Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review

doi:10.1016/j.jaad.2019.05.077

Journal of the American Academy of Dermatology

Volume 82, Issue 2, February 2020, Pages 440-459

https://doi.org/10.1016/j.jaad.2019.05.077 Get rights and content

Background

Immunotherapy using programmed cell death 1 protein (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors has been increasingly reported in a variety of nonmelanoma skin cancers (NMSCs).

Objective

To analyze the evidence of PD-1 and PD-L1 inhibitors in the treatment of NMSC.

Methods

A primary literature search was conducted with the PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases through October 28, 2018, to include studies on the use of PD-1 or PD-L1 inhibitors in patients for NMSC. Two reviewers independently performed study selection, data extraction, and critical appraisal.

Results

This systematic review included 51 articles. The most robust evidence was in the treatment of Merkel cell carcinoma and cutaneous squamous cell carcinomas, as supported by phase 1 and 2 clinical trials. Treatment of basal cell carcinoma, cutaneous sarcoma, sebaceous carcinoma, and malignant peripheral nerve sheath tumor also showed benefit with PD-1/PD-L1 inhibitors, but data are limited. There does not appear to be efficacy for PD-1/PD-L1 inhibitors in cutaneous lymphomas.

Limitations

More investigation is needed to determine the efficacy, tumor responsiveness, and the safety profile of PD-1 and PD-L1 inhibitors in NMSC.

Conclusion

PD-1 and PD-L1 inhibitors exhibit treatment efficacy in a variety of NMSCs.

Section snippets

Methods

This study was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.¹⁵ A primary literature search was conducted with the databases PubMed, Cochrane Library, Web of Science, and CINAHL on October 28, 2018. Two authors independently screened with the search terms: (pd-L1 OR pd-1 OR pd1 OR pd11 OR programmed death) AND (squamous OR basal OR NMSC OR merkel OR dermatofibrosarcoma OR sebaceous OR dermal sarcoma OR kaposi OR leiomyosarcoma OR clear

Results

Through full-text screening of 5039 nonduplicate articles from 1972 to 2018, 51 studies were included in this systematic review as depicted by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (Fig 1).¹⁵ PD-1/PD-L1 inhibitors used for each NMSC are listed in Table I19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,

Discussion

A review of the literature reveals the utility of PD-1 and PD-L1 inhibitors for difficult to treat NMSCs. The most robust evidence for use of these checkpoint inhibitors was in the treatment of MCC (multiple completed phase 1 and 2 clinical trials), cSCCs (ongoing phase 1 and 2 clinical trials), and BCC (1 nonrandomized phase 1 clinical trial) showing overall benefit (Table II). Most patients included in clinical trials of MCC, cSCC, and BCC had metastatic, locally advanced disease or disease

References (81)

N.L. Syn et al.
De-novo and acquired resistance to immune checkpoint targeting
Lancet Oncol
(2017)
E.A. Eisenhauer et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009)
A.L.S. Chang et al.
Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study
J Am Acad Dermatol
(2019)
J.G.D. Cannon et al.
A case of metastatic basal cell carcinoma treated with continuous PD-1 inhibitor exposure even after subsequent initiation of radiotherapy and surgery
JAAD Case Rep
(2018)
H.L. Kaufman et al.
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial
Lancet Oncol
(2016)
H.A. Tawbi et al.
Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial
Lancet Oncol
(2017)
A. Heine et al.
Successful treatment of refractory leiomyosarcoma with the PD-1 inhibitor nivolumab
Ann Oncol
(2016)
J. Delyon et al.
PD-1 blockade with nivolumab in endemic Kaposi sarcoma
Ann Oncol
(2018)
Y.J. Zheng et al.
Cutaneous CD56(+) T-cell lymphoma developing during pembrolizumab treatment for metastatic melanoma
JAAD Case Rep
(2018)
M. Khunger et al.
Safety and efficacy of PD-1/PD-L1 inhibitors in treatment-naive and chemotherapy-refractory patients with non-small-cell lung cancer: a systematic review and meta-analysis
Clin Lung Cancer
(2018)

Y.K. Chae et al.

Cancer immunotherapy in a neglected population: the current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients

Cancer Treat Rev

(2018)

M.A. Postow et al.

Immune-related adverse events associated with immune checkpoint blockade

N Engl J Med

(2018)

D.M. Pardoll

The blockade of immune checkpoints in cancer immunotherapy

Nat Rev Cancer

(2012)

V.A. Boussiotis

Molecular and biochemical aspects of the PD-1 checkpoint pathway

N Engl J Med

(2016)

D.R. Leach et al.

Enhancement of antitumor immunity by CTLA-4 blockade

Science

(1996)

S.M. Ansell et al.

PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

N Engl J Med

(2015)

F.S. Hodi et al.

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

(2010)

J. Larkin et al.

Combined nivolumab and ipilimumab or monotherapy in untreated melanoma

N Engl J Med

(2015)

M.A. Postow et al.

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma

N Engl J Med

(2015)

M. Reck et al.

Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer

N Engl J Med

(2016)

A. Ribas et al.

Association of pembrolizumab with tumor response and survival among patients with advanced melanoma

JAMA

(2016)

C. Robert et al.

Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

N Engl J Med

(2011)

L.B. Alexandrov et al.

