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

Autor:	Wisinski KB; Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI., Flamand Y; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA., Wilson MA; Department of Oncology, Division of Hematology/Medical Oncology, St Luke's University Health Network, Easton, PA., Luke JJ; Division of Hematology/Oncology, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA., Tawbi HA; MD Anderson Cancer Center, Houston, TX., Hong F; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA., Mitchell EP; Thomas Jefferson University Hospital, Philadelphia, PA., Zwiebel JA; Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Chen H; Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Gray RJ; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA., Li S; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA., McShane LM; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Rubinstein LV; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Patton D; Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, MD., Williams PM; Frederick National Laboratory for Cancer Research, Frederick, MD., Hamilton SR; Department of Pathology, City of Hope, Duarte, CA., Behrens RJ; Iowa-Wide Oncology Research Association NCORP, Des Moines, IA., Pennington KP; Fred Hutchinson Cancer Research Center, Seattle, WA., Conley BA; Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Arteaga CL; University of Texas Southwestern Medical Center, Dallas, TX., Harris LN; Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., O'Dwyer PJ; University of Pennsylvania, Philadelphia, PA., Chen AP; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD., Flaherty KT; Massachusetts General Hospital, Boston, MA.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2023 Apr; Vol. 7, pp. e2200421.
DOI:	10.1200/PO.22.00421
Abstrakt:	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.
Databáze:	MEDLINE
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