Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2+ Metastatic G/GEJ cancer

The standard of care (SOC) 1L treatment for HER2+ advanced G/GEJ cancer was modified by examining a new treatment method. The combination of trastuzumab (tras), chemotherapy (chemo), and pembrolizumab (pembro) showed promise in two phase 2 studies. The global, randomized, double-blind, placebo-controlled phase 3 KEYNOTE-811 study (NCT03615326) evaluated the efficacy of pembro + SOC versus SOC alone in individuals with HER2+ metastatic G/GEJ cancer. Patients (pts) with HER2+ G/GEJ cancer who never received treatment, whose cancer cannot be removed or has progressed, and who have an ECOG PS score of 0 or 1 received either 200 mg of pembro IV Q3W or a placebo IV Q3W. All patients were treated with trastuzumab and either 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX), dependent on what the researchers believed to be the most effective combination. Treatment was administered for up to two years until side effects became intolerable or until PD. PFS per RECIST v1.1 by blinded, independent central review (BICR) and OS are the primary endpoints; ORR and DOR based on RECIST v1.1 and safety are secondary endpoints.

The determined whether pembro + SOC significantly improves ORR; the superiority threshold is set at P = 0.002. The difference in ORR is calculated using the Miettinen and Nurminen methods, with geographic region, PD-L1 status, and chemotherapy selection as randomization variables. Among the first 264 participants, 133 were administered pembro + SOC, and 131 were administered placebo + SOC. Only 0.8% of malignancies are MSI-H, while 87.1% are CAPOX. The average duration of follow-up was 12 months (8.5–19.4). The confirmed ORR (95% CI) was 74.4% (66.2-81.6) for pembro + SOC and 51.9% (43.0-60.7) for placebo + SOC (difference, 22.7 percentage points [95% CI, 11.2-33.7], P = 0.00006); the CR rate was 11.3% vs. 3.1%, and the DCR (95% CI) was 96.2% (91.4-98.8) vs. 89.3 (82. The median (range) DOR for pembro + SOC was 10.6 months, compared to 9.5 months for placebo + SOC. At 6 and 9 months, the KM values for DOR were 70.3% versus 61.4% and 58.4% versus 51.1%, respectively.

After the data collection period, 433 out of 434 enrolled patients had been treated (217/217 pembro + SOC and 216/217 control + SOC). 57.1% of pembro + SOC patients and 57.4% of placebo + SOC patients experience adverse events of grade 3 or 4. About 3.2% of pembro + SOC patients and 4.6% of placebo + SOC patients died due to grade 3 or 4 AEs, and 24.4% of pembro + SOC patients and 25.9% of placebo + SOC patients discontinued treatment due to grade 3 or 4 AEs. When pembro was added to trastuzumab and chemotherapy as a 1L treatment for HER2+ metastatic G/GEJ cancer, the overall response rate (ORR) was significantly higher than when trastuzumab and chemotherapy were used alone. Responses were durable, and adverse effects were tolerable. These preliminary findings suggest that pembro plus tras and chemotherapy could be novel treatment options for this population.

Source: https://meetings.asco.org/abstracts-presentations/195925

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03615326

Yelena Y. Janjigian, Akihito Kawazoe, Patricio Eduardo Yanez, Suxia Luo, Sara Lonardi, Oleksii Kolesnik, Olga Barajas, Yuxian Bai, Lin Shen, Yong Tang, Lucjan Wyrwicz, Kohei Shitara, Shukui Qin, Eric Van Cutsem, Josep Tabernero, Lie Li, Chie-Schin Shih, Pooja Bhagia, Hyun Cheol Cheol Chung/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 39, 2021 (suppl 15; abstr 4013) DOI 10.1200/JCO.2021.39.15_suppl.4013