New Combination Shows Early Promise in Gastric Cancer

The combination of ramucirumab and pembrolizumab was relatively well tolerated in a phase I trial of several malignancies, including gastric and gastroesophageal junction adenocarcinomas, according to a study published in Lancet Oncology.           

“Mechanisms of resistance to checkpoint inhibitors are probably multifactorial and can include an absence of PD-L1, inhibitory effects in the tumor microenvironment, or both,” wrote study authors led by Roy S. Herbst, MD, PhD, of Yale School of Medicine in New Haven, Connecticut. “Antiangiogenic therapies targeting vascular endothelial growth factor (VEGF) or VEGF receptor-2 (VEGFR-2) can increase trafficking of T cells into tumors and reduce immuno-suppressive cytokines and regulatory T cells and might help to overcome resistance to checkpoint inhibitors.”

The new study combined the VEGFR-2 antagonist ramucirumab with the immune checkpoint inhibitor pembrolizumab. It included 92 patients in total, including 41 with gastric or gastroesophageal junction adenocarcinoma, 27 patients with non–small-cell lung cancer, and 24 with urothelial carcinoma. Patients were treated across 16 academic medical centers in five countries.  

All patients had progressed on previous lines of therapy (a separate cohort of previously untreated patients was also included; these will be reported separately). Eleven patients were treated during a phase Ia dose-limiting toxicity portion; one patient experienced significant toxicities and died on day 40 while on treatment, but this was deemed to be related to progressive disease. The full doses of pembrolizumab 200 mg administered on day 1 of a 21-day cycle and ramucirumab 8 mg/kg administered on days 1 and 8 for those with gastric/gastroesophageal junction adenocarcinoma was used for a phase Ib portion as well.

Patients were followed for a median of 32.8 months. Treatment-related adverse events (TRAE) occurred in 82% of the full cohort, with fatigue (36%) as the most common adverse event. The most common serious treatment-related adverse events included abdominal pain (7% of gastric/gastroesophageal junction patients). Six patients (7%) discontinued treatment due to TRAEs, and one patient died due to a TRAE (pulmonary sepsis).

In the gastric or gastroesophageal junction adenocarcinoma patients, three of 41 (7%) had a confirmed objective response. A total of 21 of those patients (57%) had a decrease in target lesion size. Those patients with programmed death ligand 1(PD-L1)-positive tumors (22 patients) appeared to fare better than those with PD-L1-negative disease, with a median overall survival of 12.6 months compared with 5.2 months, though this was not subject to a statistical comparison. Responses were observed in 30% of the non–small-cell lung cancer patients and in 13% of the urothelial carcinoma patients.

“Given the manageable safety profile and clinical activity shown in this study, the combination of ramucirumab with pembrolizumab could be explored in future trials either with or without chemotherapy, especially in tumors for which single-agent checkpoint inhibitors have failed to show benefit over chemotherapy,” the authors concluded.

In an accompanying editorial, Samuel J. Klempner, MD, of the Massachusetts General Hospital Cancer Center in Boston, and Zev A. Weinberg, MD, of the University of California, Los Angeles, wrote that precision immunotherapy will require a better understanding of patients’ molecular phenotypes.

“Ultimately,” they wrote, “randomized trials to determine the true contribution of each drug are needed to address this unresolved oncology math problem.”