Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial

Patients with cutaneous squamous cell carcinoma (CSCC) frequently require mutilating surgery and adjuvant radiotherapy (RT). CSCC has been demonstrated to be highly responsive to neoadjuvant anti-PD-1 immune-checkpoint blockade (ICB). However, efficacy and safety of neoadjuvant anti-PD-1 combined with anti-CTLA-4 are lacking. In the MATISSE trial, the primary objective was met to investigate the pathological response rate on neoadjuvant nivolumab (NIVO) and nivolumab plus ipilimumab (NIVO + IPI) at the time of standard of care (SOC: surgery ± RT), defined as the proportion of remaining viable tumor cells in the surgical specimen. Fifty patients with stage I-IVa resectable CSCC were treated with NIVO (weeks 0 and 2) or NIVO (weeks 0 and 2) plus low-dose IPI (week 0) before SOC in week 4. The median follow-up was 31 months. Forty patients underwent SOC; 9 of 20 (45%) patients who received NIVO and 10 of 20 (50%) patients who received NIVO + IPI reached a major pathological response (MPR) and 2 of 20 (10%) patients with NIVO and 6 of 20 (30%) with NIVO + IPI reached a partial pathological response (PPR), resulting in pathological response rates of 55% and 80%, respectively. MPR or PPR was accompanied by 2-year disease-specific survival (DSS) of 100%. ICB was safe with 12% (NIVO) and 8% (NIVO + IPI), grade 3, immune-related toxicity without surgical delays. Ten patients opted to decline surgery and RT, of whom nine reached durable organ preservation and a clinical complete remission on two ICB infusions alone, accompanied by a 2-year DSS of 100% and favorable health-related quality of life. Early changes in [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography's total lesion glycolysis can safely select patients for response-guided treatment de-escalation in future trials. The ClinicalTrials.gov identifier is: NCT04620200 .