Nature Medicine | Phase 2 Randomized Trial of Neoadjuvant Nivolumab Combined with Ipilimumab for Resectable Cutaneous Squamous Cell Carcinoma

This study evaluated the efficacy and safety of neoadjuvant nivolumab combined with ipilimumab in patients with resectable cutaneous squamous cell carcinoma. Results showed that the pathological response rate in the combination therapy group was significantly higher than in the monotherapy group, without significantly increasing treatment-related toxicity. Additionally, some patients achieved complete clinical remission with only two doses of immunotherapy, avoiding surgery and radiotherapy, offering a potential strategy to reduce the burden of surgical and radiation treatments.

 

Literature Overview

This paper, 'Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial,' published in Nature Medicine, reviews and summarizes neoadjuvant immunotherapy strategies for patients with resectable cutaneous squamous cell carcinoma (CSCC). The study primarily analyzed the application of nivolumab (NIVO) alone or in combination with ipilimumab (IPI) before surgery, assessing the pathological response rate, safety, and survival rates within standard treatment (SOC). A total of 50 patients with stage I–IVa resectable CSCC were enrolled, with a median follow-up of 31 months. Results indicated that the combination therapy group had a significantly higher pathological response rate compared to the monotherapy group (80% vs 55%), with no treatment-related surgical delays, providing an early predictive tool for future strategies aimed at reducing treatment intensity.

Background Knowledge

Cutaneous squamous cell carcinoma (CSCC) is one of the most common skin malignancies globally, accounting for approximately 20–25% of all skin cancers. Although most cases of CSCC can be cured surgically, about 3–5% progress to advanced stages with a high risk of recurrence, particularly among elderly patients who often have multiple comorbidities, limiting long-term survival benefits. Surgery and radiotherapy can lead to severe disfigurement, loss of function, and reduced quality of life. CSCC exhibits high tumor mutation burden (TMB), making it highly immunogenic, thus rendering immunotherapy (IT) an important treatment option. Previous studies have shown that PD-1 inhibitors have an objective response rate of 44–50% in advanced CSCC; however, the efficacy and safety of neoadjuvant PD-1 inhibitors with or without CTLA-4 inhibition remain incompletely defined. Based on the MATISSE phase 2 clinical trial, this study explores whether shortening the neoadjuvant treatment duration and adjusting subsequent treatment strategies based on early radiological or pathological evaluations can optimize therapeutic outcomes and reduce toxicity burdens.

 

 

Research Methods and Experiments

This study is a multicenter, non-comparative, phase 2 clinical trial involving 50 patients with resectable I–IVa stage CSCC, with a median age of 76 years. Patients were randomly assigned to two groups: Group A received nivolumab (NIVO) treatment (3 mg/kg at weeks 0 and 2), while Group B received a combination of NIVO (3 mg/kg at weeks 0 and 2) and ipilimumab (IPI) (1 mg/kg at week 0). All patients underwent standard-of-care (SOC) treatment (surgery ± radiotherapy) at week 4. The primary endpoint was the major pathological response (MPR) and partial pathological response (PPR). Secondary endpoints included safety, health-related quality of life (HRQoL), recurrence-free survival (RFS), and overall survival (OS). Additionally, the study evaluated whether early changes in total lesion glycolysis (ΔTLG50%) measured by [18F]FDG-PET/CT could serve as an early predictor of treatment response to guide individualized treatment de-escalation strategies.

Key Conclusions and Perspectives

• Forty patients underwent SOC surgery. In the NIVO group (n=20), 45% (9/20) achieved MPR, 10% (2/20) achieved PPR, for a total pathological response rate of 55%. In the NIVO+IPI group (n=20), 50% (10/20) achieved MPR, and 30% (6/20) achieved PPR, for a total response rate of 80%.
• Patients achieving MPR or PPR had a 2-year disease-specific survival (DSS) of 100%, and those without residual tumor also showed high survival rates. Although the PPR rate was higher in the NIVO+IPI group, it did not significantly improve the MPR rate.
• Ten patients opted out of SOC treatment and received only two doses of IT, of which 9 achieved durable organ preservation and clinical complete remission (CCR), with 2-year DSS, OS, and RFS all at 100%.
• Early ΔTLG50% in primary tumors demonstrated high sensitivity (94%), specificity (86%), and accuracy (92%) in predicting pathological response. In ILN (index lymph node), sensitivity was 91%, specificity 100%, and accuracy 88%, suggesting its feasibility as an early biomarker.
• In the NIVO+IPI group, the proportion of patients achieving PPR was higher than in the NIVO group, but without significant improvement in MPR rates, and no increase in surgical delay or treatment-related toxicity.

Research Significance and Prospects

This study is the first to evaluate the efficacy of dual PD-1 and CTLA-4 inhibition in the neoadjuvant setting for resectable CSCC. It demonstrated that the combination therapy group had a significantly higher pathological response rate, with excellent long-term survival among patients achieving MPR or PPR. Moreover, a subset of patients achieved complete remission with only two doses of IT without requiring surgery or radiotherapy, suggesting potential strategies for treatment de-escalation. The study also confirmed that ΔTLG50% measured by [18F]FDG-PET/CT early in treatment can accurately predict pathological response, providing a reliable biomarker for personalized treatment strategies. Future larger-scale studies are needed to evaluate whether treatment strategies can be dynamically adjusted based on early radiological or pathological assessments to optimize efficacy and reduce treatment burden.

 

 

Conclusion

This study evaluated the efficacy of neoadjuvant nivolumab combined with or without ipilimumab in patients with resectable cutaneous squamous cell carcinoma. Results showed that the combination therapy group had significantly higher pathological response rates compared to the nivolumab monotherapy group, with no significant increase in treatment-related toxicity. Furthermore, a subset of patients who opted out of standard surgery and radiotherapy achieved durable complete remission with only two doses of immunotherapy, demonstrating 100% 2-year survival. The study further validated that early changes in TLG50% measured by [18F]FDG-PET/CT have high sensitivity and specificity in predicting treatment response, offering a potential biomarker for future treatment de-escalation. These findings suggest that certain patients may not require standard interventions and could achieve organ preservation and disease control with short-course immunotherapy alone, opening new avenues for personalized treatment strategies.

 

Sabine E Breukers, Joleen J H Traets, Stan W van Dijk, John BAG Haanen, and Charlotte L Zuur. Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial. Nature Medicine.