Clinical trials show that an immune checkpoint inhibitor shrinks the tumours of nearly half of patients with incurable, advanced cutaneous squamous-cell carcinoma, an international team led by a researcher at The University of Texas MD Anderson Cancer Centre reports.
"These results mark a potential paradigm shift in the treatment of patients with advanced cutaneous squamous cell carcinoma, who to date have had very limited results with chemotherapy and targeted therapies," said lead author Dr Michael Migden, associate professor of dermatology and of head and neck surgery.
Migden is principal investigator of the international, multicentre phase II registrational clinical trial of cemiplimab, an immune checkpoint inhibitor that works by blocking PD1, a surface receptor on T cells that shuts down immune response to cancer.
Cutaneous squamous cell carcinoma is the second most common skin cancer, with an estimated 1m new cases diagnosed annually. More than 95% of patients are cured by surgery and radiation at the disease's early stages. But for the fraction who progress, there are no systemic therapies approved as a standard of care, the researchers note.
At a median follow-up of 7.9 months, 28 of 59 patients with metastatic disease (47.5%) had an objective response to cemiplimab, defined as at least 30% tumour shrinkage observed via imaging. Four were complete responses, 24 had partial responses, and 82% of responders remain on the drug.
"Patients continue to do well, so median progression-free survival and overall survival have not been reached yet," said Migden, a Mohs surgeon and dermatologic oncologist at MD Anderson. The durable disease control rate of responders plus those with stable disease for at least 105 days was 61%. Migden notes that response rates to chemotherapy regimens or targeted therapy against the epidermal growth factor receptor (EGFR) now used against advanced cutaneous squamous cell carcinoma range from 15%-25%, with many debilitating side effects.
Immunotherapies pose risks of inflammatory side effects that have to be monitored, but otherwise have fewer day-to-day complications than chemotherapy and EGFR inhibitors, Migden said.
Common side effects in the cemiplimab phase II trial were diarrhoea, fatigue, nausea, constipation, and rash. Four patients (6.8%) had to discontinue treatment. Three patients died of adverse events during the trial, but the deaths were not considered related to treatment.
Median age of patients in the phase II trial was 71, with 33 (55.9%) having received prior systemic therapy and 50 (84.7%) having received radiotherapy.
In the phase I trial of patients with metastatic or locally advanced but inoperable disease, 13 of 26 (50%) had a partial response. At 11 months median follow-up, seven patients remained in response. Two patients (7.7%) had to discontinue treatment due to adverse events. Median age was 73.
The US Food and Drug Administration has granted an application for breakthrough therapy status for the drug, providing a faster potential route for FDA approval. Regeneron Pharmaceuticals Inc, and Sanofi are co-developing cemiplimab.
Cutaneous squamous cell carcinoma develops from genetic damage caused by exposure to UV light. These tumours have a high mutation burden, providing a target-rich environment for immune system attack and this cancer also is strongly associated with immune suppression. Those factors made it a strong candidate for PD1 inhibition, which unleashes the immune system to attack cancer.
The clinical trials are funded by Regeneron and Sanofi.
Cutaneous squamous cell carcinoma is not included in national cancer registries, so the incidence of the disease and its mortality rates are unknown. Estimates or annual diagnoses range from 700,000 to 1m. One study estimated that between 3,900 and 8,700 people died from this cancer in 2012.
Background: No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.
Methods: We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.
Results: In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.
Conclusions: Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors.
Michael R Migden, Danny Rischin, Chrysalyne D. Schmults, Alexander Guminski, Axel Hauschild, Karl D Lewis, Christine H Chung, Leonel Hernandez-Aya, Annette M Lim, Anne Lynn S Chang, Guilherme Rabinowits, Alesha A Thai, Lara A Dunn, Brett GM Hughes, Nikhil I Khushalani, Badri Modi, Dirk Schadendorf, Bo Gao, Frank Seebach, Siyu Li, Jingjin Li, Melissa Mathias, Jocelyn Booth, Kosalai Mohan, Elizabeth Stankevich, Hani M Babiker, Irene Brana, Marta Gil-Martin, Jade Homsi, Melissa L Johnson, Victor Moreno, Jiaxin Niu, Taofeek K Owonikoko, Kyriakos P Papadopoulos, George D Yancopoulos, Israel Lowy, Matthew G Fury