Dual Immune Checkpoint Blockade and Hypofractionated Radiation in Recurrent/Metastatic Squamous Cell Carcinomas of the Head and Neck Previously Treated with Immune Checkpoint Inhibitors

Abstract

<h3>Purpose/Objective(s)</h3> This single arm open label phase II study sought to explore the safety and antitumor activity of combined antiPDL1 and CTLA4 blockade with hypofractionated radiation (XRT) in patients with recurrent/metastatic head and neck squamous cell carcinomas (RMHNSCC) who have previously been treated with an immune checkpoint inhibitor (ICI). <h3>Materials/Methods</h3> Patients with RMHNSCC who progressed on prior ICI, ECOG 0/1, a bone or lung metastatic site amenable to XRT and RECIST 1.1 measurable disease apart from the radiated site were eligible. Durvalumab 1500mg IV x 13 doses and tremelimumab 75mg IV x 4 doses were both administered every 4 weeks. Hypofractionated image-guided (HIGRT) or stereotactic (SBRT) XRT was given in 3 fractions every other day to a total dose of 24 Gy starting week 2. The primary endpoint was safety; secondary endpoints were RECIST 1.1 responses in non-radiated measurable lesions and overall survival (OS). Blood was obtained at baseline and at week 4 for flow cytometric peripheral T cell analysis. The accrual goal was 20 patients with the first 6 patients representing a safety run in cohort. This project was approved by our institutional IRB and registered at clinicaltrials.gov (NCT035225). <h3>Results</h3> Between August 2018 and November 2020, 6 patients were enrolled, followed by study closure by the sponsor due to funding. All patients were male, 4 white and 2 Asian, with a median age of 64 years (range 47-67), 4 had oropharynx, 1 oral cavity and 1 hypopharynx as primary sites, 5 were never smokers. All patients had progressed on ICI in the R/M setting (2 nivolumab, 2 pembrolizumab, 1 avelumab and 1 durvalumab). Five patients completed XRT: 4 to lung lesions and 1 to a superior mediastinal LN, no toxicities attributed to the radiation were observed. One patient was unable to receive XRT due to progression. Only 2 patients completed more than 4 treatment cycles (median 2.5, range 1-13 cycles). One dose limiting toxicity (recurrent Grade 2 diarrhea) was observed. Four grade 3 toxicities (neck pain due to tumor, shingles, dyspnea due to disease progression and fatigue) were observed in 3 patients, one of which was deemed treatment related (fatigue). Among 5 evaluable pts, we observed 1 complete response (CR), 3 stable disease (SD), 1 disease progression (PD). The patient with a CR showed an increase in PDL1+ and PD1+ T cells at 4 weeks, which was not observed in the 3 other evaluable patients with PD and SD. With one surviving patient in follow up for 14 months, median OS was 8 months (range 4-14). <h3>Conclusion</h3> In this small study population of previously ICI treated RMHNSCC, durvalumab, tremelimumab and XRT resulted in expected toxicities and limited efficacy. Increase in peripheral PDL1+ and PD1+ T cells may correlate with response and may merit further study.