Volume 122, Issue 21 p. 3354-3362
Original Article
Free Access

The efficacy of anti-PD-1 agents in acral and mucosal melanoma

Alexander N. Shoushtari MD

Corresponding Author

Alexander N. Shoushtari MD

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

Weill Cornell Medical College, New York, New York

The first 2 authors contributed equally to this work.

Corresponding author: Alexander N. Shoushtari MD, Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065; Fax: (646) 227-7265; [email protected]Search for more papers by this author
Rodrigo R. Munhoz MD

Rodrigo R. Munhoz MD

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

The first 2 authors contributed equally to this work.

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Deborah Kuk MS

Deborah Kuk MS

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York

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Patrick A. Ott MD, PhD

Patrick A. Ott MD, PhD

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

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Douglas B. Johnson MD

Douglas B. Johnson MD

Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee

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Katy K. Tsai MD

Katy K. Tsai MD

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California

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Suthee Rapisuwon MD

Suthee Rapisuwon MD

Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia

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Zeynep Eroglu MD

Zeynep Eroglu MD

Moffitt Cancer Center, Tampa, Florida

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Ryan J. Sullivan MD

Ryan J. Sullivan MD

Massachussetts General Hospital, Harvard Medical School, Boston, Massachusetts

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Jason J. Luke MD

Jason J. Luke MD

University of Chicago Comprehensive Cancer Center Chicago, Illinois

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Tara C. Gangadhar MD

Tara C. Gangadhar MD

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

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April K. S. Salama MD

April K. S. Salama MD

Duke University School of Medicine, Durham, North Carolina

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Varina Clark BA

Varina Clark BA

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

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Clare Burias BA

Clare Burias BA

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

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Igor Puzanov MD

Igor Puzanov MD

Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee

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Michael B. Atkins MD

Michael B. Atkins MD

Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia

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Alain P. Algazi MD

Alain P. Algazi MD

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California

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Antoni Ribas MD, PhD

Antoni Ribas MD, PhD

Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California

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Jedd D. Wolchok MD, PhD

Jedd D. Wolchok MD, PhD

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

Weill Cornell Medical College, New York, New York

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Michael A. Postow MD

Michael A. Postow MD

Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, New York

Weill Cornell Medical College, New York, New York

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First published: 17 August 2016
Citations: 222

See referenced editorial and related original article on pages 3263-66 and 3344-53, this issue.

Abstract

BACKGROUND

Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described.

METHODS

A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method.

RESULTS

Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity.

CONCLUSIONS

Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354–3362. © 2016 American Cancer Society.

INTRODUCTION

Malignant melanomas encompass a genetically heterogeneous group of neoplasms diagnosed in 74,000 individuals in the United States each year and resulted in approximately 10,000 deaths in 2015.1 Although melanomas most commonly arise from melanocytes in the basal layer of the epidermis (cutaneous melanoma), they can also originate from melanocytes situated within the mucosal surfaces of the body (mucosal melanoma); glabrous skin, including the palms of the hands or the soles of the feet (acral melanoma); or the uveal tract of the eye.2-5 Mucosal and acral melanomas comprise <10% of all newly diagnosed cases in the United States each year; they have distinct genetic and clinical characteristics,6, 7 lower somatic mutational burden,8, 9 and poorer prognosis than stage-matched cutaneous melanomas.10, 11

Historically, the prognosis of all patients with unresectable or metastatic melanoma has been poor, with a 5-year survival rate as low as 6%.12 Over the past 5 years, however, the treatment of cutaneous melanoma has been revolutionized by targeted therapy against mutant v-Raf murine sarcoma viral oncogene homolog (BRAF) and immune-checkpoint inhibitors expressed on T lymphocytes and other immune cells that enhance antitumor immunity. To date, 3 agents that block immune-checkpoint molecules have been approved by the US Food and Drug Administration (FDA) to treat patients with advanced melanoma: ipilimumab (Bristol-Myers Squibb, NY), a monoclonal antibody against cytotoxic T-lymphocyte associated protein 4 (CTLA-4); the anti-programmed cell death receptor 1 (PD-1) agents pembrolizumab (Merck, Darmstadt, Germany) and nivolumab (Bristol-Myers Squibb); as well as the combination of ipilimumab plus nivolumab. Across different trials, PD-1 blockade with either nivolumab or pembrolizumab resulted in response rates of approximately 26% to 44% when used as single agents13-19 and significantly improved overall survival (OS) compared with ipilimumab and dacarbazine.17, 20

