Phase I data support dual VEGFR2, PD-1 inhibition
medwireNews: Phase I study data suggest that ramucirumab plus pembrolizumab is a feasible treatment option for patients with previously treated advanced non-small-cell lung cancer (NSCLC), urothelial carcinoma, and gastric or gastroesophageal junction adenocarcinoma.
The JVDF trial included 27 patients with NSCLC, 24 with urothelial carcinoma, and 41 with gastric or gastroesophageal junction adenocarcinoma.
All patients received a standard dose of the PD-1 inhibitor pembrolizumab (200 mg intravenously) every 3 weeks in combination with the VEGFR2 antagonist ramucirumab at a dose of 10 mg/kg intravenously on day 1 of a 21-day cycle (NSCLC and urothelial carcinoma patients) or 8 mg/kg intravenously on days 1 and 8 (gastric or gastroesophageal junction adenocarcinoma patients).
Overall, 82% of patients experienced at least one treatment-related adverse event (TRAE), and the researchers, led by Roy Herbst, from Yale School of Medicine in New Haven, Connecticut, USA, say that the treatment combination “showed a manageable safety profile, with no indication that ramucirumab potentiates pembrolizumab toxicity (or vice versa).”
The most common TRAE was fatigue, which was reported by 36% of patients and was typically grade 1 or 2 in severity, followed by hypertension (17%), hypothyroidism (14%), nausea (12%), and decreased appetite (11%).
A quarter (24%) of patients experienced one or more TRAEs of grade 3 or higher, most commonly hypertension (7%) or colitis (5%), and six (7%) patients discontinued treatment due to TRAEs.
Serious adverse events were reported by 58% of patients, just under half of which were related to treatment. These included asthenia and myocardial infarction in 7% of patients with NSCLC each, colitis in 8% of patients with urothelial carcinoma, and abdominal pain in 7% of patients with gastric or gastroesophageal junction adenocarcinoma.
One death, due to pulmonary sepsis in a patient with gastric or gastroesophageal junction adenocarcinoma, was deemed related to treatment.
The researchers also report that “[e]fficacy endpoints in our study showed favourable outcomes compared with immune checkpoint inhibitor monotherapy in other studies.”
Indeed, 30% of patients with NSCLC had a confirmed objective response, as did 13% of those with urothelial carcinoma and 7% of those with gastric or gastroesophageal junction adenocarcinoma. The disease control rates were 85%, 50%, and 51%, respectively.
Median progression-free survival was 9.7, 1.9, and 2.5 months, in the NSCLC, urothelial carcinoma, and gastric or gastroesophageal junction adenocarcinoma cohorts, respectively, while median overall survival was a respective 26.2, 6.4 and 5.9 months.
Writing in The Lancet Oncology, Herbst and co-authors say that their findings “contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways in patients with previously treated advanced or metastatic cancer.”
They continue: “Antitumour activity outcomes in the non-small-cell lung cancer cohort were particularly striking when compared with the other tumour types in this study, which could be driven by the robust activity results in both PD-L1-negative and PD-L1-positive non-small-cell lung tumours.
“Promising antitumour activity results in the gastric or gastro-oesophageal junction adenocarcinoma and urothelial cancer cohorts mainly occurred in PD-L1-positive tumours.”
They researchers conclude: “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 tumours for which single-agent checkpoint inhibitors have failed to show benefit over chemotherapy.”
By Laura Cowen
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