When added to first-line chemotherapy in patients with untreated metastatic HER2-positive esophageal, gastroesophageal junction, and gastric adenocarcinoma, the combination of pembrolizumab and trastuzumab produced responses in 87% of patients, with 100% of patients experiencing disease control and the median progression-free survival was almost 1 year, according to the results of a single-center phase II trial from Memorial Sloan Kettering Cancer Center.1
There is synergy and benefit for this [pembrolizumab/trastuzumab] combination in metastatic gastric and gastroesophageal junction tumors.— Yelena Y. Janjigian, MD
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This outcome compares favorably to the historical response rate of 47% reported for patients who received trastuzumab plus chemotherapy in the pivotal ToGA trial,2 which established the current standard of care, according to Yelena Y. Janjigian, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering, who reported the findings at the 2019 Gastrointestinal Cancers Symposium.
The findings suggest “there is synergy and benefit for this combination in metastatic gastric and gastroesophageal junction tumors,” said Dr. Janjigian. “There was an encouraging overall response rate that compares favorably with what we see with historical controls.”
Trastuzumab is approved in combination with chemotherapy as a first-line treatment of metastatic HER2-positive gastric and gastroesophageal junction cancer. Pembrolizumab is approved for use in patients with programmed cell death ligand 1 (PD-L1)–positive recurrent or advanced gastric or gastroesophageal junction adenocarcinoma after two or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing regimens and, if appropriate, HER2-targeted therapy.
Based on preclinical evidence of the benefit of this combination, the researchers hypothesized that combining anti–programmed cell death protein 1 (PD-1) and anti-HER2 therapy would induce T-cell activation, augment antibody-dependent cellular cytosis, and potentiate the antitumor immune response in patients with HER2-positive disease.
For the study, 35 patients were treated, including 14 patients with esophageal cancer, 12 with gastroesophageal junction cancer, and 9 with gastric cancer. Patients had untreated stage IV HER2-positive disease and any PD-L1 expression. Six patients were subsequently found to be HER2-negative; PD-L1 expression status was negative in 12 patients, positive in 14, and unavailable in 9.
Patients received induction treatment with trastuzumab at 8 mg/kg plus pembrolizumab at 200 mg for 1 cycle. Then the doublet was given in combination with capecitabine and oxaliplatin every 3 weeks (5-FU and cisplatin were permitted). The primary endpoint was 6-month progression-free survival.
Among 32 evaluable patients, 87% of patients responded, including complete responses in 9%, and stable disease was seen in 11%. After 6.6 months’ follow-up (range = 0.03–23.3 months), the median progression-free survival was 11.4 months, and 67% of patients were progression-free at 6 months. Median overall survival was not reached, and at 12 months, 76% of patients were alive. These data compare favorably with a reported median overall survival of 13.8 months shown with trastuzumab alone plus chemotherapy in ToGA,2 Dr. Janjigian said.
Computed tomography scans of 23 patients, performed after pembrolizumab/trastuzumab induction therapy but before the start of chemotherapy, showed that 12 patients (52%) had a reduction in tumor volume “even without chemotherapy,” she noted.
No unexpected adverse events/toxicities occurred during the trial. Grade 3 or 4 adverse events were infrequent, the most common being decreased lymphocyte count (12%).
According to the biomarker analysis, patients with PD-L1–positive or –negative tumors had similar progression-free and overall survival times, but nonamplification of ERBB2 by next-generation sequencing was associated with a short duration of response.
No tumors had microsatellite instability. “HER2 status remains important, but PD-L1 status is not a predictor of progression-free survival,” Dr. Janjigian commented. The correlative analysis is looking at T-cell receptor clonality, levels of myeloid-deprived suppressor cells, and cell-free DNA.
An ongoing phase III trial of the combination in the front-line setting, KEYNOTE-811 (ClinicalTrials.gov identifier NCT03615326), “will definitively show what this combination will do with respect to the survival benefit in this population,” she added. ■
DISCLOSURE: Dr. Janjigian has consulted for Bristol-Myers Squibb, Eli Lilly, Daiichi-Sankyo, and Pfizer and has received research funding from Bristol-Myers Squibb, Merck, Amgen, Bayer, Boehringer Ingelheim, and Eli Lilly.
1. Janjigian YY, Chou JF, Simmons M, et al: First-line pembrolizumab, trastuzumab, capecitabine and oxaliplatin in HER2-positive metastatic esophagogastric adenocarcinoma. 2019 Gastrointestinal Cancers Symposium. Abstract 62. Presented January 17, 2019.
2. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.
Harry H. Yoon, MD
Harry H. Yoon, MD, Associate Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, the invited discussant of the study presented by Janjigan et al, commented on the strong rationale for combining an anti-HER2 agent, anti–programmed cell death protein 1 (PD-1)...!-->!-->