Because of their rarity, acral and mucosal melanomas were not reported separately from most clinical trials accruing patients with advanced melanoma. Consequently, despite the routine clinical use of PD-1 blockade, less is known about its efficacy for these specific subtypes. Recent data investigating the efficacy of immune-checkpoint inhibition in cutaneous melanoma, nonsmall cell lung cancer, and microsatellite-unstable colorectal and gynecologic carcinomas suggest that tumors with a higher mutational burden are more likely to respond to these therapies.21-24 Given the lower somatic mutation rates of acral and mucosal melanomas versus cutaneous melanomas, we hypothesized that the efficacy of immune-checkpoint blockade may be lower in these subgroups.

To investigate the efficacy of PD-1 blockade in these less common subtypes of melanoma, we assembled a retrospective, multicenter cohort of patients with advanced or unresectable mucosal or acral melanoma who received treatment with the anti-PD-1 agents nivolumab or pembrolizumab as standard therapy (after FDA approval), through an Expanded Access Program (EAP), or on published clinical trials.

MATERIALS AND METHODS

Study Population

After we obtained approval from the institutional review board at each site, patients aged ≥18 years with advanced acral or mucosal melanoma who received at least 1 dose of nivolumab or pembrolizumab were identified using electronic databases and data query systems of the participating institutions (Memorial Sloan Kettering Cancer Center; n = 29; Dana-Farber Cancer Institute, n = 8; Vanderbilt University Medical Center, n = 8; Massachusetts General Hospital, n = 3; University of California at San Francisco, n = 6; Georgetown University Medical Center, n = 5; and the University of Chicago, n = 1). Patients were included in this study if they received pembrolizumab or nivolumab between January 1, 2010, and April 1, 2015 either as standard clinical practice after approval by the FDA, through an EAP, on national clinical trial 02083484 (NCT02083484), or on another published clinical trial (NCT01295827,13 NCT01295827,25 NCT01927419,26 NCT01024231,27 or NCT0172174619.

Relevant clinical data were retrieved from electronic medical records and included sex; age; stage; Eastern Cooperative Oncology Group performance status; sites of metastatic disease at the initiation of anti-PD1 treatment; the presence of BRAF, neuroblastoma rat sarcoma viral oncogene homolog (NRAS), and KIT proto-oncogene receptor tyrosine kinase (KIT) mutations; the number and characteristics of prior and subsequent systemic therapies; treatment-related variables (anti-PD-1 agent used, duration of treatment, reason for discontinuation, toxicities); and survival status. Toxicities were retrieved from medical records and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, if they were attributed to anti-PD-1 therapy.

Efficacy Assessment and Statistical Considerations

The primary objective of this study was to determine the objective response rate (ORR) of patients with acral and mucosal melanoma who received treatment with anti-PD-1 agents. Radiologic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1,28 and was determined by a study-participating reference radiologist at each site for those patients enrolled in a non-EAP prospective clinical trial. For patients who received treatment with a commercially available drug or through the pembrolizumab EAP, local investigators interpreted responses using RECIST 1.1, with the exception that confirmation scans were not required for objective responses. The ORR was defined as the proportion of patients who achieved a complete response (CR) or a partial response (PR). Patients who received 1 or more doses of therapy without subsequent radiographic evaluation were considered to have progressive disease.

Baseline and treatment characteristics are presented as frequencies and percentages for categorical variables and as medians and ranges for continuous variables and were analyzed using descriptive statistics. Progression free-survival (PFS) was calculated from the date of anti-PD-1 treatment initiation to radiologic progression, change in therapy, death, or last follow-up. OS was estimated from the date of anti-PD-1 treatment initiation to the date of death from any cause or last follow-up. Patients who were alive at the last follow-up were censored. PFS and OS were estimated using the Kaplan-Meier method and are expressed as median values with 2-sided 95% confidence intervals (CIs). The log-rank test was used for comparisons between categorical variables, and the score test was used for continuous variables. Univariate analyses were performed for factors that influenced PFS and OS. P values < .05 were considered significant. All analysis was done using R version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Demographics and Clinical Characteristics at Baseline

