Immunotherapy for the Treatment of Nonmelanoma Skin Cancer

Publication Date: March 19, 2024
Last Updated: May 31, 2024

Diagnosis, workup, and initial staging for MCC

  • Histopathological diagnosis of MCC should include hematoxylin and eosin (H&E) and IHC with evaluation by a pathologist with experience in the diagnosis of skin cancers, when feasible.
  • For patients with MCC, multidisciplinary care team management is optimal.
  • Baseline imaging should be considered in all patients with MCC for the detection of metastatic disease (LE:4).
  • Baseline MCPyV oncoprotein serology testing (eg, AMERK) should be considered, as this has implications for surveillance (LE:3).
  • If, by clinical examination or imaging, a patient is suspected of having nodal or distant metastatic disease, a biopsy should be performed for histological confirmation (LE:3).
  • If imaging and clinical evaluation are negative for metastatic disease, patients should be considered for sentinel lymph node biopsy for staging (LE:1).

Recommended immunotherapies for MCC

  • For patients with metastatic, recurrent, or locally advanced MCC that is not amenable to curative surgery or radiation and for whom no contraindications to immunotherapy are present, first-line therapy with an approved anti-PD-(L)1 ICI is recommended (LE:2).
  • For patients with MCC who experience disease progression while on anti-PD-(L)1 immunotherapy, therapeutic options are limited and include the addition of an anti-CTLA-4 antibody to anti-PD-(L)1 therapy, clinical trials, or chemotherapy. Switching treatments from one anti-PD-(L)1 antibody to another anti-PD-(L)1 antibody is unlikely to be beneficial.
  • While responses to PD-(L)1 blockade are frequent and generally durable, disease progression may occur in a subset of responders, and hence, continued surveillance for MCC progression is warranted.
  • For patients with MCC being treated with anti-PD-(L)1 ICIs, there are no validated biomarkers to predict benefit (including MCPyV viral status or PD-L1 expression).

Novel strategies and promising future directions for MCC

  • For patients with resectable MCC at high risk of recurrence, enrollment in clinical trials of neoadjuvant or adjuvant therapy should be offered where available.
  • For patients with unresectable, locally advanced, metastatic, or recurrent MCC, enrollment in clinical trials of novel agents and novel combinations should be offered where available.
  • Patient selection for immunotherapy treatment of MCC

Special patient populations for MCC

  • For solid organ transplant recipients with MCC who are potential candidates for ICI therapy, healthcare professionals should have a careful risk–benefit discussion with the patient that includes the potential risk of allograft loss, which may result in the need for dialysis (ie, for kidney transplant recipients) or death (eg, recipients of heart, lung, or liver transplants) (LE:1). Chemotherapy is an acceptable alternative first-line therapy in this population (LE:3). Enrollment in clinical trials should be encouraged.
  • For patients with MCC on therapeutic immune suppression, a discussion should be initiated on reducing or modifying immune suppression, if appropriate, before proceeding with ICI therapy.
  • For patients with MCC who are receiving high-dose corticosteroids for reasons other than solid organ allograft preservation, the dose of corticosteroids should be reduced to ≤10 mg prednisone (or equivalent) per day, if possible, prior to initiation of ICI therapy.
  • Caution is advised when treating with ICIs in patients with MCC who have a history of autoimmune disease, as they may experience a flare of their autoimmune disease and/or a distinct irAE. Healthcare professionals should have a careful risk–benefit discussion with the patient, which includes the potential risks associated with an autoimmune flare (LE:1).

Diagnosis, workup, and initial staging for CSCC

  • Histopathological diagnosis of advanced CSCC should include H&E evaluation by a pathologist with experience in the diagnosis of skin cancers, when feasible.
  • For patients with advanced CSCC, multidisciplinary care team management is optimal.
  • Patients with CSCC who are being considered for systemic therapy should be evaluated by appropriate radiological imaging.

Recommended immunotherapies for CSCC

  • For patients with metastatic, recurrent, or locally advanced CSCC that is not amenable to curative surgery or radiation and for whom no contraindications to immunotherapy are present, first-line therapy with an approved anti-PD-1 ICI is recommended (LE:2).
  • While responses to PD-1 blockade are frequent and generally durable, disease progression may eventually occur in a subset of responders, and hence continued surveillance for CSCC progression is warranted.
  • For patients with CSCC being treated with anti-PD-(L)1 ICIs, there are no validated biomarkers that predict benefit (including PD-L1 expression).
  • Neoadjuvant anti-PD-1 therapy prior to curative-intent surgery was associated with a pCR rate of 51% and a major pathologic response rate of 13% in 70 patients with resectable stage II, III, or IV (M0) CSCC in a phase II study (LE:3). Notably, an additional 9 patients were treated but did not undergo surgery. Although not FDA-approved in this setting, neoadjuvant therapy may be considered for carefully selected patients.

Novel strategies and promising future directions for CSCC

  • For patients with resectable CSCC at high-risk of recurrence, neoadjuvant anti-PD-1 therapy may be considered for carefully selected patients. Enrollment in clinical trials of neoadjuvant or adjuvant therapy should be offered where available.
  • For patients with unresectable locally advanced or metastatic CSCC, enrollment in clinical trials of novel agents and novel combinations should be offered where available.

