- Among 50 patients with advanced CSCC planning to undergo extensive or potentially mutilating curative surgery with or without adjuvant RT, a short course (2 infusions) of neoadjuvant immunotherapy with nivolumab or nivolumab plus ipilimumab induced a major pathologic response or a clinical complete response in 54% and 58% of patients, respectively.
- In an exploratory finding, 9 of 50 patients refused surgery and RT after noticing remission of their cancer in weeks 3 to 4; all remained cancer-free after a median follow-up of 18 months, without surgery or RT and without additional immunotherapy courses.
- Prospective studies are needed to validate these findings.
In patients with advanced cutaneous squamous cell carcinoma (CSCC) planning to undergo extensive or mutilating curative surgery, a brief course of neoadjuvant immunotherapy induces high pathologic response rates, according to results from the randomized, phase 2 MATISSE trial presented during the 2023 ASCO Annual Meeting (Abstract 9507).
Among 50 patients who received 2 cycles of nivolumab or nivolumab plus ipilimumab, 54% and 58%, respectively, attained a major pathologic response or a clinical complete response after 4 weeks, reported Charlotte (Lotje) Zuur, MD, PhD, of the Netherlands Cancer Institute Antoni van Leeuwenhoek in Amsterdam (Figure).
Abstract Discussant Ines Pires da Silva, MD, PhD, of the Melanoma Institute Australia and The University of Sydney, called the reported response rates “quite impressive and consistent with a previous neoadjuvant study with anti–PD-1 monotherapy in patients with stage II-IV CSCC.”
The second notable result was an exploratory finding that 9 of the 50 enrolled patients withdrew consent to surgery and radiation therapy (RT) because they noticed remission of their cancer upon 2 infusions of immunotherapy only; all 9 of these patients remained cancer-free after a median follow-up of 18 months, without surgery or RT or additional immunotherapy courses.
The MATISSE trial “provides proof of concept that organ preservation and cure in elderly CSCC patients can be reached via 3 weeks of just 2 infusions of neoadjuvant immunotherapy,” commented Dr. Zuur. However, the trial was not designed to evaluate organ preservation, and this finding must be validated in a prospective study.
The MATISSE trial “provides proof of concept that organ preservation and cure in elderly CSCC patients can be reached via 3 weeks of just 2 infusions of neoadjuvant immunotherapy.” — Dr. Charlotte Zuur
Rationale and Study Design
Today, no systemic therapy has been established as a standard of care for the curative treatment of CSCC, and surgery can be disfiguring.1 Given the activity of immunotherapy in advanced-stage CSCC,2 efforts are underway to evaluate these agents in early-stage disease. A pilot study and a phase 2 study have reported activity with the anti–PD-1 antibody cemiplimab as neoadjuvant therapy in patients with resectable CSCC.1,3
The MATISSE study enrolled patients with stage I-IVa CSCC with an indication for extensive and/or mutilative curative surgery. Patients were assigned to receive either 2 doses of neoadjuvant nivolumab (26 patients) or 1 dose of neoadjuvant nivolumab and ipilimumab followed by 1 dose of neoadjuvant nivolumab alone (24 patients). Surgery was performed in week 4. FDG-PET scanning was performed at baseline and single days before surgery. The primary outcome was histopathologic response rate.
At week 4, after 2 cycles of neoadjuvant therapy, 54% of patients in the nivolumab arm and 58% of patients in the nivolumab/ipilimumab arm had attained a major or complete pathologic response; 60% and 80%, respectively, had attained at least a partial pathologic response.
Forty patients (20 from each arm) proceeded to surgery with or without adjuvant RT. Ten patients withdrew consent to surgery. Nine out of those 10 patients refused surgery and RT after noticing a substantial remission of their cancer in weeks 3 to 4.
After a median follow-up of 18 months, all 9 of these patients remained cancer-free. Exploratory analyses suggest that avoiding surgery and RT also has favorable effects on quality of life and that the use of immunotherapy while withholding standard-of-care treatment could also have health care capacity and cost benefits.
Additionally, the researchers found that sequential FDG-PET scanning at baseline and single days prior to surgery could identify responders to neoadjuvant immunotherapy who might be able to avoid standard-of-care surgery and RT, although prospective validation is needed.
Dr. Zuur emphasized that the organ preservation finding in the MATISSE trial is “anecdotal evidence—it’s only 9 patients.” Thus, there is a need to conduct prospective studies to evaluate whether neoadjuvant immunotherapy can enable organ preservation and cure in those patients.
Dr. da Silva noted that the MATISSE study brings up several questions regarding the potential use of immunotherapy in patients with CSCC, including its role as neoadjuvant therapy to induce pathologic responses and consequently better relapse-free survival. She pointed out that, at a median follow-up of 13 months, patients who had achieved a major pathologic response did not relapse; however, “we need longer follow-up,” she said.
Given that patients in the combination arm only received 1 cycle of combination therapy, she also wondered whether some responses could have deepened with the addition of anti–CTLA-4 in cycle 2.
In addition, Dr. da Silva said that this study provides proof of concept that organ preservation with immunotherapy is achievable in a subset of patients, but requires good biomarkers of response. She emphasized the importance of biomarkers for predicting which patients may be able to “avoid” surgery.
Although these data and other recent studies suggest a potential role for immunotherapy in the treatment of resectable stage I-IVa CSCC, longer follow-up and additional prospective data are needed before immunotherapy can be established as a standard of care for these patients.
— Mindy Tanzola, PhD
- Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568.
- Rischin D, Khushalani NI, Schmults CD, et al. Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis. J Immunother Cancer. 2021;9(8):e002757.
- Ferrarotto R, Amit M, Nagarajan P, et al. Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2021;27(16):4557-4565.