In total, 60 patients who received treatment with anti-PD-1 agents were identified, including 35 (58%) who had tumors arising from mucosal sites and 25 (42%) who had tumors arising from acral sites. The median age at the time of PD-1 blockade therapy for the entire cohort was 64 years (range, 35-94 years). The cohort was 55% women overall. Thirty-five patients (58%) had stage IV-M1c disease at the time of PD-1 treatment, and central nervous system (CNS) involvement was present in 9 patients (15%). Among patients with mucosal melanoma, 40% of tumors arose from vulvovaginal sites, 34% arose from anorectal sites, and 26% from head and neck mucosal sites. Demographic details are described in Table 1. An alteration in BRAF, KIT, or NRAS was identified in 17 of 52 tumors (33%) that tested for at least 1 genomic aberration (BRAF, n = 2; KIT, n = 5; NRAS, n = 10) (detailed mutational data are provided in Supporting Table 1; see online supporting information).

Table 1. Demographics and Clinical Characteristics
No. of Patients (%)
Variable Total Acral Melanoma Mucosal Melanoma P
Total no. of patients 60 25 35
Age at PD-1 treatment: Median [range], y 64 [35-94] 64 [35-94] 65 [37-89] .85
Sex .02a
Women 33 (55) 9 (36) 24 (69)
Men 27 (45) 16 (64) 11 (31)
ECOG at treatment initiation 1.00
0 30 (50) 12 (48) 18 (51)
≥1 30 (50) 13 (52) 17 (49)
Site
Hand/foot 18 (30) 18 (72)
Nailbed 3 (5) 3 (12)
Anorectal 12 (20) 12 (34)
Vulvovaginal 14 (23) 14 (40)
Head/neck 9 (15) 9 (26)
Unknownb 4 (7) 4 (16)
Stage at treatment .11
III 6 (10) 5 (20) 1 (3)
IV, M1A 8 (13) 4 (16) 4 (11)
IV, M1B 11 (18) 5 (20) 6 (17)
IV, M1C 35 (58) 11 (44) 24 (69)
Brain metastases 1.00
Yes 9 (15) 4 (16) 5 (14)
No 51 (85) 21 (84) 30 (86)
Liver metastases .053
Yes 18 (30) 4 (16) 14 (40)
No 42 (70) 21 (84) 21 (60)
Mutations .02a
BRAF 2 (3) 2 (8) 0 (0)
KIT 5 (8) 3 (12) 2 (6)
NRAS 10 (16) 6 (24) 4 (11)
Wild typec 35 (58) 9 (36) 26 (74)
NA 8 (13) 5 (20) 3 (9)
Prior systemic therapyd .28
Yes 51 (85) 23 (92) 28 (80)
No 9 (15) 2 (8) 7 (20)
Prior ipilimumab .76
Yes 46 (77) 20 (80) 26 (74)
No 14 (23) 5 (20) 9 (26)
Response to ipilimumabe .03a
POD 37 (80) 13 (65) 24 (92)
PR or SD 9 (20) 7 (35) 2 (8)
  • Abbreviations: BRAF, B-raf proto-oncogene, serine/threonine kinase; ECOG, Eastern Cooperative Oncology Group; KIT, KIT proto-oncogene receptor tyrosine kinase; NA, not assessed; NRAS, neuroblastoma rat sarcoma viral oncogene homolog; PD-1, programmed cell death receptor 1; POD, progression of disease; PR, partial response; SD, stable disease.
  • a These P values indicate statistically significant differences.
  • b These were melanomas for which a precise description of the primary site was missing or was not available.
  • c These mutations were wild type for at least 1 of BRAF, KIT, or NRAS.
  • d Prior systemic therapy for advanced disease included ipilimumab (n = 46), interleukin-2 (n = 6), cytotoxic chemotherapy (n = 7), interferon plus cisplatin (n = 1), trametinib (n = 1), and others (n = 3).
  • e Responses were analyzed among those who had previously received ipilimumab.

Fifty-one patients (85%) had received prior systemic treatments, and the median number of prior therapies was 1 (range, 0-5 therapies). Forty-six patients (77%) received ipilimumab, of whom 9 (20%) achieved stable disease (n = 4) or had an antitumor response (n = 5).