Special patient populations for CSCC

  • For solid organ transplant recipients with CSCC who are potential candidates for ICI therapy, healthcare professionals should have a careful risk–benefit discussion with the patient that includes the potential risk of allograft loss, which may result in the need for dialysis (ie, for kidney transplant recipients) or death (eg, recipients of heart, lung, or liver transplants) (LE:1). Chemotherapy (LE:1) and/or EGFR inhibitors (LE:3) are acceptable alternative first-line therapies in this population. Enrollment in clinical trials should be encouraged.
  • For patients with CSCC who are receiving high-dose corticosteroids for reasons other than solid organ allograft preservation, the dose of corticosteroids should be reduced to ≤10 mg prednisone (or equivalent) per day, if possible, prior to initiation of ICI therapy.
  • Caution is advised when treating with ICIs in patients with CSCC who have a history of autoimmune disease, as they may experience a flare of their autoimmune disease. Healthcare professionals should have a careful risk–benefit discussion with the patient, which includes the potential risks associated with an autoimmune flare (LE:1).
  • For patients with CSCC on therapeutic immune suppression, a discussion should be initiated on reducing or modifying immune suppression, if appropriate, before proceeding with ICI therapy.

Immunotherapy for the treatment of other types of NMSCS

  • For patients with locally advanced or metastatic BCC that is relapsed/refractory to HHIs, or for patients who are intolerant to or not appropriate for HHIs, an approved anti-PD-1 therapy is recommended (LE:3).
  • For patients with resectable BCC at high risk of recurrence, enrollment in clinical trials of neoadjuvant or adjuvant therapy should be offered where available.
  • For patients with unresectable, locally advanced or metastatic BCC, clinical trial enrollment should be offered where available.
  • For patients with advanced rare skin cancers (eg, cutaneous sarcomas, adnexal carcinomas, or sebaceous carcinomas) with progressive disease after first-line therapies or for whom no standard first-line therapies exist, tumors should be analyzed for TMB-H and dMMR/MSI-H. Off-label use of ICIs may be considered, and clinical trial enrollment should be encouraged.
  • For patients with NMSCs who are receiving ICIs, optimal duration is unknown at this time. The panel recommends that therapy should continue for at least 1─2 years. If a patient experiences a confirmed CR, ICI therapy may be discontinued earlier.
  • Patients with MCC, advanced CSCC, or advanced BCC should perform monthly self-skin and lymph node exams. They should also have clinical skin exams by a dermatologist and lymph node exams every 3─6 months for the first 24─36 months after diagnosis, and every 6─12 months thereafter.
  • Post-treatment surveillance imaging for advanced MCC, CSCC, and BCC should be conducted using diagnostic CT with contrast or FDG-PET/CT scans. If indicated by symptoms, MRI may be helpful to image the head and extremities.
  • The frequency of surveillance imaging for MCC should be based on recurrence risk. Surveillance imaging for high-risk MCC is typically conducted every 3─6 months during the first 2 years after diagnosis, and every 6─12 months thereafter until 5 years.
  • Monitoring MCPyV oncoprotein serology (eg, AMERK) every 3─6 months may be used for surveillance of recurrent MCC in seropositive patients as an adjunct to physical exams and scans (LE:3).
  • The frequency of surveillance imaging for advanced CSCC should be based on recurrence risk. Surveillance imaging for high-risk CSCC is typically conducted every 3─6 months for 3 years after diagnosis.
  • For patients with NMSCs being treated with immunotherapy, physical functioning and symptoms should be assessed throughout treatment and post-treatment surveillance.
  • Prior to being treated with immunotherapy, patients and caregivers should be educated about the treatment plan and potential AEs. Explicit call parameters for AEs should be provided. Listing practical information on pamphlets, wallet cards, medical alert bracelets, or other easy-to-carry media is encouraged.
  • For patients undergoing treatment for advanced NMSCs, a multidisciplinary care approach is encouraged with attention to survivorship and consideration for referrals as needed to physical therapy, nutrition, pain and symptoms management, wound care, mental healthcare, financial counseling, fertility counseling, and end of life planning, as needed.

Figures and Tables

Figure 1. Recommended immunotherapies for MCC

Recommendation Grading

Overview

Title

Immunotherapy for the Treatment of Nonmelanoma Skin Cancer

Authoring Organization

Society for Immunotherapy of Cancer

Publication Month/Year

March 19, 2024

Last Updated Month/Year

May 31, 2024

Document Type

Guideline

Country of Publication

US

Document Objectives

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Outpatient, Radiology services, Operating and recovery room

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D002294 - Carcinoma, Squamous Cell, D015266 - Carcinoma, Merkel Cell

Keywords

squamous cell carcinoma, skin cancer, nonmelanoma, Merkel cell carcinoma

Source Citation

Silk AW, Barker CA, Bhatia S, Bollin KB, Chandra S, Eroglu Z, Gastman BR, Kendra KL, Kluger H, Lipson EJ, Madden K, Miller DM, Nghiem P, Pavlick AC, Puzanov I, Rabinowits G, Ruiz ES, Sondak VK, Tavss EA, Tetzlaff MT, Brownell I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer. J Immunother Cancer. 2022 Jul;10(7):e004434. doi: 10.1136/jitc-2021-004434. PMID: 35902131.