Reference Detail

Ref Type

Abstract

PMID

Authors

R.B. Corcoran K.T. Do J. Cleary A. Parikh O. Yeku C.D. Weekes L. Ahronian G. Mauri J. Tian J. Brugge D. Juric K.T. Flaherty R.J. Sullivan J. Clark R. Heist U.A. Matulonis J.F. Liu G.I. Shapiro

Title

664P Final results of a 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
Annals of Oncology	34	Supplement 2	October 2023	S467	Ann Oncol

URL

https://www.annalsofoncology.org/article/S0923-7534(23)02687-X/fulltext

Abstract Text

Background MEK inhibitors (MEKi) lack clinical monotherapy efficacy in most RAS-mutant cancers and typically produce only a cytostatic response in preclinical RAS-mutant cancer models. BCL-XL is an anti-apoptotic BCL2 family protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. Combined BCL-XL/MEK inhibition led to tumor regressions in mouse models of RAS-mutant cancers. Methods We conducted a dose escalation study (NCT02079740) of the BCL2, BCL-xL and BCL-w inhibitor navitoclax and the MEK inhibitor trametinib in patients with RAS-mutant tumors with dose expansion cohorts for (1) pancreatic cancer, (2) gynecologic (GYN) cancers, (3) non-small cell lung cancer (NSCLC), and (4) other cancers harboring NRAS mutation. Paired pre-treatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. Results 91 patients initiated study treatment, 38 in dose escalation. Overall 58.2% had 3 or more prior therapies. 15 patients (16.5%) had colorectal cancer (CRC), 19 (10.9%) pancreatic, 15 (16.5% NSCLC, and 32 (35.2%) GYN cancers. The recommended phase 2 dose (RP2D) was established as trametinib 2mg daily days 1-14 and navitoclax 250mg daily days 1-28 of each cycle after a 7-day lead-in of navitoclax at 150 mg daily during cycle 1. The most common adverse events included diarrhea, thrombocytopenia, increased AST and ALT, and acneiform rash. At RP2D, 8/49 (16.3%) evaluable pts had a partial response (PR) with disease control rate (DCR) 59.2%. Disease-specific differences in efficacy were noted. In GYN patients at the RP2D, 7/21 (33.3%) achieved a confirmed PR, with DCR 85.7% and median duration of response of 8.2 months. By contrast, no PRs were observed in any CRC, NSCLC, or pancreatic patients. Evidence of MAPK pathway inhibition was observed in paired pre- and on-treatment tumor biopsies, and reductions in KRAS or NRAS mutation levels in cfDNA correlated with clinical benefit. Conclusions Navitoclax in combination with trametinib was tolerable, and the R2PD was established. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation of combined BCL-XL/MEK inhibition in this population. Clinical trial identification NCT02079740.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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	predicted - 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), a disease control rate of 85.7%, and a median duration of response of 8.2 months in patients with gynecologic cancers harboring mutations in NRAS or KRAS (Ann Oncol 34 (2023): S467; NCT02079740).	detail...