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

doi:10.1016/S1470-2045(19)30728-4

The Lancet Oncology

Volume 21, Issue 2, February 2020, Pages 294-305

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https://doi.org/10.1016/S1470-2045(19)30728-4 Get rights and content

Summary

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.

Introduction

Advanced cutaneous squamous cell carcinoma comprises locally advanced and metastatic cutaneous squamous cell carcinoma not amenable to curative surgery or curative radiotherapy, or both. Patients with advanced cutaneous squamous cell carcinoma might respond to cytotoxic chemotherapy or epidermal growth factor receptor (EGFR) inhibitors.1, 2, 3 However, durable responses are uncommon with these treatments.⁴ In prospective studies of EGFR inhibition with antibodies or small molecules in patients with advanced cutaneous squamous cell carcinoma, an objective response was reported in 10–31% of patients and median overall survival times were 11–13 months.1, 5, 6, 7 A phase 2 study of cetuximab reported an objective response of 28% and mean overall survival of 8·1 months.²

The low efficacy with cytotoxic chemotherapy or EGFR inhibitors has recently been confirmed in a retrospective study of 32 patients with advanced cutaneous squamous cell carcinoma by the Dermatologic Cooperative Oncology Group (DeCOG) of Germany and Austria.⁴ Similarly, a retrospective analysis of 82 patients with advanced cutaneous squamous cell carcinoma treated with conventional systemic therapy reported a median overall survival of 15 months from the start of first-line therapy.⁸ Therefore, advanced cutaneous squamous cell carcinoma is a life-threatening condition for patients who are treated with cytotoxic chemotherapy or EGFR inhibitors, and it is associated with substantial morbidity, impact on quality of life, and health-care burden.8, 9, 10 Patients older than 65 years are more likely than younger patients to require dose reductions in the first cycle of chemotherapy, underscoring the need for new treatment approaches for patients with advanced cutaneous squamous cell carcinoma, a predominantly elderly population.11, 12

Research in context

Evidence before this study

Until recently, there was no approved systemic therapy for patients with advanced cutaneous squamous cell carcinoma. We previously reported substantial antitumour activity of cemiplimab with durable responses in patients in the metastatic and locally advanced cutaneous squamous cell carcinoma expansion cohorts in a phase 1 study and in a primary analysis of the metastatic cutaneous squamous cell carcinoma cohort (group 1) of a phase 2 study. We searched PubMed from Sept 1, 2010, to Sept 1, 2015, with the search terms “cutaneous squamous cell carcinoma OR squamous cell cancer of the skin AND treatment”, “immunotherapy AND cutaneous squamous cell carcinoma”, and “anti-PD-1 OR pembrolizumab OR nivolumab AND cutaneous squamous cell carcinoma”. This search was restricted to clinical trials. We found two studies that evaluated immunotherapy in cutaneous squamous cell carcinoma. In a phase 2 study, single-agent panitumumab showed an objective response in five (31%) of 16 patients with incurable cutaneous squamous cell carcinoma but the median duration of response was 6 months (range 5·0–17·5) and median overall survival was 11 months. In another relevant phase 2 study, cetuximab showed an objective response in ten (28%; 95% CI 14–45) of 36 patients with incurable cutaneous squamous cell carcinoma; the median duration of response was 6·8 months (95% CI 4·1–8·3) and mean overall survival was 8·1 months (95% CI 6·9–9·3). None of these immunotherapy agents was approved by regulatory bodies for the treatment of patients with cutaneous squamous cell carcinoma. A retrospective study confirmed low efficacy with chemotherapy or targeted therapy in this patient group.

Added value of this study

Findings from this study suggest that cemiplimab is an active treatment option for locally advanced cutaneous squamous cell carcinoma and has an acceptable safety profile. Associations between programmed cell death-ligand 1 (PD-L1) tumour proportion score and clinical activity of cemiplimab and between tumour mutational burden and clinical activity of cemiplimab were explored. Antitumour activity was observed regardless of PD-L1 status. A wide range of tumour mutational burden was found in both responders and non-responders.

Implications of all the available evidence

Our analysis shows meaningful clinical benefit in a patient population that previously had no widely accepted standard of care. It strengthens the previously available evidence that supported the US Food and Drug Administration's approval of cemiplimab-rwlc for patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation, addressing a large unmet need. In exploratory correlative science objectives, immunohistochemistry results indicate that PD-L1 and tumour mutational burden are not predictive biomarkers in locally advanced cutaneous squamous cell carcinoma.

Because of ultraviolet-mediated mutagenesis, the median tumour mutational burden of cutaneous squamous cell carcinoma is approximately 45 mutations per megabase, three times higher than that of skin melanoma.¹³ High tumour mutational burden has been associated with efficacy of programmed cell death 1 (PD-1) checkpoint inhibition in various advanced solid tumour types.¹⁴ Additionally, the strong link between immunosuppression and risk of cutaneous squamous cell carcinoma¹⁵ indicates that natural immunosurveillance has an unusually strong role in controlling this tumour type, suggesting that approaches to enhance antitumour immune responses could be efficacious in treating this disease.

Cemiplimab is a high-affinity, highly potent, human, hinge-stabilised IgG4 monoclonal antibody to the PD-1 receptor.¹⁶ The primary analysis of the metastatic cutaneous squamous cell carcinoma cohort (group 1) of the phase 2 study of cemiplimab showed an objective response in 47% of patients as per independent central review, with emerging evidence of durable response and disease control.¹⁷ Here, we report the clinical activity of cemiplimab from the primary analysis and biomarker evaluation of patients with locally advanced cutaneous squamous cell carcinoma (group 2) from the phase 2 study (NCT02760498).

Section snippets

Study design and participants

Patients with locally advanced cutaneous squamous cell carcinoma (without nodal or distant metastasis) were enrolled in group 2 of the pivotal open-label, phase 2, single-arm trial assessing the clinical activity and safety of cemiplimab in patients with advanced cutaneous squamous cell carcinoma across 25 outpatient clinics in Australia, Germany, and the USA (appendix p 2). Eligible patients were aged 18 years or older, had histologically confirmed locally advanced cutaneous squamous cell

Results

Between June 14, 2016, and April 25, 2018, 78 patients with locally advanced cutaneous squamous cell carcinoma were enrolled, treated with cemiplimab, and included in the present analysis. Baseline characteristics, including reasons why patients were not considered candidates for surgery or radiotherapy according to the investigators, are shown in table 1. Data on the number of patients who were on treatment or off treatment (with reasons) as of the data cutoff are shown in the appendix (p 5).

Discussion

In this primary analysis, the clinical activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma was evident with an objective response observed in 34 (44%) patients by independent central review and in 41 (53%) patients by investigator assessment. Most responses were rapid, with median observed time to response corresponding to the time of first tumour assessment. Responses also show preliminary evidence of durability; longer follow-up analysis will better

Data sharing

Qualified researchers can request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this report. Individual anonymised participant data will be made available once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification.

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

J Am Acad Dermatol

Eur J Cancer

Eur J Cancer

Ann Oncol

J Geriatr Oncol

ESMO Open

Eur J Cancer

Eur J Cancer

Cancer Treat Rev

J Thorac Oncol

Lancet Oncol

Lancet Oncol

Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin

J Clin Oncol

Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer

J Clin Oncol

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase 2 clinical trial

Cancer

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