Elsevier

European Journal of Cancer

Volume 138, October 2020, Pages 125-132
European Journal of Cancer

Original Research
Programmed cell death protein 1 inhibitors in advanced cutaneous squamous cell carcinoma: real-world data of a retrospective, multicenter study

https://doi.org/10.1016/j.ejca.2020.07.029Get rights and content

Highlights

  • Patients treated with programmed cell death protein 1 inhibitorsfor advanced cutaneous squamous cell carcinoma were retrospectively analyzed.

  • An extraordinary efficacy in routine clinical use was found, comparable to clinical trials.

  • The response rate was 59%, disease control rate was 80%.

  • Efficacy was high in both locally advanced and metastasized disease.

  • The treatment was very well tolerated in the mostly elderly patients.

Abstract

Background

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending.

Methods

Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity.

Results

Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan–Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity.

Conclusions

PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated.

Introduction

Cutaneous squamous cell carcinoma (cSCC) has the second highest incidence of skin cancers after basal cell carcinoma [1], with rising incidence especially in elderly patients [2]. About 95% of cases are cured with surgery [3], but in unresectable or metastatic disease, treatment remains challenging, with limited data on any type of therapy [4]. Historically, treatment options primarily included palliative chemotherapy and radiotherapy [5]. The introduction of programmed cell death protein 1 (PD-1) inhibitors appeared promising: the pathogenesis of cSCC involves chronic ultraviolet (UV) exposition and therefore high mutational burden [6], as well as immunosuppression [7], making a response to immune checkpoint inhibitors (ICIs) likely.

Phase I and II trials were able to identify that benefit: the PD-1 inhibitor cemiplimab showed an objective response rate (RR) of almost 50% for locally advanced and metastatic cSCC [8]. First data of the CARSKIN trial reported a RR of 38% for the PD-1 inhibitor pembrolizumab [9]. Besides these clinical trials, evidence on real-world patients and long-term outcome are limited [10,11], and there is a need for studies reporting these real-world data [12].

With cSCC being prone to respond to ICIs and due to the lack of potent alternatives, an off label use of PD-1 inhibitors was common even before publication of first data and approval by the Food and Drug Administration and the European Commission.

In this study, we retrospectively evaluated patients treated with PD-1 inhibitors for advanced cSCC outside of clinical trials in German skin cancer centers. We report clinical outcomes including response, progression-free and overall survival (OS), as well as toxicity, including patients with a long follow-up period.

Section snippets

Patient population

This is a multicenter, retrospective study. Patients were included if they received a PD-1–directed therapy, regardless of therapy line, for cSCC. Patients with locally advanced disease, lymphonodular metastases, as well as distant metastases were included. Patients were excluded if treatment initiation was less than 3 months before the time of data collection. All patients were treated in routine clinical practice and not for the purpose of this study. The clinical data were collected from six

Patient characteristics (Table 1)

A total of 46 patients were included, 31 men (67%), with a median age of 77 years (range: 39–92). Six patients (13%) had locally advanced disease with no metastases, 19 patients (41%) had lymphonodular and in transit metastases with no distant metastases and 21 patients (46%) had distant metastases. Primary locations included head and neck in 33 cases (72%, including: lower lip [3], face [14], ears [5], upper head [11]), extremities in 4 cases (9%, all lower extremity), trunk in 7 cases (15%),

Discussion

To the best of our knowledge, this is the first dedicated study of real-world patients on the efficacy of PD-1 inhibitors in advanced cSCC reporting a decent number of patients. Our data confirm the outstanding results of phase II data, transferring them into real world cases. An ORR of 58.7%, combined with a high chance of durable disease control and a relatively low toxicity even in elderly patients shows the potential of ICI in immune-sensitive tumors.

Our clinical data backs the hypothesis

Conclusions

Treatment with PD-1 inhibitors for advanced cSCC provides an exceptional therapy both in clinical trials, and in real-world patients. It should be the new standard of care for patients without contraindications. The very promising data leads to new treatment approaches, with adjuvant and neoadjuvant trials of PD-1 inhibitors already launched. With a high RR and good chance of durable disease control, patients with limited disease may be subject for primary systemic therapy, with or without

Previous publications of patients involved in this study

A 74-year-old patient involved in this study has been subject of a case report published in 2017 [11].

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval

Retrospective analyses of clinical data were approved by the institutional review board of the Medical Faculty of the University Hospital Heidelberg (no. S-069/2010). The ethical committee had agreed to the retrospective analysis of routinely collected clinical data without prior informed consent of patients.

Data availability statement

The data sets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Conflict of interest statement

M.S. received honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD) and Novartis and Pfizer. U.L. has received honoraria from Roche, Merck Sharp and Dohme, Novartis, SUN, Sanofi; has received speaker fees and advisory Board honoraria from Roche, Novartis, Sun, Sanofi; has received research funding from MSD. C.L. has been a member of the advisory board of BMS, MSD, Merck, Sanofi, Roche, Pierre Fabre, Sun Pharma, Amgen, Biontech, Almirall Hermal,

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