Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas

Abstract

Purpose: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.

Experimental design: Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.

Results: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months.

Conclusions: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.

Figure 1.

(A) Oncoprint of 696 cutaneous and unknown primary melanomas naïve to targeted therapy depicting 9 mutually exclusive classes of RTK-RAS-MAPK pathway drivers and their relationship to primary site, percentage of mutations attributable to an ultraviolet signature, and TMB. (B) Plotting the frequency of oncogenic and presumed oncogenic RTK-RAS-MAPK alterations and how often they are co-altered with other RTK-RAS-MAPK driver alterations identifies a rough dichotomy between ‘sole drivers’ BRAF V600, NRAS Q61, BRAF Class 2 alterations and MAP2K1 indels and frequently co-altered ‘backseat drivers’ such as NRAS non-Q61 alterations, CBL, RAC1, and other RTKs. (C) Plotting the frequency of specific pairs of validated alterations identifies an enrichment for NF1 co-alterations with BRAF Class 3 alterations, CBL, PTPN11/RASA1, and RTKs. (D) Clonality was calculated among 428 cases with driver mutations only (no fusions or copy number changes) and adequate sequencing quality. Of those, 92% had only clonal mutations, 5% had clonal and subclonal, and 3% had subclonal driver alterations only.

Figure 2.

(A) The relationship between mutually exclusive driver class, primary site of melanoma, and TMB. NF1 is the driver with highest TMB and is enriched in head/neck primary sites. BRAF V600E and NRAS Q61 tumors are depleted in head/neck primary sites. (B) TMB gradually rises with increasing patient age at time of primary melanoma diagnosis. (C) Patients with BRAF V600E melanomas have the youngest median age at diagnosis, whereas those with KIT mutant melanomas have the oldest median age.

Figure 3.

(A) Time to treatment failure (TTF) varies significantly by driver class for 181 patients treated with PD-1 monotherapy. Patients with tumors harboring BRAF V600 and NRAS Q61 alterations have inferior TTF and those with NF1 and other driver alterations. (B) TTF does not vary by driver class for 141 patients treated with nivolumab plus ipilimumab. (C) TTF of PD-1 monotherapy varies significantly by primary site of melanoma, with tumors arising from the head/neck faring better than those arising from other sites of the body or with unknown primary melanomas. (D) TTF of nivolumab plus ipilimumab does not vary significantly by primary site of melanoma.

Figure 4.

(A) Swimmer plot of 27 patients treated with genomically-matched therapy following progression on PD-1 +/− CTLA-4 therapy. Eight patients had a TTF >6 months and four patients achieved durable complete responses. (B) Kaplan-Meier curve depicting a median TTF of 3.2 months. (C) Radiographic partial response and pathologic complete response to crizotinib in a cutaneous melanoma harboring a ROS1 fusion. (D) Rapid metabolic complete response to larotrectenib in a cutaneous melanoma with in-transit metastases harboring an NTRK1 fusion (E) Rapid metabolic complete response in bone and liver to trametinib in a cutaneous melanoma harboring BRAF K601E and MEK1 (MAP2K1) E203K missense mutations. (F) Metabolic complete response to PLX8394 in a patient with M1b cutaneous melanoma harboring a BRAF-AGK fusion.