Keytruda Plus Herceptin, Chemo Boosts PFS in HER2+ Gastric/GEJ Cancer

Patients with metastatic HER2-positive gastric or gastroesophageal junction (GEJ) cancer saw improvements in progression-free survival (PFS, the time a patient lives following treatment without a disease spreading or worsening) following the addition of Keytruda (pembrolizumab) to the combination of Herceptin (trastuzumab) and chemotherapy when compared to patients treated with placebo plus Herceptin and chemotherapy in first-line treatment, particularly among patients whose tumors had a PD-L1 combined positive score (CPS) of 1 or more, according to updated data from the phase 3 KEYNOTE-811 trial.

Findings presented at the 2023 ESMO Congress and simultaneously published in The Lancet showed at the second interim analysis conducted at a median follow-up of 28.3 months for the Keytruda arm and 28.5 months for the placebo arm, patients treated with the Keytruda regimen (350 patients) experienced a median PFS of 10 months versus 8.1 months for those given the placebo regimen (348 patients). In patients with a PD-L1 CPS of 1 or more, the median PFS was 10.8 months for the Keytruda arm (298 patients) and 7.2 months for the placebo arm (296 patients).

In findings from the third interim analysis at a median follow-up 38.4 months in the Keytruda group and 38.6 months in the placebo group, the median PFS was 10 months versus 8.1 months for the overall populations in the Keytruda and placebo arms, respectively. In patients with a PD-L1 CPS of at least 1, the median PFS was 10.9 months for the Keytruda arm versus 7.3 months for the placebo arm.

Additional data from the third interim analysis showed that the Keytruda regimen elicited a median overall survival (OS, the time a patient lives following treatment) of 20 months versus 16.8 months for the placebo regimen in the overall population. The median OS in patients with a PD-L1 CPS of 1 or more was 20 months versus 15.7 months for the Keytruda and placebo arms, respectively.

“The addition of (Keytruda) to first-line (Herceptin) and chemotherapy led to meaningful improvement in PFS and overall response rate (ORR, patients whose disease responded to treatment), particularly in patients with dual overexpression of HER2 and PD-L1 in their tumor,” lead study author Dr. Yelena Y. Janjigian, chief of gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center in New York, said in a presentation of the data.

In May 2021, the FDA granted accelerated approval to Keytruda in combination with Herceptin and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma, based on ORR data from the first interim analysis of KEYNOTE-811.

The median age of patients were 62 years and 63 years in the Keytruda and placebo groups, respectively; a majority of patients across both treatment groups were male (81% and 80% for Keytruda and placebo, respectively) and had an ECOG performance state of 1 (58% and 58%). Across both groups, 32% of patients were from Australia, Europe, Israel and North America, 34% were from Asia and 34% were from the rest of the world.

Regarding histology, patients in the Keytruda cohort had diffuse (19%), intestinal (57%) or unknown (24%) subtypes. Patients in the placebo group had diffuse (15%), intestinal (54%) or unknown (31%) subtypes. Furthermore, 69% and 65% of patients in the Keytruda and placebo groups had a primary tumor location of the stomach, respectively. Notably, 85% of patients in both groups had a PD-L1 CPS of 1 or more. Two percent of patients in the Keytruda group versus 1% in the placebo group had microsatellite instability–high disease.

The chemotherapy of choice was capecitabine/oxaliplatin in 85% of patients in both the Keytruda and placebo groups, respectively, and fluoropyrimidine/cisplatin was used in 15% and 14% of patients, respectively.

Additional data showed that the ORR was 73% in patients treated with Keytruda, including a complete response (CR) rate of 17%, a partial response (PR) rate of 56% and stable disease (SD) rate of 19%. The disease control rate (DCR) was 92% and the median DOR was 11.3 months.

The ORR in patients treated with placebo was 60%, including a CR rate of 11%, a PR rate of 49%, a SD rate of 27%, a DCR of 87% and a median DOR of 9.5 months.

Patients who were randomly assigned to the study who received at least one dose of the treatment were evaluated for safety. In the Keytruda group and placebo group, 99% and 100% of patients experienced any-grade treatment-related side effects, respectively. The rates of grade 3 or 4 side effects were 58% and 50%, respectively.

The rates of serious side effects were 26% and 23%, respectively. Four patients (1%) in the Keytruda arm and three patients (1%) in the placebo arm died due to treatment-related side effects. Discontinuation of any drug due to side effects occurred in 36% and 33% of patients treated with Keytruda versus placebo, respectively.

The most frequent side effects of any grade included diarrhea at 47% in the Keytruda group and 42% in the placebo group, nausea at 44% in the Keytruda group and 44% in the placebo group and anemia at 31% in the Keytruda group and 33% in the placebo group.

Janjigian concluded by saying that although the PFS data suggest consideration of this regimen as a first-line treatment option for patients with metastatic HER2-positive gastric/GEJ cancer, the OS benefits of this regimen are yet to be determined.

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