Purpose/Objective(s): We recently reported the results of a phase Ib clinical trial in which 10 patients with previously untreated stage I-III (AJCC 8th Ed) p16+ head and neck squamous cell carcinoma (HNSCC) underwent neoadjuvant immunoradiotherapy (NIRT) with nivolumab 240mg IV q2 weeks x3 prior to surgery (NCT03247712). Stereotactic body radiation (SBRT) to gross tumor volume was delivered between doses 1 & 2 of nivolumab in one of two dose finding cohorts: Cohort A (40Gy, 8Gy X5, M-F); and Cohort B (24Gy, 8Gy X3, M-W-F). The pathologic complete response rate (pCR) was 90% and all patients were successfully down-staged prior to surgery. Here we aim to test the hypothesis that nivolumab contributed to the exceptional local response to radiation by modulating the tumor microenvironment via blockade of upregulated PD-L1.
Materials/Methods: Following assessment of dose limiting toxicity in the safety portion of the trial, we opened two expansion cohorts that evaluated NIRT at the lower radiation dose (24Gy, 8Gy X3) with and without immunotherapy: Cohort C consisted of patients with stage I-III HPV+ HNSCC who were treated with SBRT alone; Patients in Cohort D had stage III-IV HPV-negative HNSCC and were treated with nivolumab and SBRT as in Cohort B. Surgery in all cohorts was performed five weeks post-SBRT, followed by adjuvant nivolumab 480mg IV q 4 weeks X3 starting four weeks after surgery. The primary endpoints were pathological response by irPRC and rate of pathologic and radiographic down-staging after neoadjuvant therapy. A Simon two-stage optimal design was applied, assuming that a decrement in T or N stage by week 6 in \u3e 10% of cases would be clinically significant (alpha Z.05 level of significance with a power of 90% to detect a difference when the true rate of down-staging _ 33%).
Results: Between April 8, 2019 and December 17, 2019, 11 patients with previously untreated, loco-regionally advanced HNSCC involving the oral cavity (NZ2), oropharynx (NZ7), and larynx (NZ2) were enrolled into Cohort C (NZ6) or D (NZ5). Neoadjuvant treatment was well tolerated and there were no grade 3 or 4 adverse events. To date, 8/11 patients completed surgery and had evaluable pathologic reports. Of these, all patients were successfully down-staged and one patient with HPV-negative cancer required adjuvant radiation per protocol. Although the pCR rate was higher in Cohorts A and B than in the expansion cohorts evaluated to date, resection specimens were characterized by major pathologic responses (\u3c10% viable tumor cells) in the majority of patients, as well as robust inflammatory infiltrates into the regression bed, plasma cells and cholesterol clefts.
Conclusion: NIRT prior to surgery for loco-regionally advanced HNSCC results in significant rates of major pathologic response and pathologic downstaging regardless of HPV status
