Abstract
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.
Highlights
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival
The IMCISION trial has shown that therapy with nivolumab or nivolumab plus ipilimumab prior to extensive surgery for patients with HNSCC is safe and does not delay standard-of-care
Grade 3‒4 Immune-related adverse events (irAEs) were seen in 33% of patients after NIVO MONO and 38% after COMBO immune checkpoint blockade (ICB), underlining the necessity to closely monitor patients for the occurrence of irAEs in the neoadjuvant and postoperative phase
Summary
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/ 32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). Evidence on neoadjuvant ICB in HPV-negative HNSCC is limited but suggests modest activity of anti-PD-1 monotherapy, with a major pathological response rate at the primary tumor site of 8‒14%25,26. We present a nonrandomized phase Ib/IIa trial (IMCISION, NCT03003637), in which we investigated the safety, feasibility and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to SOC surgery in patients with HNSCC. We show that neoadjuvant NIVO MONO or COMBO ICB can be administered safely, without jeopardizing surgical timelines, and leads to a major pathological response in a substantial minority of patients (17% and 35%, respectively)
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