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Soo Park, MD
Soo Park, MD
Posted: Tuesday, October 21, 2025
Cutaneous squamous cell carcinoma (CSCC) represents about one-fifth of all skin cancers. While most cases are curable, approximately 3% to 5% of CSCCs progress to advanced disease. The standard of care for these patients—extensive surgery with or without radiotherapy—may result in reduced quality of life. Previous studies have shown CSCC to be highly responsive to neoadjuvant anti–PD-1 immune-checkpoint blockade; however, the efficacy and safety of neoadjuvant PD-1 inhibition combined with CTLA-4 inhibition has not been established.
MATISSE
In the multicenter, randomized phase II MATISSE trial—reported in Nature Medicine by Sabine E. Breukers, MD, of the Netherlands Cancer Institute, and colleagues—the primary objective was to investigate pathological response rate on two cycles of neoadjuvant nivolumab (arm A) or the combination of nivolumab plus ipilimumab (arm B) before surgery and/or radiotherapy.
Fifty patients with stage I to IVa resectable CSCC (median age = 76 years) were enrolled in the study between August 2020 and December 2022. Of these, 40 patients were randomized to arm A (nivolumab at 3 mg kg-1 in weeks 0 and 2, n = 20) or arm B (nivolumab at 3 mg kg-1 in weeks 0 and 2 and ipilimumab at 1 mg kg-1 in week 0, n = 20) before receiving standard-of-care surgery in week 4. Ten patients chose to forgo surgery after immunotherapy and were replaced to meet the trial’s primary endpoint, defined as the proportion of remaining viable tumor cells in the surgical specimen. The median follow-up was 31 months at data cutoff (September 2024).
Key Results
Among the 40 patients who underwent surgery, major pathological response was achieved in 45% of the nivolumab group (n = 9) and 50% of the nivolumab plus ipilimumab group (n = 10), while partial pathological response occurred in 10% and 30%, respectively, yielding overall pathological response rates of 55% for arm A and 80% for arm B. Patients who achieved major or partial pathological response had a 2-year disease-specific survival rate of 100%. Of the 10 patients who opted out of surgery and radiotherapy after neoadjuvant therapy, 9 achieved durable organ preservation and clinical complete remission after only two infusions—all maintaining 100% 2-year disease-specific survival.
As the authors observed, these findings lead to “the crucial question of whether the current [standard of care] is still required for cure in early responders to ultra-short nivolumab or nivolumab plus ipilimumab in CSCC.”
Treatment was well tolerated, with grade 3 immune-related adverse events occurring in 12% of the nivolumab alone group and 8% of the combination group. The most common adverse events of any grade were fatigue (46%) and infusion reaction (18%). No grade 4 or 5 events were observed, and no surgical delays or increased complication rates occurred based on Clavien-Dindo classification data.
The MATISSE trial demonstrated that short-course nivolumab with or without ipilimumab induces high response rates and durable survival with minimal toxicity in resectable CSCC. According to the investigators, future efforts should focus on response-guided de-escalation using early imaging and biopsy findings so that more patients may be able to avoid surgery or adjuvant radiotherapy.
“Future trials should aim for substantial treatment de-escalation in responders to neoadjuvant [immunotherapy], guided by early and individually reliable biomarkers, to avoid losing the opportunity for cure in nonresponders,” they stated.
Disclosure: For full disclosures of all study authors, visit nature.com.
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