Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial

Abstract

Background: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma.

Methods: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498.

Findings: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia.

Interpretation: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care.

Funding: Regeneron Pharmaceuticals and Sanofi.

Figure 1:. Characteristics of tumour response to cemiplimab as per independent central review

(A) Best change (percentage) in the sum of product (or products) of perpendicular longest dimensions of skin target lesion (or lesions) from baseline for 56 patients who had baseline skin target lesions and underwent at least one evaluable post-baseline medical photography evaluation as per modified WHO criteria by independent central review. Lesion measurements after progression were excluded. The dashed lines indicate WHO criteria for partial response (≥50% decrease in the sum of products of skin target lesion diameters) and progressive disease (≥25% increase in the sum of products of skin target lesion diameters). 22 patients who either did not have baseline skin target lesions or did not have evaluable post-baseline photography assessment are not included in the figure, but are included as non-responders in the overall response analysis as per the intention-to-treat principle. Eight patients had tumour reductions that met criteria for response on photographic measurements, but are classified as stable (blue bars >50% reduction in target lesions), either because there was no subsequent scan to confirm response (in seven patients) or because the composite response assessment was stable disease (in one patient). Eight of 34 patients with objective responses are not shown in this plot because the composite response assessments per independent central review included consideration of radiology results. (B) Time to response and duration of response in patients who responded to treatment. Each horizontal line represents one patient. Of the 34 responding patients, three had subsequent progressive disease. Among the remaining 31 patients who were still responding at the time of data cutoff, 12 were still on study treatment, nine were in post-treatment follow-up, and ten were off the study. One patient (sixth from bottom) had four progressive disease assessments because of discordance between investigator assessment and independent central review. Five patients with complete responses (top bar, and second, 12th, 17th, and 25th from top) are no longer on the study.

Figure 2:. Kaplan-Meier curves for progression-free survival (as per independent central review; A) and overall survival (B)

Median progression-free survival and median overall survival had not been reached at data cutoff.

Figure 3:. Clinical activity of cemiplimab and tumour mutational burden

(A) Tumour mutational burden for responders (complete or partial response) versus non-responders (stable disease, progressive disease, or not evaluable) as per independent central review. (B) Tumour mutational burden for patients who achieved durable disease control (patients without progressive disease for at least 105 days) versus those who did not. Black lines in each box denote the median; lower and upper boundaries of box denote the IQR; and upper and lower whiskers indicate maximum and minimum values. Individual patients are indicated by open black circles. Open black circles beyond the whiskers are outliers. Open green circles and closed red boxes are duplicates of the outliers (the plots overlap box plots and scatter plots).