEYNOTE-811 trial (NCT03615326).¹

A prespecified subset analysis by PD-L1 expression revealed that the PFS improvement observed in the intention-to-treat (ITT) population with the pembrolizumab combination was limited to those with PD-L1–positive tumors defined as a combined positive score (CPS) of 1 or higher. Notably, most patients (more than 80%) had PD-L1 positivity.

At the time of the prespecified interim analysis, a trend toward improved overall survival (OS with the pembrolizumab regimen was also observed in the ITT population, although this difference was not determined to be statistically significant. This end point will be evaluated at a subsequent analysis, according to Merck. The toxicity profile of the immunotherapy proved to be consistent to what had previously been reported.

Previously, in May 2021, the FDA granted accelerated approval to the combination of pembrolizumab, trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for first-line use in patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma based on KEYNOTE-811 data.² At the time, the pembrolizumab combination elicited an overall response rate (ORR) of 74% (95% CI, 66%-82%) compared with 52% (95% CI, 43%-61%) with the control regimen (1-sided P < .0001). The median duration of response (DOR) was 10.6 months (range, 1.1+ to 16.5+) and 9.5 months (range, 1.4+ to 15.4+), respectively.

Merck has discussed the updated data with the regulatory agency and is working with them to update the current indication for the immunotherapy in HER2-positive gastric or GEJ adenocarcinoma to those with PD-L1–positive disease.¹

Data from the trial will be shared at an upcoming medical conference and with regulatory authorities on a global scale.

“These new data from KEYNOTE-811, demonstrating a significant improvement in PFS, are meaningful and build on the earlier insights from this study that supported the accelerated approval of this [pembrolizumab] combination in the United States for certain patients with HER2-positive gastric or GEJ adenocarcinoma,” Scot Ebbinghaus, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release.

The double-blind, global, phase 3 study enrolled patients with advanced gastric or GEJ adenocarcinoma who had not previously received treatment for advanced disease.³ To participate, patients were required to have HER2 positivity.

Study participants were randomly assigned 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo plus trastuzumab at 6 mg/kg every 3 weeks following a 8-mg/kg loading dose and 5-fluorouracil at 800 mg/m² on days 1 to 5 every 3 weeks plus cisplatin at 80 mg/m² every 3 weeks or CAPOX comprised of capecitabine at 1000 mg/m² twice daily on days 1 to 14 every 3 weeks plus oxaliplatin at 130 mg/m² every 3 weeks.

Key stratification factors comprised geographic region, chemotherapy choice, and PD-1 CPS.

The co-primary end points of the trial were OS and PFS by RECIST v1.1 criteria and by blinded independent central review (BICR). Secondary end points comprised ORR and DOR by RECIST v1.1 criteria and BICR, as well as safety.

At the time of the protocol-specified first interim analysis, 133 patients were in the pembrolizumab arm and 131 were in the placebo arm. The median age was 61.5 years (range, 19-84), and most patients were male and from regions outside of Australia, Europe, Israel, North America, or Asia. About half of patients had an ECOG performance status of 1, and the majority had the primary location of their tumor in the stomach. Regarding histologic subtype, most patients had intestinal disease, followed by indeterminate and diffuse disease. More than 85% of patients had a PD-L1 CPS of 1 or higher. The preferred choice of chemotherapy was CAPOX.

At the 2021 ASCO Annual Meeting, additional data showed that the disease control rate with pembrolizumab vs placebo was 96.2% (95% CI, 91.4%-98.8%) and 89.3% (95% CI, 82.7%-94.0%), respectively. Moreover, 70.3% and 61.4% of patients, respectively, experienced a response that lasted for at least 6 months, and 58.4% and 51.1% of patients, respectively, experienced a response that persisted for 9 or more months

The most common grade 3 to 5 toxicities occurring in at least 20% of patients in the investigative and control arms included diarrhea (7% vs 8%), nausea (5% vs 6%), anemia (9% vs 9%), reduced appetite (2% vs 4%), vomiting (5% vs 2%), decreased platelet count (8% vs 7%), fatigue (4% vs 3%), decreased neutrophil count (7% vs 7%), peripheral sensory neuropathy (3% vs 1%), and increased aspartate aminotransferase (.5% vs .5%).

“We look forward to sharing these results with the medical community and regulatory authorities to ensure this [pembrolizumab]-based regimen is available to appropriate patients, and we are working with the FDA to update the current indication for [pembrolizumab] to those patients whose tumors are PD-L1 positive,” Ebbinghaus added in the press release.¹

References

1. 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 June 16, 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/
2. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. FDA. May 5, 2021. Accessed June 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer
3. Janjigian YY, Kawazoe A, Yanez PE, et al. 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. J Clin Oncol. 2021;39(suppl 15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013