Treatment Details

Nivolumab was received by 20 patients (n = 8 with acral melanoma, n = 12 with mucosal melanoma), all of whom were participants in clinical trials. Ten of 20 patients received standard 3 mg/kg intravenous dosing every 2 weeks, and the remainder received doses ranging from 0.3 mg/kg to 10 mg/kg intravenously every 2 to 3 weeks. Pembrolizumab was received by 40 patients (n = 17 with acral melanoma, n = 23 with mucosal melanoma). The standard dosing of 2 mg/kg every 3 weeks was received by 34 patients (85%), and the remainder (15%) received 10 mg/kg every 2 to 3 weeks.

Overall, 28 patients (47%) received treatment as a part of a clinical trial, and 32 (53%) received treatment with a commercial drug or through an EAP. The median number of doses administered was 6 (range, 1-52 doses), and the median time on treatment was 3.4 months (range, 0.7-37.5 months). Treatment details according to each specific subtype are summarized in Supporting Table 2 (see online supporting information).

Information regarding subsequent treatment after progression on anti-PD-1 therapy was available for 59 of 60 patients. Twenty-eight patients (47%) received at least 1 additional systemic therapy. Seventeen patients (29%) received at least 1 cytotoxic therapy. Twelve patients (20%) received at least 1 immune-based therapy, most commonly ipilimumab (n = 9; 15%) or a standard anti-PD-1 agent (n = 4; 7%), including 2 patients who initially received nivolumab and subsequently received pembrolizumab, 1 patient who received pembrolizumab and subsequently received nivolumab, and 1 patient who was rechallenged with pembrolizumab.

Efficacy Analyses

ORR

Treatment outcomes are summarized in Table 2. Among the patients with acral melanoma, 2 had a CR, and 6 had a PR, for an ORR of 32% (95% CI, 15%-54%). Among those with mucosal melanoma, the ORR was 23% (95% CI, 10%-40%). Progressive disease was the best response for 40% of patients with acral melanoma (95% CI, 21%-61%) and for 57% of patients with mucosal melanoma (95% CI, 39%-74%). The changes in disease burden from baseline are illustrated in Figure 1.

Table 2. Treatment Outcomes
No. of Patients (%)
Outcome Acral Melanoma, n = 25 Mucosal Melanoma, n = 35
Best responsea
CR 2 (8) 0 (0)
PR 6 (24) 8 (23)
SD 7 (28) 7 (20)
POD 10 (40) 20 (57)
ORR [95% CI], % 32 [15-54] 23 [10-40]
mDoR/range, mo 14.7/3.7 to ≥44.0 12.9/2.1 to 15.9
mPFS, mo 4.1 3.9
mOS, mo 31.7 12.4
  • Abbreviations: CI, confidence interval; CR, complete response; mDoR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate; POD, progression of disease; PR, partial response; SD, stable disease.
  • a Response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
Details are in the caption following the image

This is a waterfall plot of objective response for n = 60 patients with primary acral (blue) and mucosal (green) melanoma according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Diamonds indicate patients who clinically progressed without a repeat radiographic assessment (n = 6). Triangles indicate that the best response was progressive disease because of growth in nontarget lesions. Stars indicate partial responses (n = 14) and CR indicates a complete response (n = 2). Dashed outlines indicate investigator-assessed responses (n = 26). Changes > 100% are truncated.

Among the 16 patients whose tumors had a PR or CR, 8 have progressed (50%) during evaluable follow-up. After a median follow-up of 26 months, the median response duration was 14.7 months (range, 3.7 to ≥ 44 months) for patients with acral melanoma and 12.9 months (range, 2.1-15.9 months) for those with mucosal melanoma. There were no objective responses among 4 patients who were rechallenged with anti-PD-1 therapy after progressing on prior pembrolizumab or nivolumab.

On univariate analysis, no variables were associated with response for patients with either acral or mucosal melanomas (Supporting Tables 3 and 4; see online supporting information). Among the 17 patients who had tumors with a known driver in BRAF, NRAS, or KIT, 4 of 10 patients with NRAS mutations responded to PD-1 blockade versus 0 of 5 patients with KIT mutations and 0 of 2 patients with BRAF mutations; however, the difference did not reach statistical significance (P = .41).

