Neoadjuvant Nivolumab With or Without Ipilimumab in Resectable CSCC

Cutaneous squamous cell carcinoma (CSCC) often forces a difficult tradeoff. Surgery remains curative for many patients, but resections can be disfiguring, functionally morbid, and frequently followed by radiotherapy in an older, comorbid population. Anti–PD-1 therapy has already demonstrated activity in advanced CSCC. The next question is more ambitious: can a brief course of immunotherapy before surgery deepen response enough to reduce the need for extensive local therapy?

In a randomized phase 2 study published in Nature Medicine, investigators evaluated 2 cycles of neoadjuvant nivolumab with or without a single low dose of ipilimumab in patients with Stage I to IVa resectable CSCC who were candidates for extensive surgery with or without adjuvant radiotherapy.

Here’s a quick look at the trials and its findings.

High Pathologic Response Within 4 weeks

50 patients, with a median age of 76 years, were randomized 1:1 to nivolumab alone or nivolumab plus ipilimumab. Surgery occurred at week four. The primary endpoint was pathologic response in the surgical specimen.

Among the 40 patients who proceeded to surgery:

• Major pathologic response, defined as ≤10% viable tumor, occurred in 45% with nivolumab and 50% with nivolumab plus ipilimumab.
• Partial pathologic response, defined as 11% to 50% viable tumor, occurred in 10% and 30%, respectively.
• The combined pathologic response rate reached 55% with nivolumab and 80% with the combination.

Pathologic response carried prognostic weight. Patients achieving MPR or PPR had 100% 2-year disease-specific survival, irrespective of treatment arm. And 91% of major responders with a baseline indication for radiotherapy had pathologic downstaging, with several complete responders forgoing radiotherapy was omitted altogether.

Organ Preservation as a Proof of Concept

10 patients declined surgery after immunotherapy. 9 achieved a clinical complete response without further treatment and remained disease-free beyond 2 years. Although not protocol-driven, this observation raises the possibility that surgery may be avoidable in carefully selected early responders.

Safety Considerations

Toxicity was manageable. Grade 3 immune-related adverse events occurred in 12% of patients receiving nivolumab and 8% receiving the combination, with no grade 4 or 5 events and no surgical delays attributable to immune toxicity. This is notable given the advanced age of the cohort.

Health-related quality-of-life analyses suggested that patients who avoided surgery reported better role and social functioning and global health scores early in follow-up. Cost-effectiveness modeling, though exploratory, favored immunotherapy alone in those achieving complete response.

Biomarkers for Response-Guided De-Escalation

The study also explored early biomarkers. A reduction in total lesion glycolysis on FDG-PET at week 4 predicted pathologic response with approximately 90% accuracy and may offer a practical route toward response-adaptive strategies. In contrast, baseline tumor mutational burden was high overall and did not distinguish responders.

Interpreting the Signal

Of course, there are a few factors to keep in mind when interpreting the results. The noncomparative study had a modest sample size and was not powered to detect differences between the treatment arms. Omission of surgery as an outcome here reflected patient preference rather than predefined study criteria. Additional prospective de-escalation trials with longer follow-up are still needed, and external validation is essential before considering omission of routinely in practice.

But the data from this study are compelling. In resectable CSCC, 2 cycles of neoadjuvant nivolumab, with or without ipilimumab produced high pathologic response rates and durable 2-year disease-specific survival, with manageable toxicity. That some patients were able to achieve durable remission without surgery challenges long-standing assumptions about the necessity of extensive resection for many cases.

For clinicians managing high-risk CSCC, the data suggest that a short neoadjuvant immunotherapy window may soon shift treatment planning from mandatory surgery to response-adapted care.

Reference:

Breukers SE, Traets JJH, van Dijk SW, et al. Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial. Nat Med. 2025;31(12):4055-4064. doi:10.1038/s41591-025-03943-w