A Phase 2 Clinical Trial of Pembrolizumab with Radiation Following Progression on anti-PD-1 Therapy in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

Purpose/Objective(s) Treatment options for patients (pts) with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who have progressed on anti-PD-1 directed therapy are limited. Some of these pts may have more limited disease (oligo) progression that may be amenable to radiation therapy (RT). RT has not been tested prospectively in this setting. Materials/Methods We performed a Phase 2 trial investigating focused RT with concurrent pembrolizumab (pembro) in pts with SCCHN whose disease progressed on prior PD-1 blockade. Cohort A allowed RT to a single lesion while Cohort B allowed for RT to up to 6 lesions. The primary endpoint was overall progression-free survival (PFS) at 3 months. A two-stage design was used in each cohort with the goal to distinguish 3-month (mo) PFS >65% vs. 35%. Cytometry by time of flight (CyTOF) evaluated circulating immune populations in peripheral blood samples obtained at baseline and over the course of therapy. Results Eighteen pts were enrolled, 6 in Cohort A and 12 in Cohort B. Eight (44%) pts had HPV+ disease (3 in Cohort A, 5 in Cohort B); 16 received prior chemoRT to the HN. Median number of metastases were 8.5 (Cohort A, range 1,>10) and 2 (Cohort B, range 1,>10). The most common protocol RT dose was 40 Gy in 5 fractions (n=9). The two most common sites of radiation were head and neck (n=10) and lung (n=10). Treatment was generally well tolerated with 2 pts experiencing grade 3 toxicity (fatigue, esophagitis) and 2 pts grade 4 toxicity (laryngeal edema, bleeding), all in Cohort B. Median PFS for Cohort A was 1.8 mo (95% CI 0.7-32.9 mo) with one pt progression-free at 3 mo (17%); therefore, this cohort did not proceed to the second stage. In Cohort B, median PFS was 6.5 mo (95% CI 3.3-10.2) with 8/12 pts progression free at 3mo (67%). PFS was associated with smaller RT target (prescription isodose <80cm3, p=0.04), 1-2 vs. >2 metastases (p=0.01), and RT to >50% of metastases (p<0.0001). Median OS was 7.6 mos (95% CI 0.7-32.9 mo) in Cohort A and 10.2 mos in Cohort B (95% CI 6.0-49.7 mo). CyTOF identified that the fraction of circulating CD8+ central memory T-cells (Tcm) was higher at baseline (mean freq. 3.0% vs. 0.9%) and remained elevated following cycle 2 of pembro (mean freq. 3.2% vs. 0.6%), in pts progression free >3mo. Expression of the trafficking and homing marker CXCR5 was also elevated on treatment (p adj.= 0.03) in memory B-cells from pts with PFS>3 mo. Conclusion This prospective phase 2 trial evaluated RT in R/M SCCHN pts following disease oligo-progression on prior anti-PD-1 therapy. RT/pembro resulted in more promising outcomes when RT was used to target the majority/entirety of measurable disease, with median PFS exceeding 6mo. Multiplexed immune cell measurements identified potential biomarkers that may help select patients who may benefit from integrated RT following progression on anti-PD-1 therapy.