Trametinib in Patients With NF1-, GNAQ-, or GNA11-Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2

Abstract

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors.

Methods: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss.

Results: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common.

Conclusion: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Trial registration: ClinicalTrials.gov NCT02465060.

FIG 1.

Diagrams for subprotocols (A) S1 and (B) S2. ^aReasons for not receiving an assignment: study suspended (n = 15), assigned to another arm for which the qualifying variant’s level of evidence was higher (n = 7), before study activation (n = 6), assigned to another arm for which accrual was lower (n = 2), and prior treatment of trametinib (n = 1). ^bReasons not enrolled after receiving an assignment: active infection and abnormal brain MRI (n = 1), deteriorating performance status (n = 6), eye problems (n = 1), in hospice care (n = 1), inadequate organ/marrow function (n = 2), interstitial lung disease/pneumonitis (n = 2), intervening news/targeted treatment (n = 2), other investigational treatment (n = 1), patient died (n = 6), patient refusal (n = 4), receiving other therapy (n = 2), and unknown (n = 3). ^cReasons for being nonevaluable: no disease assessment done before death (n = 4), no disease assessment done before NPT (n = 1), baseline scans done outside of specified window (n = 5), withdrew consent (n = 2), different methods of evaluation used (n = 1), no evaluation during treatment (n = 1). ^dReasons for not receiving an assignment: ineligible histology—uveal melanoma (n = 13). ^eReasons not enrolled after receiving an assignment: central screening cohort: ineligible histology (n = 1), ineligible histology and inadequate organ/marrow function (n = 1), and unknown (n = 1). NPT, nonprotocol therapy.

FIG 1.

Diagrams for subprotocols (A) S1 and (B) S2. ^aReasons for not receiving an assignment: study suspended (n = 15), assigned to another arm for which the qualifying variant’s level of evidence was higher (n = 7), before study activation (n = 6), assigned to another arm for which accrual was lower (n = 2), and prior treatment of trametinib (n = 1). ^bReasons not enrolled after receiving an assignment: active infection and abnormal brain MRI (n = 1), deteriorating performance status (n = 6), eye problems (n = 1), in hospice care (n = 1), inadequate organ/marrow function (n = 2), interstitial lung disease/pneumonitis (n = 2), intervening news/targeted treatment (n = 2), other investigational treatment (n = 1), patient died (n = 6), patient refusal (n = 4), receiving other therapy (n = 2), and unknown (n = 3). ^cReasons for being nonevaluable: no disease assessment done before death (n = 4), no disease assessment done before NPT (n = 1), baseline scans done outside of specified window (n = 5), withdrew consent (n = 2), different methods of evaluation used (n = 1), no evaluation during treatment (n = 1). ^dReasons for not receiving an assignment: ineligible histology—uveal melanoma (n = 13). ^eReasons not enrolled after receiving an assignment: central screening cohort: ineligible histology (n = 1), ineligible histology and inadequate organ/marrow function (n = 1), and unknown (n = 1). NPT, nonprotocol therapy.

FIG 2.

Subprotocol 1 response and Kaplan-Meier curves for PFS. (A) Waterfall plot (N = 30) of best % change from baseline responses. This includes the 32 evaluable patients, excluding two patients who had a best response of PD with new lesions that had no recorded measurements. (B) Treatment duration in the 15 patients who achieved a best response of SD or PR. (C) Kaplan-Meier curve for PFS. ^aNew lesions. Cholangio, cholangiocarcinoma; endo, endocrine cancer; gall, gallbladder cancer; GBM, glioblastoma; neuro, peripheral nerve sheath tumor or neurofibroma; neuroendo, neuroendocrine carcinoma; ovar/fallop, ovarian/fallopian tube cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; stom/small int, gastric or small intestine carcinoma; SD, stable disease.

FIG 3.

Subprotocol 2 response and Kaplan-Meier curves for PFS. (A) Waterfall plot (N = 4) of best % change from baseline responses. (B) Treatment duration in the three patients who achieved a best response of SD or PR. (C) Kaplan-Meier curve for PFS. NA, not applicable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIG 4.

Co-occurring genomic alterations in subprotocols S1 and S2. Co-occurring genomic alterations using the NCI-MATCH assay color-coded by: left: variant type; top: copy-number variant (pink), SNV (red), indel (purple), and unified gene fusion (magenta) for each eligible patient; and bottom: information regarding histology and best response on treatment: PR, SD, PD, and UE. Cholangio, cholangiocarcinoma; endo, endocrine cancer; gall, gallbladder cancer; GBM, glioblastoma; neuro, peripheral nerve sheath tumor or neurofibroma; neuroendo, neuroendocrine carcinoma; ovar/fallop, ovarian/fallopian tube cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SNV, single-nucleotide variant; stom/small int, gastric or small intestine carcinoma; UE, unevaluable.

FIG A1.

Lollipop plot showing location and sequence of NF1 mutations in S1 cohort.