Differential Outcomes in Codon 12/13 and Codon 61NRAS-Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients withNRAS-Mutated Tumors

Abstract

Purpose: Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers. Patients and Methods: Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post hoc analysis examined the association of NRAS mutation type with outcome. Results: In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61–mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61–mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (P = 0.03) and PFS (P = 0.007) than those with codon 12 or 13 mutations (n = 16). Conclusions: Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.

Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion

“…Although targeting some genomic alterations such as NTRK fusions have shown frequent and durable responses across tumor types, note that many therapies linked to putative driver alterations lack compelling antitumor efficacy in trials such as NCI-MATCH or TAPUR. [153][154][155][156] This highlights the importance of treating patients on clinical trials instead of off-label use whenever possible so that efficacy and lack of efficacy can be captured and efficacious biomarker-therapy pairs receive regulatory approvals, enabling greater access to effective treatments.…”

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

“…EGFR ) and activating GTPases (e.g. NRAS ) ( Figure 1B, C ) and others 39,40 . Exemplarily, activating (bioinformatically predicted or functionally predescribed) mutations in tyrosine kinase genes such as MET, PDGFRA and methyltransferase enzymes, including EZH2 or deleterious mutations in TSGs like CDKN2A , pose viable targets for molecularly tailored therapy approaches (e.g.…”

Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma

“…Despite having a co-occurring NRAS codon 13 mutation, Patient #2 showed prolonged clinical benefit with ivosidenib. NRAS is mutated in ~3% of cholangiocarcinomas and efforts to therapeutically target NRAS mutations in patients have been unsuccessful to date 4 , 6 , 26 . NRAS mutations promote primary and secondary resistance to ivosidenib in AML but are not a universal marker of resistance, as one study reported a complete response to ivosidenib in 2 of 23 patients with NRAS -mutant AML 14 , 17 .…”