Pembrolizumab Improves Survival for Gastric/GEJ Adenocarcinoma

The addition of pembrolizumab (Keytruda) to trastuzumab plus chemotherapy reduced the risk of death by 20% compared with trastuzumab and chemotherapy alone for patients with advanced, unresectable, or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to the final overall survival (OS) analysis of the phase 3 KEYNOTE-811 study (NCT03615326) presented at the 2024 ESMO Congress.¹

After a median follow-up for the final analysis of 50.2 months (range, 31.1-64.4), the median OS was 20.0 months (95% CI, 17.8-22.1) with the addition of pembrolizumab compared with 16.8 months (95% CI, 14.9-18.7) in the comparator arm (HR, 0.80; 95% CI, 0.67-0.94; P = .004). The 36-month OS rate was 28% with the addition of pembrolizumab compared with 23% in the control arm. PD-L1 combined positive score was 1 or greater for 85% of patients in both arms.

"These data support pembrolizumab pus trastuzumab plus chemotherapy as first-line therapy in patients with unresectable or metastatic HER2-positive gastric/GEJ adenocarcinoma with PD-L1 CPS of 1 or more and confirm this regimen as the standard of care in this setting," study investigator Sara Lonardi, MD, from the Veneto Institute of Oncology, said during a presentation of the results. "The curves separate early and stay parallel for all of the time. There is an absolute gain at the prespecified points of 6% at 12 months and 5% at 24 and 36 months."

In the study, 698 patients with G/GEJ adenocarcinoma were randomized to pembrolizumab (n = 350) or matched placebo (n = 348). In both arms, trastuzumab was given at 6 mg/kg following an 8 mg/kg loading dose every 3 weeks (Q3W). This was combined with a chemotherapy regimen of standard dose 5-fluorouracil plus cisplatin or CAPOX. In the investigational arm, pembrolizumab was administered at 200 mg intravenously Q3W. At the final analysis, most patients had discontinued due to disease progression with 11 still ongoing with treatment in the investigational arm compared with 4 in the placebo group.

The baseline characteristics were well balanced between groups. In the pembrolizumab arm, the median age of patients was 62 years, with 41% being older than 65 years. Most patients were male (81%) and most had an ECOG performance status of 1 (58%), with the remainder being an ECOG status of 0. The most common histological subtype was intestinal (57%), with the primary location being the stomach (69%). HER2 IHC was 3% for 82% of patients and 2+ with ISH+ in the remaining 18%. Microsatellite instability was present in 2% of patients. Most selected CAPOX as their chemotherapy regimen (85%).

The progression-free survival (PFS) at the final analysis replicated what was seen at the interim analysis, Lonardi noted, which she said led to this combination already becoming the standard of care in the first line. The median PFS was 10.0 months (95% CI, 8.6-12.2) with pembrolizumab compared with 8.1 months (95% CI, 7.0-8.5) with trastuzumab and chemotherapy alone (HR, 0.73; 95% CI, 0.61-0.87). The 36-month PFS rate was 18% with pembrolizumab compared with 11% in the placebo arm.

There was a gain of 12.6% in the response rate with the addition of pembrolizumab, Lonardi noted. The overall response rate (ORR) with pembrolizumab was 72.6% compared with 60.1% in the placebo arm. The median duration of response was 11.3 months with pembrolizumab compared with 9.5 months in the control arm. At 36 months, 24% of patients in the pembrolizumab arm continued to respond compared with 15% in the placebo group.

In key subgroup population analyses, there were not any specific populations with significant differences, Lonardi said, although some differences were noted. Those of Asian race had less benefit with the addition of pembrolizumab. In this group, which comprised 34% of the study (n = 240), the hazard ratio was 1.05 (95% CI, 0.77-1.43) compared with non-Asian populations (n = 456) where the hazard ratio was 0.72 (95% CI, 0.59-0.87).

By PD-L1 status, those with a CPS of 1 or more saw a 21% reduction in the risk of death with pembrolizumab (HR, 0.79; 95% CI, 0.66-0.95) whereas those with a CPS of less than 1 did not experience a benefit from the PD-1 inhibitor (HR, 1.10; 0.72-1.68). "The group with the CPS of less than 1 is only 15%, which is why the confidence interval is limited in this group," Lonardi noted.

The median OS in the group of patients with CPS of 1 or more was 20.1 months (95% CI, 17.9-22.9) with pembrolizumab compared with 15.7 months (95% CI, 0.13.5-18.5) with placebo. In this same group, the median PFS was 10.9 months (95% CI, 8.5-12.5) with pembrolizumab compared with 7.3 months (95% CI, 6.6-8.4) in the control arm (HR, 0.72; 95% CI, 0.60-0.87). The ORR in this group was 73.2% with pembrolizumab compared with 58.4% in the control arm.

Lonardi said the adverse event (AE) profile remained unchanged at the final analysis. AEs were experienced by most patients, with treatment-related AEs seen in 97% of patients in both arms. Serious AEs were more common in the pembrolizumab arm at 26% compared with 23% in the control group. Grade 3/4 AEs were experienced by 58% of those in the pembrolizumab arm compared with 50% in the control group. An AE led to discontinuation of any drug for 37% of those in the investigational arm and for 34% in the control arm. The most common treatment-related AEs were diarrhea, nausea, and anemia.

"These are mainly due to the chemotherapy part of the regimen, obviously, but there is nothing new here compared to the previously interim analysis or in the immune-mediate adverse event description," Lonardi said.

Based on the earlier assessment of the study, the FDA amended the label for pembrolizumab in November 2023 to include PD-L1 expression.²

References

1. Janjigian YY, Kawazoe A, Bai Y, et al. Final Overall Survival for the Phase III, KEYNOTE-811 Study of Pembrolizumab plus Trastuzumab and Chemotherapy for HER2+ Advanced, Unresectable or Metastatic G/GEJ Adenocarcinoma. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1400O.
2. FDA amends pembrolizumab’s gastric cancer indication. FDA. November 23, 2023. Accessed September 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-amends-pembrolizumabs-gastric-cancer-indication