PFS

Disease progression status was known in 59 of 60 patients (98%). The majority of patients (74%) experienced progression of disease, whereas 8 patients (13%) remained on PD-1 blockade without progression. Patients with acral melanoma had a median PFS of 4.1 months with a median follow-up of 20 months. Patients with mucosal melanoma had a median PFS of 3.9 months with a median follow-up of 10.6 months (see Fig. 2). On univariate analysis, there was no significant association between primary subsite, mutation status, stage at treatment, CNS or liver involvement, prior therapy, or response to prior ipilimumab with PFS in either acral or mucosal subtypes (Supporting Tables 5 and 6; see online supporting information).

Details are in the caption following the image

The median progression-free survival (PFS) from the time of anti-programmed cell death receptor 1 (anti-PD-1) therapy is illustrated. (A) The median PFS in patients with acral melanoma was 4.1 months with a median follow-up of 20 months. (B) The median PFS in patients with mucosal melanoma was 3.9 months with a median follow-up of 10.6 months.

OS

Across the entire cohort, 25 of 60 patients died. After a median follow-up of 20 months, the median OS for those who had primary acral melanoma was 31.7 months (see Fig. 3). There was no significant association with age, sex, mutation status, CNS/liver involvement, or prior therapy outcomes in acral subtypes (Supporting Table 7; see online supporting information). Given the median follow-up of 10.6 months in patients who had primary mucosal melanoma, OS data are not mature enough to report.

Details are in the caption following the image

The median overall survival (OS) from the time of anti-programmed cell death receptor 1 (anti-PD-1) therapy in patients with acral melanoma was 31.7 months with a median follow-up of 20 months. Follow-up was not mature enough to report the median OS in patients with mucosal melanoma.

Toxicity

Across the entire cohort, 31 of 60 patients (51%) had at least 1 adverse event (AE) attributable to anti-PD-1 treatment. The majority of AEs (81%) were grade 1 or 2. Overall, the most common AEs were fatigue (n = 16), rash (n = 6), and hepatitis (n = 5). No patients in this cohort were diagnosed with pneumonitis. Grade 3 or 4 AEs included grade 4 hemolytic anemia (n = 1); and grade 3 hepatitis (n = 2), retinopathy (n = 1), hyperglycemia (n = 1), and tenosynovitis/arthralgias (n = 1). Two patients (3%) discontinued treatment because of toxicity (grade 3 arthralgias and grade 3 retinopathy). There were no treatment-related deaths.

DISCUSSION

Acral and mucosal melanomas are epidemiologically and molecularly distinct from nonacral cutaneous melanoma,6-9 but limited evidence exists to support the efficacy of immune-checkpoint blockade with anti-PD-1 agents in this setting. To our knowledge, the current cohort represents the first published report of patients with acral melanoma who received treatment with nivolumab or pembrolizumab and is 1 of the first to include patients with mucosal melanoma. In a largely second-line setting, we observed that the response rate was similar in both the acral group (32%) and the mucosal group (23%). The ORR in our patients with mucosal melanoma is numerically identical to the 23% ORR in 86 patients with mucosal melanoma who were treated across multiple prospective trials of nivolumab, although this may have been influenced by an overlap of 7 patients who were included in both cohorts.29 These response rates in mucosal and acral melanoma also are in line with prior published response rates of 26% to 31% in second-line cutaneous melanoma trials of PD-1 blockade with nivolumab or pembrolizumab.15, 16, 18

In our analysis of this cohort, we could not detect a difference in ORR by age, subsite, site of metastasis, or prior therapy. Treatment was well tolerated, and only 2 of 60 patients discontinued therapy because of toxicity. Therefore, the current data support the routine use of PD-1 blockade for patients with advanced or unresectable acral and mucosal melanoma regardless of age, site of primary or metastatic disease, or response to prior therapy. Extrapolating from the ORRs in patients with treatment-naive versus ipilimumab-refractory cutaneous melanoma, it may be reasonable to expect that the efficacy in a treatment-naive cohort would be even higher than that reported in this mostly (85%) pretreated population. Parallels to biochemotherapy in mucosal melanoma can be drawn, in which the ORR ranged from 36% to 54% in a smaller, heterogeneously treated series that demonstrated durable responses in some patients.28, 30, 31 Given the general understanding that PD-1 blockade is tolerated better than biochemotherapy and has demonstrated an OS benefit in cutaneous melanomas, this report supports the use of anti-PD-1–based therapy in the frontline setting for acral and mucosal melanomas.