Signatures of mutational processes in human cancer

Nature

(2013)

E. Soura et al.

Programmed cell death protein-1 inhibitors for immunotherapy of advanced nonmelanoma skin cancer: showing early promise

Br J Dermatol

(2016)

A. Liberati et al.

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

BMJ

(2009)

J. Higgins et al.

Cochrane Handbook for Systematic Reviews of Interventions

(2011)

J. Howick et al.

Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence

M.R. Migden et al.

PD-1 Blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

N Engl J Med

(2018)

D. Rischin et al.

Primary analysis of phase 2 results for cemiplimab, a human monoclonal anti-PD-1, in patients with metastatic cutaneous squamous cell carcinoma (mCSCC)

J Clin Oncol

(2018)

K.P. Papadopoulos et al.

Cemiplimab (REGN2810): a fully human anti-PD-1 monoclonal antibody for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—initial safety and efficacy from expansion cohorts (ECs) of phase I study

J Clin Oncol

(2018)

T.K. Owonikoko et al.

Phase 1 study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): final efficacy and safety data

J Clin Oncol

(2018)

G.S. Falchook et al.

Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810

J Immunother Cancer

(2016)

L. Borradori et al.

Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases

Br J Dermatol

(2016)

D.C. Tran et al.

Follow-up on programmed cell death 1 inhibitor for cutaneous squamous cell carcinoma

JAMA Dermatol

(2017)

V. Blum et al.

Nivolumab for recurrent cutaneous squamous cell carcinoma: three cases

Eur J Dermatol

(2018)

A. Chen et al.

Clinical remission of cutaneous squamous cell carcinoma of the auricle with cetuximab and nivolumab

J Clin Med

(2018)

E. Maubec et al.

Pembrolizumab as first line therapy in patients with unresectable squamous cell carcinoma of the skin: interim results of the phase 2 CARSKIN trial

J Clin Oncol

(2018)

D.J. Hermel et al.

PD-1 inhibition in cutaneous squamous cell carcinoma (cSCC). 2018 ASCO Annual Meeting Abstracts

J Clin Oncol

(2018)

A.L.S. Chang et al.

A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell death protein 1 inhibitor

JAMA Dermatol

(2016)

J.K. Winkler et al.

Anti-programmed cell death-1 therapy in nonmelanoma skin cancer

Br J Dermatol

(2017)

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: Funding sources: None.

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ReviewProgrammed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Methods

Results

Discussion

Lancet Oncol

Eur J Cancer

J Am Acad Dermatol

JAAD Case Rep

Lancet Oncol

Lancet Oncol

Ann Oncol

Ann Oncol

JAAD Case Rep

Clin Lung Cancer

Cancer Treat Rev

Immune-related adverse events associated with immune checkpoint blockade

N Engl J Med

The blockade of immune checkpoints in cancer immunotherapy

Nat Rev Cancer

Molecular and biochemical aspects of the PD-1 checkpoint pathway

N Engl J Med

Enhancement of antitumor immunity by CTLA-4 blockade

Science

PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma

N Engl J Med

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

Combined nivolumab and ipilimumab or monotherapy in untreated melanoma

N Engl J Med

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma

N Engl J Med

Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer

N Engl J Med

Association of pembrolizumab with tumor response and survival among patients with advanced melanoma

JAMA

Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

N Engl J Med

Signatures of mutational processes in human cancer

Nature

Programmed cell death protein-1 inhibitors for immunotherapy of advanced nonmelanoma skin cancer: showing early promise

Br J Dermatol

The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

BMJ

Cochrane Handbook for Systematic Reviews of Interventions

Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence

PD-1 Blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

N Engl J Med

Primary analysis of phase 2 results for cemiplimab, a human monoclonal anti-PD-1, in patients with metastatic cutaneous squamous cell carcinoma (mCSCC)

J Clin Oncol

Cemiplimab (REGN2810): a fully human anti-PD-1 monoclonal antibody for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC)—initial safety and efficacy from expansion cohorts (ECs) of phase I study

J Clin Oncol

Phase 1 study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): final efficacy and safety data

J Clin Oncol

Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810

J Immunother Cancer

Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases

Br J Dermatol

Follow-up on programmed cell death 1 inhibitor for cutaneous squamous cell carcinoma

JAMA Dermatol

Nivolumab for recurrent cutaneous squamous cell carcinoma: three cases

Eur J Dermatol

Clinical remission of cutaneous squamous cell carcinoma of the auricle with cetuximab and nivolumab

J Clin Med

Pembrolizumab as first line therapy in patients with unresectable squamous cell carcinoma of the skin: interim results of the phase 2 CARSKIN trial

J Clin Oncol

PD-1 inhibition in cutaneous squamous cell carcinoma (cSCC). 2018 ASCO Annual Meeting Abstracts

J Clin Oncol

A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell death protein 1 inhibitor

JAMA Dermatol

Anti-programmed cell death-1 therapy in nonmelanoma skin cancer

Br J Dermatol

Review
Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review