Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster session 17

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

Date

21 Oct 2023

Session

Poster session 17

Topics

Clinical Research;  Translational Research;  Therapy

Tumour Site

Gynaecological Malignancies

Presenters

Ryan Corcoran

Citation

Annals of Oncology (2023) 34 (suppl_2): S458-S497. 10.1016/S0923-7534(23)01936-1

Authors

R.B. Corcoran1, K.T. Do2, J. Cleary3, A. Parikh4, O. Yeku5, C.D. Weekes1, L. Ahronian1, G. Mauri6, J. Tian1, J. Brugge7, D. Juric8, K.T. Flaherty1, R.J. Sullivan1, J. Clark1, R. Heist9, U.A. Matulonis10, J.F. Liu11, G.I. Shapiro2

Author affiliations

  • 1 Cancer Center, MGH - Massachusetts General Hospital, 02114 - Boston/US
  • 2 Medical Oncology, Dana Farber Cancer Institute, 02215 - Boston/US
  • 3 Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, MA 02215 - Boston/US
  • 4 Gastrointestinal Oncology Dept., MGH - Massachusetts General Hospital, 02114 - Boston/US
  • 5 Gynecologic Medical Oncology Department, Massachusetts General Hospital Cancer Center, Harvard Medical School, 02114 - Boston/US
  • 6 Dipartimento Di Ematologia E Oncologia, Università degli Studi di Milano, 20122 - Milan/IT
  • 7 Medicine, Harvard Medical School, 2115 - Boston/US
  • 8 Hematology/oncology, MGH - Massachusetts General Hospital, 02114 - Boston/US
  • 9 Medical Oncology Department, MGH - Massachusetts General Hospital, 02114 - Boston/US
  • 10 Medical Oncology, Dana Farber Cancer Institute, 02115 - Boston/US
  • 11 Medical Oncology Department, Dana Farber Cancer Institute, 02215 - Boston/US

Resources

Login to get immediate access to this content.

If you do not have an ESMO account, please create one for free.

Abstract 664P

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.

Editorial acknowledgement

Legal entity responsible for the study

Massachusetts General Hospital.

Funding

National Institutes of Health | National Cancer Institute, Cancer Therapy Evaluation Program.

Disclosure

R.B. Corcoran: Financial Interests, Personal, Member of Board of Directors: Alterome Therapeutics, Sidewinder Therapeutics; Financial Interests, Personal, Ownership Interest: Alterome Therapeutics, Sidewinder Therapeutics; Financial Interests, Personal, Stocks/Shares: Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Kinnate Biopharma, Interline Therapeutics, Nested Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines; Financial Interests, Personal, Advisory Role: AbbVie, Astellas, Daiichi Sankyo, Elicio, FOG Pharma, Guardant Health, Ipsen, Merck, Natera, Qiagen, Syndax; Financial Interests, Personal, Advisory Board: Pfizer, Asana Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Interline Therapeutics, Kinnate Biopharma, nRichDx, Remix Therapeutics, Revolution Medicines, Taiho, Theonys; Financial Interests, Personal and Institutional, Research Funding: Asana, Lilly, Pfizer, Novartis. J. Cleary: Financial Interests, Personal, Advisory Board: Incyte, Blueprint Medicines; Financial Interests, Personal and Institutional, Research Funding: Merck, AstraZeneca, Esperas Pharam, Bayer, Tesaro, Apexigen; Financial Interests, Institutional, Research Funding: Merus, Roche, BMS. A. Parikh: Financial Interests, Personal, Speaker, Consultant, Advisor: Lilly, Pfizer, Inivata, Biofidelity, Checkmate Pharmaceuticals, Foundation Medicine, Guardant, AbbVie, Bayer, Delcath, Taiho, CVS, Value Analytics Lab, Seagen, Saga, AstraZeneca, Scare Inc., Illumina, Science for America, Up to Date; Financial Interests, Institutional, Research Funding: PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Mirati, Novartis, Erasca, Genentech, Daiichi Sankyo. O. Yeku: Financial Interests, Personal and Institutional, Research Grant: Ascendis Pharma, Avenge Bio, Immunocore Limited, Duality Biologics, Merck Sharp & Dohme, Pionyr Immunotherapeutics, ProfoundBio; Financial Interests, Personal, Advisory Role: Celldex Therapeutics, GIMV NV, TigaTx; Financial Interests, Personal, Advisory Board: hC Bioscience. C.D. Weekes: Financial Interests, Personal, Advisory Role: Genentech, Ipsen; Financial Interests, Personal and Institutional, Research Funding: Novartis, Mirati, Elicio, Deciphera, Actuate. L. Ahronian: Financial Interests, Personal, Full or part-time Employment: Tango Therapeutics. J. Brugge: Financial Interests, Personal, Advisory Board: Frontier Medicines, eFFECTOR Pharmaceuticals. K.T. Flaherty: Financial Interests, Personal, Member of Board of Directors: Loxo Oncology, Clovis Oncology, Strata Oncology, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics; Financial Interests, Personal, Advisory Board: PIC Therapeutics, Apricity, Oncoceutics, FOG Pharma, Tvardi, xCures, Monopteros, Vibliome, ALX Oncology, OMRx, Soley Therapeutics, Alterome Therapeutics; Financial Interests, Personal, Advisory Role: Lilly, Novartis, Genentech, Takeda; Financial Interests, Personal and Institutional, Research Funding: Novartis, Sanofi. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune, Marengo; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Local PI: GSK, Sanofi, Moderna, BiomedValley DIscoveries, Astex, Compugen, BeiGene, Novartis, Rubius, Alkermes, Synthekine; Financial Interests, Institutional, Coordinating PI: Pfizer, Roche-Genentech, Simcha Therapeutics, OnKure, Marengo. R. Heist: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Novartis, EMD Serono, Lilly, AstraZeneca, Regeneron, Sanofi; Financial Interests, Personal, Writing Engagement: Chugai Roche; Financial Interests, Personal, Other, review of cancer histories: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, consulting honoraria: AbbVie; Financial Interests, Personal, Other, Consulting: Claim Therapeutics; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Novartis, AbbVie, Roche, Incyte, Mirati, Lilly, Agios, Corvus, Turning Point, Exelixis; Financial Interests, Institutional, Local PI, clinical trial funding to institution, not to self: Mythic, Erasca; Non-Financial Interests, Member: IASLC, ASCO, AACR. U.A. Matulonis: Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Merck, Trillium, CureLab, Blueprint Medicines, Agenus, MorphoSys; Financial Interests, Personal, Advisory Board: ImmunoGen, NextCure, Allarity, Ovarian Cancer Research Alliance, Rivkin Foundation, Clearity. J.F. Liu: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Genentech, GSK, Regeneron; Financial Interests, Institutional, Research Funding: 2X Oncology, Aravive, Arch Oncology, AstraZeneca, BMS, Clovis Oncology, CytomX Therapeutics, GSK, Impact Therapeutics, Regeneron, Surface Oncology, Vigeo Therapeutics, Zentalis. G.I. Shapiro: Financial Interests, Personal, Advisory Board: Merck KgA, EMD Serono, Bicycle Therapeutics, Cybrexa Therapeutics, Bayer, Boehringer Ingelheim, Blueprint Medicines, ImmunoMet, Artios, Concarlo Holdings, Syros, Zentalis, CytomX, Kymera Therapeutics, Janssen, Xinthera; Financial Interests, Personal and Institutional, Research Funding: Merck KgA, EMD-Serono, Tango Therapeutics, BMS, Merck, Pfizer, Lilly. All other authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.