We acknowledge that the major limitations of this analysis are that it is retrospective in nature and represents a pooled analysis of various doses and schedules for 2 distinct PD-1–blocking agents (nivolumab and pembrolizumab). We believe this is an acceptable limitation because ORRs and PFS rates have not varied significantly within trials that have tested various schedules and doses of anti-PD-1 antibodies. For example, a randomized trial of pembrolizumab at a dose of 10 mg/kg given every 2 or 3 weeks could not detect a difference in the response rate (34% vs 33%, respectively) or the 6-month PFS rate (47% vs 46%, respectively).17 In a second-line setting after ipilimumab, patients who received with pembrolizumab at a dose of either 10 mg/kg or 2 mg/kg every 3 weeks had similar ORRs in both phase 1 and phase 2 trials.16, 18 The phase 1 escalation of nivolumab in patients with cutaneous melanoma did not appear to follow linear dose-response kinetics.14 Therefore, the exact dose and schedule is unlikely to have significantly impacted the clinical efficacy. In addition, the inclusion of patients who received commercial agents or pembrolizumab through the EAP likely provides a more relevant, “real-world” response rate for practitioners who treat patients with these rare tumors outside the context of a clinical trial.

We did not intend to compare nivolumab and pembrolizumab in this study; instead, we pooled patients who had these rare melanoma subtypes to explore the clinical efficacy of anti-PD-1 therapy in this population. It is possible that differences in efficacy between nivolumab and pembrolizumab exist within these subtypes of melanoma. This will require further study once more patients have received treatment with each agent.

Recognizing the limitations of a retrospective analysis that compares unplanned cohorts, the numerically similar response rates in mucosal, acral, and cutaneous melanoma to anti-PD1 therapy raise the question of what biologic mechanisms underlie responses in these subtypes. Several groups have reported that the probability of obtaining clinical benefit to checkpoint blockade in different tumor types is linked to the mutational burden of the tumors themselves. In patients with cutaneous melanoma who received ipilimumab, a higher mutational burden was associated with improved survival.23, 24 In a recent phase 2 trial of nivolumab in patients with mismatch repair (MMR)-deficient carcinomas and MMR-proficient colorectal adenocarcinomas, MMR-deficient cancers had a significantly higher mutational burden (>20-fold) and response rate (40%; 95% CI, 12%-74%) than MMR-proficient colorectal cancers (0%; 95% CI, 0%-20%).21 In a concurrent publication in this issue of Cancer,32 the ORR to PD-1/PD-L1 in uveal melanoma, which has a very low mutational burden,33 was 3%, supporting this notion. However, the somatic mutation rate of both acral and mucosal melanomas has been established as 5-fold to 10-fold lower than the rate of melanomas arising in chronically sun-damaged skin.8, 9 This suggests that the response rate, if it were strictly related to somatic mutational burden, should be lower for mucosal and acral melanomas than for their cutaneous counterparts. More complex mechanisms beyond mutational burden may be contributing to immune responses in these rare melanoma subtypes.

One mechanism of response to PD-1 inhibition may be related to the specific tumor microenvironment present within each tumor. In a retrospective analysis of a prospective trial in patients with cutaneous melanoma who received pembrolizumab, those who had pretreatment tumors that had higher densities of CD8-positive T cells at the invasive margin (particularly those that expressed PD-1) or more clonal expansion of the T-cell receptor were more likely to obtain objective responses.34 A similar analysis of a prospective trial of the PD-L1 inhibitor MPDL3280 across multiple tumor types indicated an association between objective responses and higher PD-L1 and CTLA4 expression as well as a T-helper type 1 gene expression signature.35

Currently, there is a dearth of published data regarding the prevalence and subtypes of tumor-infiltrating lymphocytes (TILs) in acral and mucosal melanomas. The histologic presence of TILs can be a useful marker for distinguishing acral melanoma in situ lesions from benign acral nevi,36 suggesting that most acral melanomas overcome some degree of immune surveillance to metastasize. The presence of TILs was associated with superior clinical outcomes in retrospective analyses of primary acral melanomas and oral cavity mucosal melanomas.37, 38 Future research into TILs and other immune subsets will help elucidate the mechanisms of resistance to immune surveillance, such as β-catenin signaling.39 This, in turn, will help identify patients whose tumors will respond to PD-1 blockade and suggest rational combination strategies.

