An open-label, randomized phase 2 trial of ramucirumab and pembrolizumab versus pembrolizumab as first-line therapy for PD-L1–positive, recurrent or metastatic head and neck squamous cell carcinoma (RM-HNSCC).

6026 Background: Vascular endothelial growth factor (VEGF) is commonly overexpressed in head and neck squamous cell carcinoma (HNSCC). Combination therapies inhibiting VEGF and PD-(L)1 have improved efficacy outcomes compared to PD-(L)1 inhibitors alone in pre-clinical models and in other cancer types. The hypothesis of this randomized phase 2 trial in RM-HNSCC was the objective response rate (ORR) with ramucirumab (a VEGF-2 inhibitor) and pembrolizumab would be higher than pembrolizumab alone. Methods: Eligible patients had untreated RM-HNSCC with PD-L1 CPS >1, an ECOG performance status of 0 or 1, and adequate organ function. RM disease within 6 months of curative-intent systemic therapy was permitted. Patients were randomized (stratification factors: HPV status [+ or -] and PD-L1 CPS [1-19 or ≥20]) 2:1 to ramucirumab 10mg/kg and pembrolizumab 200mg (Arm 1) or pembrolizumab (Arm 2) given on Day 1 of each 3-week cycle. The primary endpoint was tumor response as assessed with RECIST v1.1 by BICR. A two-stage group sequential design was used with an O’Brien-Fleming stopping rule to accept the null hypothesis at a one-sided alternative hypothesis. We hypothesized an ORR of ≥50% in Arm 1 and ≤19% in Arm 2. The required sample sizes for stage 1 and stage 2 to obtain 80% power at the type I error of 5% were 36 and 72, respectively. At the end of stage 1, if the standardized Z test statistic was ≥0.453, the study could proceed to stage 2. Otherwise, the study was to be stopped, and the null hypothesis accepted. Secondary endpoints include duration of response (DoR), progression free survival (PFS), overall survival (OS) and adverse events. Here, the results of the interim analysis are reported per protocol. Results: Thirty-seven patients were enrolled and treated in stage 1. Median age was 65 years (IQR 60-70), 76% were male, and tumor characteristics (including status of HPV and PD-L1 CPS and prior systemic therapy within 6 months) were balanced between the two arms. The ORR was 28% (7 of 25 patients, 95% CI: 12.1-49.4%) in Arm 1 and 33.3% (4 of 12 patients, 95% CI: 9.9-65.1%) in Arm 2 [z= -0.327]. The null hypothesis was accepted, and the trial did not proceed to stage 2. Conclusions: Among patients with previously untreated PD-L1 positive, RM-HNSCC, ramucirumab and pembrolizumab did not result in a higher ORR than pembrolizumab. Clinical trial information: NCT05980000 .