Abstract 561P
Background
In preclinical and preliminary clinical studies, the combined inhibition of MEK and CDK4/6 showed synergistic antitumor activity. This study aimed to determine the recommended phase II regimen (RP2R) and characterize the safety and preliminary efficacy of T (MEK inhibitor) in combination with R (CDK4/6 inhibitor) in pts with advanced solid tumours.
Methods
Adult pts with advanced/metastatic solid tumours who failed ≥ 1 prior line of systemic therapy were enrolled in this multicenter, open-label study (NCT02703571). Here, we report results from the phase Ib part of the study. The safety of T (dose range, 1-2 mg) + R (dose range, 200-500 mg) was assessed across 11 cohorts using 2 different treatment schedules. The initial 28-day cycle of continuous T (2 mg) + 3W on/1W off R (200 mg) was modified to an intermittent schedule for safety reasons. A 21-day schedule of 2W on/1W off T + R was then explored. The primary objective was to determine maximum tolerated dose (MTD) and/or RP2R of the combination. The secondary objectives included safety, preliminary antitumor activity, and pharmacokinetics (PK). Biomarker analyses are ongoing as part of the exploratory objectives.
Results
A total of 95 pts were enrolled between June 2016 and September 2019. The median age was 58 y; 31% of the pts were aged ≥ 65 years. The primary sites of cancer at initial diagnosis were colon (27%), rectum (13%), and pancreas (11%). The median time since most recent relapse/progression to study entry was 2 mo. In the dose-determining set (n = 79), 12 pts (15%) experienced a dose-limiting toxicity. All pts (n = 95) experienced at least 1 adverse event (AE); most common was fatigue (57%). Serious AEs were reported in 42% of the pts. RP2R was T 1 mg + R 300 mg and MTD was T 1 mg + R 400 mg (T on W 1 and 2 + R on W 2 and 3 of a 21-day schedule). The objective response rate using RECIST 1.1 was 4%. The median progression-free survival was 2.6 mo. An increasing trend in T exposure was observed with increasing R dose.
Conclusions
RP2R and MTD for T + R oral coadministration were established. The safety and tolerability profile of T + R combination was consistent with the prior experience as single agents. The efficacy of this combination was limited; phase 2 portion of the study was not pursued.
Clinical trial identification
NCT02703571.
Editorial acknowledgement
Medical editorial assistance was provided by Sharol Janice Rodrigues (Novartis Healthcare Pvt. Ltd).
Legal entity responsible for the study
Novartis.
Funding
Novartis.
Disclosure
P. LoRusso: Advisory/Consultancy: AbbVie; Advisory/Consultancy, Data Safety Monitoring Board: Agios; Advisory/Consultancy, Data Safety Monitoring Committee: Five Prime; Advisory/Consultancy: GenMab; Advisory/Consultancy, Data Safety Monitoring Board: Halozyme; Advisory/Consultancy, imCORE Alliance: Roche-Genentech; Advisory/Consultancy: Genentech; Advisory/Consultancy: CytomX; Advisory/Consultancy: Takeda; Advisory/Consultancy: SOTIO; Advisory/Consultancy: Cybrexa; Advisory/Consultancy: Agenus; Advisory/Consultancy, Data Safety Monitoring Committee: Tyme; Advisory/Consultancy: IQVIA; Advisory/Consultancy: TRIGR; Advisory/Consultancy: Pfizer; Advisory/Consultancy: I-MAB; Advisory/Consultancy: ImmunoMet; Advisory/Consultancy: Black Diamond; Advisory/Consultancy: Glaxo-Smith Kline; Advisory/Consultancy: QED Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Shattuck; Advisory/Consultancy: Astellas; Advisory/Consultancy: Salarius; Advisory/Consultancy: Silverback; Advisory/Consultancy: MacroGenics; Advisory/Consultancy: Kyowa Kirin Pharmaceutical Development; Advisory/Consultancy: Kineta, Inc., Zentalis Pharmaceuticals, Molecular Templates. M. Fakih: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Amgen; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: TAIHO; Honoraria (self), Advisory/Consultancy: Array; Honoraria (self), Speaker Bureau/Expert testimony: Guardant; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Novartis. F.Y.F.L. De Vos: Research grant/Funding (institution): GlaxoSmithKline; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): BioClin Therapeutics; Research grant/Funding (institution): VAXIMM; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Octimed Oncology BV; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: Roche/Genentech. J.T. Beck: Research grant/Funding (institution): Highlands Oncology Group PA. J. Merchan: Advisory/Consultancy: Exelixis; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Genentech; Research grant/Funding (self), Research grant/Funding (institution): Sillagen; Research grant/Funding (institution): Vyriad; Research grant/Funding (institution): Replimune; Research grant/Funding (institution): Tizona; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Peloton; Research grant/Funding (institution): Calithera; Licensing/Royalties: UpToDate, Inc. G. Shapiro: Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: Roche; Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Merck KGaA/EMD-Serono; Advisory/Consultancy, Research grant/Funding (institution): Sierra Oncology; Advisory/Consultancy: Bicycle Therapeutics; Advisory/Consultancy: Fusion Pharmaceuticals; Advisory/Consultancy: Cybrexa Therapeutics; Advisory/Consultancy: Astex; Advisory/Consultancy: Almac; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Angiex; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: ImmunoMet; Advisory/Consultancy: Asana; Advisory/Consultancy: Artios; Advisory/Consultancy: Atrin ; Advisory/Consultancy: Concarlo Holdings; Licensing/Royalties, Patent: Dosage regimen for sapacitabine and seliciclib, also issued to Cyclacel Pharmaceuticals: Cyclacel Pharmaceuticals; Licensing/Royalties, Pending patent: Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition: Liam Cornell. C-C. Lin: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Takeda; Travel/Accommodation/Expenses: BeiGene; Travel/Accommodation/Expenses: Eli Lilly. J. Desai: Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Eisai; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): BMS; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Beigene . J. Spratlin: Honoraria (self), Advisory/Consultancy: Taiho; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS; Advisory/Consultancy: PharmaMatrix; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Sanofi. T. Cascella: Full/Part-time employment: Novartis. L. Sandalic: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. A.M. Abdelhady: Full/Part-time employment: Novartis. A. Boran: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. E. Gasal: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. F. Janku: Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy: IFM Therapeutics; Advisory/Consultancy: Synlogic; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Ideaya; Advisory/Consultancy: PureTech Health; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Trovagene; Advisory/Consultancy: Immunomet; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy: Sotio; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): BioMed Valley Discoveries; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): FujiFilm Corporation ; Research grant/Funding (institution): Upsher-Smith Laboratories; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Asana; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Proximagen; Research grant/Funding (institution): Bristol-Myers Squibb. E. Van Cutsem: Advisory/Consultancy: Array; Advisory/Consultancy: AstraZenca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Halozyme; Advisory/Consultancy: GSK; Advisory/Consultancy: Incyte; Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pierre-Fabre; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Servier; Advisory/Consultancy: Sirtex; Advisory/Consultancy: Taiho; Research grant/Funding (institution): Boehringer Ingelheim.