A large, single-institution analysis of median OS from the time of metastasis for 2920 patients with various melanoma subtypes demonstrated an inferior median OS for the 237 patients who had mucosal melanoma versus the 105 patients who had acral melanomas spanning several decades (9.1 vs 11.4 months; P < .001).11 The median OS in the current cohort for patients with acral melanoma was 31 months, underscoring the magnitude of clinical benefit achieved with modern checkpoint inhibitors and targeted therapy for these patients. The OS data for patients with mucosal melanoma were not mature enough for presentation in this report, and further study is warranted to understand whether this subtype continues to display more aggressive clinical behavior in the era of PD-1 blockade.

Overall, this analysis is the first published report on the efficacy of PD-1 blockade in patients with advanced or unresectable acral and mucosal melanomas, and the results support the routine use of these agents for these rare melanoma subtypes. The role of specific driver mutations, immunologic infiltrates, and potential biomarkers of response and resistance needs to be investigated further in these tumors. The efficacy of newer therapies, such as the combination of ipilimumab and nivolumab, also should be investigated.

FUNDING SUPPORT

Bristol-Myers Squibb (BMS) and Merck provided financial support for the conduct of the trials analyzed retrospectively in this article. Alexander N. Shoushtari, Deborah Kuk, Jedd D. Wolchok, and Michael A. Postow receive support through the National Institutes of Health Cancer Center Support Grant (P30 CA008748).

CONFLICT OF INTEREST DISCLOSURES

Alexander N. Shoushtari reports travel support from BMS and personal fees from Vaccinex and Castle Biosciences outside the submitted work. Rodrigo R. Munhoz reports travel grants from Merck Serrano and personal fees from BMS, Vaccinex, and MSD Pharmaceuticals outside the submitted work. Patrick A. Ott reports personal fees from Amgen, BMS, and Alexion, outside the submitted work. Douglas B. Johnson reports serving on the BMS and Genoptix advisory boards. Tara C. Gangadhar reports grants from Merck outside the submitted work. April K. S. Salama reports grants and personal fees from BMS and grants from Merck and Genentech outside the submitted work. Michael B. Atkins reports grants from BMS; and personal fees from BMS, Merck, and Nektar outside the submitted work; and has served on scientific advisory boards for Caladrius, BMS, and Amgen. Antoni Ribas reports personal fees from Merck, Novartis, Genentech, GlaxoSmithKline, Flexus, Compugen, and Amgen outside the submitted work; has worked as a consultant on behalf of the University of California, Los Angeles for Amgen, Roche, Merck, and Novartis; and has ownership/stock in Kite Pharma. Jedd D. Wolchok reports grants and personal fees from BMS and personal fees from Merck during the conduct of the study.

AUTHOR CONTRIBUTIONS

Alexander N. Shoushtari: Conception/design, data acquisition, data analysis, drafting article, final approval of document, agreement to be accountable for all aspects of the work, and responsible for overall content as guarantor. Rodrigo R. Munhoz: Conception/design, data acquisition, data analysis, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Deborah Kuk: Data analysis and interpretation, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Patrick A. Ott: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Douglas B. Johnson: Data acquisition, drafting article, final approval of document, agreement to be accountable for all aspects of the work. Katy K. Tsai: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Suthee Rapisuwon: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Zeynep Eroglu: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Ryan J. Sullivan: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Jason J. Luke: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Tara C. Gangadhar: Data acquisition, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. April K. S. Salama: Data acquisition, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. Varina Clark: Data acquisition and curation, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Clare Burias: Data acquisition and curation, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Igor Puzanov: Data acquisition, drafting article, final approval of document, and agreement to be accountable for all aspects of the work. Michael B. Atkins: Data acquisition, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. Alain Algazi: Conception/design, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. Antoni Ribas: Conception/design, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. Jedd D. Wolchok: Conception/design, review/editing article, final approval of document, and agreement to be accountable for all aspects of the work. Michael A. Postow: Conception/design, review/editing article, final approval of document, agreement to be accountable for all aspects of the work