Abstract
Background: Mutations in the RAS/RAF/MEK/ERK pathway result in resistance to several acute myeloid leukemia (AML) therapies, including hypomethylating agents (HMAs) plus venetoclax. Trametinib is an oral MEK inhibitor that has been studied as monotherapy in relapsed/refractory (R/R) AML with KRAS/NRAS mutations. Preclinical studies have suggested synergy between venetoclax and trametinib in RAS-mutated AML. We therefore sought to evaluate the combination of azacitidine, venetoclax, and trametinib in patients (pts) with R/R AML with Ras pathway-activating mutations.
Methods: In this phase II study, adult pts with R/R AML or higher-risk R/R MDS or CMML (intermediate-2 or high-risk by the International Prognostic Scoring System with ≥10% blasts) harboring a Ras pathway-activating mutation involving HRAS/NRAS/KRAS, KIT, BRAF, CBL, PTPN11 or NF1 were eligible). Pts were required to have a performance status ≤2, total bilirubin ≤2.5 x upper limit of normal (ULN), ALT/AST ≤ 3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28 (100mg on day 1, 200mg on day 2, 400mg on days 3-28), and trametinib 2mg PO on days 1-28. Bone marrow examination was performed on day 21 and if blasts <5% or aplastic marrow, then venetoclax was held. For cycles 2 and beyond, azacitidine 75 mg/m 2 SC/IV was given on days 1-7, venetoclax was given for daily on days 1 - 21 and trametinib 2mg was given continuously.
Results: Between 8/2020 and 5/2021, 16 pts were treated. Baseline characteristics are shown in Table 1. The median age was 67 years (range, 28-84 years) and 6 pts (38%) were ≥75 years of age. This was a very heavily pretreated population, and the median number of prior therapies was 4 (range, 1-7). All pts had received prior HMAs, including 13 pts (81%) who had received prior HMA plus venetoclax. Eight pts (50%) had undergone prior hematopoietic stem cell transplant (HSCT). Fourteen pts (88%) had adverse-risk disease, including 6 (38%) with complex karyotype and 3 (19%) with TP53 mutation. Excluding Ras pathway mutations, ASXL1 was the most common co-mutation and was present in 50% of pts.
Overall, 4 pts (25%) responded (1 with CR, 1 with CRi and 2 with MLFS). The only pt with CMML responded and attained CR. Two of the 3 pts (67%) who had not previously received HMA plus venetoclax responded (1 CR and 1 MLFS); in contrast, only 2 of the 13 pts (15%) who had previously received HMA plus venetoclax responded (1 CRi and 1 MLFS). Three of the 4 responders had diploid karyotype and one NRAS mutation; the other pt had complex karyotype and an NF1 mutation. Of the 3 responding pts with a NRAS mutations, 2 showed a dramatic decrease in their respective NRAS variant allelic frequencies (0.15 to 0.05 and 0.51 to 0.02). In addition to the 4 pts with formal responses, 4 pts (25%) had a bone marrow blast reduction of ≥50%, including 1 pt with prior treatment with HMA plus venetoclax who had blast reduction from 26% to 6% and who continued on study for 5.5 months.
The median duration of follow-up is 7.4 months. One pt who achieved MLFS relapsed after 2 months of remission. The other 3 pts remain in remission. Two of these pts remain on study with ongoing remissions of 3 and 8 months, and the other pt underwent HSCT and has ongoing remission of 7 months. The median overall survival (OS) of the entire cohort was 2.7 months and the 6-month OS rate was 25% (Figure 1A). The median OS for responders and non-responders was not reached and 1.7 months, respectively (P=0.02; Figure 1B).
The most common non-hematologic adverse events of any grade were diarrhea (88%) and nausea (63%). Grade 3 non-hematologic adverse events possibly related to study treatment included: mucositis (n=3), diarrhea (n=1), and decreased ejection fraction (EF) (n=1). Six pts (38%) required dose reduction or temporary cessation of trametinib due to mucositis (n=2), retinopathy (n=1), decreased EF (n=1), rash (n=1), and diarrhea (n=1).
Conclusion: In this heavily pretreated pt population with poor-risk disease with Ras pathway-activating myeloid malignancies, the triplet combination of azacitidine, venetoclax and trametinib resulted in a response rate of 25%. Two of 3 pts without prior exposure to HMA plus venetoclax responded, and although response rate was modest (15%) in pts with prior HMA plus venetoclax, the activity in this population suggests potential benefit of adding trametinib in these pts.
Ravandi: Taiho: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Pemmaraju: Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; MustangBio: Consultancy, Other; Aptitude Health: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; Ascentage: Other: grant support, Research Funding; KisoJi: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Borthakur: Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jain: Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; TG Therapeutics: Honoraria; Aprea Therapeutics: Research Funding; Beigene: Honoraria; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kadia: Genfleet: Other; Ascentage: Other; AstraZeneca: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Astellas: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Kantarjian: BMS: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy.
Trametinib is a MEK inhibitor working in the RAS/RAF pathway. In patients with relapse/refractory AML with mutations in this pathway, downstream inhibition might provide an avenue for treatment.
