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 [<sup>18</sup>F]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 .
Authors
- Ton N. Schumacher (ORCID: https://orcid.org/0000-0003-0517-8804)
- Michiel W. M. van den Brekel (ORCID: https://orcid.org/0000-0002-6338-6743)
- Daniela S. Thommen (ORCID: https://orcid.org/0000-0002-7431-2854)
- John B.A.G. Haanen (ORCID: https://orcid.org/0000-0001-5884-7704)
- L.H.E. Karssemakers (ORCID: https://orcid.org/0000-0002-0257-8709)
- Elsemieke I. Plasmeijer (ORCID: https://orcid.org/0000-0002-8846-1930)
- Maurits Wondergem (ORCID: https://orcid.org/0000-0001-8227-9145)
- Lonneke V. van de Poll‐Franse (ORCID: https://orcid.org/0000-0003-0413-6872)
- Barış Karakullukçu (ORCID: https://orcid.org/0000-0002-1700-5743)
- Wouter V. Vogel (ORCID: https://orcid.org/0000-0002-4992-8024)
- Annegien Broeks (ORCID: https://orcid.org/0000-0002-8699-5058)
- Willem Hans Schreuder (ORCID: https://orcid.org/0000-0003-0944-4356)
- Joris L. Vos (ORCID: https://orcid.org/0000-0002-8318-5455)
- Joleen J.H. Traets (ORCID: https://orcid.org/0000-0003-0505-9776)
- Itske Fraterman (ORCID: https://orcid.org/0000-0001-7974-8422)
- Thomas Boere
- Vincent van der Noort (ORCID: https://orcid.org/0000-0002-4910-4535)
- Sten Cornelissen (ORCID: https://orcid.org/0000-0002-9045-6129)
- Laura A. Smit (ORCID: https://orcid.org/0000-0003-1325-4790)
- Petra K. de Koekkoek‐Doll (ORCID: https://orcid.org/0000-0001-9370-6026)
- Arash Navran (ORCID: https://orcid.org/0000-0001-7006-7807)
- Peter J. F. M. Lohuis
- Bram Westerink (ORCID: https://orcid.org/0009-0003-7483-8260)
- Charlotte L. Zuur (ORCID: https://orcid.org/0000-0002-1777-012X)
- Jonas A. Castelijns (ORCID: https://orcid.org/0000-0001-5105-4023)
- Hedda J. van der Hulst (ORCID: https://orcid.org/0000-0002-6932-9838)
- Winan J. van Houdt (ORCID: https://orcid.org/0000-0002-2303-3468)
- W. Martin C. Klop (ORCID: https://orcid.org/0000-0002-6333-971X)
- Jan Paul de Boer (ORCID: https://orcid.org/0000-0001-6218-6128)
- Suzanne Onderwater
- Bernard M. Tijink (ORCID: https://orcid.org/0000-0002-4223-2833)
- Richard Dirven (ORCID: https://orcid.org/0000-0001-9626-9925)
- Fons J. M. Balm
- Sabine E. Breukers (ORCID: https://orcid.org/0009-0007-5667-1187)
- Francesco Missale (ORCID: https://orcid.org/0000-0002-5357-5348)
- Ludi E. Smeele (ORCID: https://orcid.org/0000-0002-9961-4760)
- Lot A. Devriese (ORCID: https://orcid.org/0009-0009-9324-7814)
- Christian U. Blank (ORCID: https://orcid.org/0000-0002-7945-5846)
- Remco de Bree (ORCID: https://orcid.org/0000-0001-7128-5814)
- Valesca P. Retèl (ORCID: https://orcid.org/0000-0002-5624-3234)
- Robert D. Crommelin
- Alexandra G. L. Toppenberg (ORCID: https://orcid.org/0009-0006-5091-1058)
- Stan W. van Dijk (ORCID: https://orcid.org/0009-0006-3161-5659)
- Xiaohang Qiao (ORCID: https://orcid.org/0000-0002-8690-4179)
- Anke Kuijpers
- Martijn van der Heijden
- M. Ostos
- Lilly‐Ann van der Velden
- Esther Maas-Bannink
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Utrecht University (NL)
- Leiden University Medical Center (NL)
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- University Hospital Regensburg (DE)
- Oncode Institute (NL)
- Amsterdam University Medical Centers (NL)
- University of Regensburg (DE)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-10-08
- DOI
- https://doi.org/10.1038/s41591-025-03943-w
- Citations
- 3
- Primary Topic
- Nonmelanoma Skin Cancer Studies
- Type
- article
- Field-Weighted Citation Impact
- 4.06
Funders
- Bristol-Myers Squibb
- American Society of Clinical Oncology