Neoadjuvant immunotherapy could be ‘transformative’ in cutaneous squamous cell carcinoma
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Neoadjuvant cemiplimab induced a pathologic complete response among a majority of patients with resectable cutaneous squamous cell carcinoma, according to results of a nonrandomized phase 2 study presented at ESMO Congress.
The 63.3% rate of pathologic complete or major pathologic response is the highest achieved in a multicenter study of single-agent anti-PD-1 neoadjuvant therapy for any solid tumor type, researchers wrote.
The findings, simultaneously published in The New England Journal of Medicine, also showed cemiplimab (Libtayo; Regeneron Pharmaceuticals, Sanofi) had a safety profile consistent with previous reports.
Background
More than 1 million new nonmelanoma skin cancers are diagnosed annually in the U.S., which is nearly equivalent to the number of all other cancer types diagnosed across the country each year, Neil D. Gross, MD, FACS, director of clinical research in the department of head and neck surgery at The University of Texas MD Anderson Cancer Center, told Healio.
“Of these, approximately 20% are squamous cell-derived, making cutaneous squamous cell carcinoma one of the most common cancer types in the U.S.,” he continued.
As incidence of these cancers continues to rise, the cost of treatment has been shown to pose a significant public health burden, Gross said.
“Most cutaneous squamous cell carcinomas are located in the head and neck region, proportionally matching areas of greatest exposure to ultraviolet radiation,” he said. “The proximity of pathology to tissues critical in communication, such as the eyes and ears, and cosmesis ensures substantial morbidity for most patients with cutaneous squamous cell carcinoma.”
Gross and colleagues previously conducted a pilot study that included 20 patients with cutaneous squamous cell carcinoma assigned to two doses of neoadjuvant immunotherapy.
“That study demonstrated unexpectedly extraordinary results, with more than half of patients having a complete pathologic response,” Gross said. “This prompted the current study.”
The study included 79 patients (median age, 73 years; 84.8% men) with resectable stage II to stage IV cutaneous squamous cell carcinoma assigned neoadjuvant cemiplimab dosed at 350 mg once every 3 weeks for up to four doses.
Pathologic complete response on independent review with an assumed historical pathologic complete response of 25% served as the primary endpoint. Pathologic major response on independent review, pathologic complete response and pathologic major response on investigator assessment, objective response on imaging and adverse events served as secondary endpoints.
Key findings
Researchers identified 40 patients (51%; 95% CI, 39-62) with a pathologic complete response and 10 patients (13%; 95% CI, 6-22) with a pathologic major response on independent review.
“To my knowledge, this is the highest response rate to single agent immunotherapy for any solid tumor reported to date,” Gross said.
Researchers additionally observed an objective response on imaging among 54 patients (68%; 95% CI, 57-78).
Adverse events of any grade occurred among 87% of patients, and 18% of patients experienced grade 3 or higher adverse events. The most common any-grade events included fatigue (30.4%) and rash, diarrhea and nausea (13.9% each).
“Based on response to neoadjuvant therapy, several patients in this study were spared function-impairing surgery,” Gross said.
The approach confirmed in the study has the potential to dramatically improve the quality of life for many patients with advanced-stage disease, he added.
Implications
“A new approach to treating advanced-stage, resectable cutaneous squamous cell carcinoma using neoadjuvant immunotherapy has the potential to be transformative and I expect will harken a paradigm shift in how these patients are managed in the future,” Gross said.
“Long-term follow up, including survival and quality-of-life outcomes, are necessary before broad adoption of this approach,” he continued. “Several important questions remain unanswered, including the optimal duration of neoadjuvant therapy, the extent of surgery needed to confirm response and the role of adjuvant therapies. Some patients will progress on neoadjuvant immunotherapy, but for now, neoadjuvant immunotherapy should only be offered to patients with advanced-stage, resectable cutaneous squamous cell carcinoma on trial.”
References:
- Gross ND, et al. Abstract 7890. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
- Gross ND, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2209813.
Perspective
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Leonel Hernandez Aya, MD
The results of this phase 2 trial are practice changing and a meaningful step toward advancing the care of patients with cutaneous squamous cell carcinoma.
Historically, surgery has been the front-line therapy recommended to patients with newly diagnosed or recurrent squamous cell carcinoma that is considered resectable. However, a large proportion of patients present with primary or recurrent tumors in the head and neck, and upfront surgery frequently carries a high risk for morbidity with cosmetic/functional impairment. Furthermore, there is a risk for relapse after surgery and approved adjuvant therapies have limited benefit.
The high pathologic and radiographic responses without new safety signals reported in this study support the use of neoadjuvant cemiplimab for up to four doses in patients with stage II, stage III or stage IV resectable cutaneous squamous cell carcinoma. This approach will allow a large proportion of patients to undergo function-preserving surgery and may improve long-term clinical outcomes. PD-L1 expression and tumor mutational burden are not clearly correlated with responses; therefore, future research on predictive biomarkers and mechanisms of resistance to cemiplimab are needed to develop personalized and effective combination strategies.
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Gross ND, et al. Abstract 7890. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
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