Reference Detail

Ref Type

Journal Article

PMID

(38456660)

Authors

Corcoran RB, Do KT, Kim JE, Cleary JM, Parikh AR, Yeku OO, Xiong N, Weekes CD, Veneris J, Ahronian LG, Mauri G, Tian J, Norden BL, Michel AG, Van Seventer EE, Siravegna G, Camphausen K, Chi G, Fetter IJ, Brugge JS, Chen H, Takebe N, Penson RT, Juric D, Flaherty KT, Sullivan RJ, Clark JW, Heist RS, Matulonis UA, Liu JF, Shapiro GI

Title

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	30	9	2024 May 01	1739-1749	Clin Cancer Res

URL

Abstract Text

MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi.We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed.A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit.Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS mutant	female reproductive organ cancer	sensitive	Navitoclax + Trametinib	Phase Ib/II	Actionable	In a Phase I/II trial, treatment with the combination of Navitoclax (ABT-263) and Mekinist (trametinib) resulted in a partial response rate of 33.3% (7/21) amongst efficacy evaluable patients with gynecologic cancers harboring mutations in KRAS or NRAS, with a median duration of response of 8.17 months, a median progression-free survival of 4.8 months, and a median overall survival of 18.13 months (PMID: 38456660; NCT02079740).	38456660
NRAS Q61R	ovarian cancer	predicted - sensitive	Navitoclax + Trametinib	Case Reports/Case Series	Actionable	In a Phase I/II trial, treatment with the combination of Navitoclax (ABT-263) and Mekinist (trametinib) resulted in a partial response rate of 33.3% (7/21) amongst efficacy evaluable patients with gynecologic cancers harboring mutations in KRAS or NRAS, including a partial response in a patient with ovarian cancer harboring NRAS Q61R (PMID: 38456660; NCT02079740).	38456660