Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade

Abstract

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population.

Keywords: KIT mutation; genetics; immune checkpoint blockade; immunotherapy; mucosal melanoma.

FIGURE 1

(A) Progression‐Free Survival (PFS), and Overall Survival (OS) in months after first immunotherapy for entire DFCI mucosal melanoma cohort. (B) Duration of disease control (DDC)

FIGURE 2

Mutational patterns in mucosal melanoma (top panels, *anal/rectal or vulvovaginal, **periorbital) vary by primary location. (A) entire cohort, (B) DFCI patients only. Mutational patterns observed in mucosal melanoma vary from those observed in cutaneous melanoma (bottom panel). The y‐axis of the color map lists genes that are mutated in 8% or more mucosal melanoma cases or are reported genes of interest in mucosal or cutaneous melanoma. Tumor mutation load (fraction of measured genes with alteration) is displayed for each patient (x‐axis) above the color map

FIGURE 3

(A) Common mutations in mucosal melanoma vary from those observed in cutaneous melanoma, (B‐D) within mucosal melanoma samples, sites of disease also differed in variant composition between anal/rectal, vulvovaginal, and sinus/nasopharynx cases. The y‐axis indicates the negative logtransformed p‐value of the Fisher's exact test between variant/non‐variant counts for each gene between the disease sites (higher is more significant), with thresholds for the individual nominal p‐values indicated by a dotted line at alpha=0.05. The FDR‐adjusted p‐value at alpha=0.1 is shown as a solid line. The x‐axis indicates the relative difference in the frequency of the mutation between the sites described in the panel

FIGURE 4

(A) Mutational load in immunotherapy in patients with and without durable clinical benefit (DCB). (B) Correlation between specific mutations and durable clinical benefit rate for the DFCI mucosal melanoma cohort, ATM (adjusted p‐value =0.15), KIT (adjusted p‐value =0.16). The y‐axis indicates the negative log‐transformed pvalue of the Fisher's exact test between variant/non‐variant counts for DCB and non‐DCB groups (higher is more significant), with thresholds for the individual nominal pvalues indicated by a dotted line at alpha=0.05. The FDR‐adjusted p‐value at alpha=0.1 is shown as a solid line. The x‐axis indicates the relative difference in the rate of clinical benefit between cases with and without a variant for each respective gene; only genes altered in at least 10% of cases are displayed