Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia
Authors: Choe Sung , Wang Hongfang , DiNardo Courtney D. , Stein Eytan M. , De Botton Stephane , Fathi Amir T. , Tallman Martin S. , Kantarjian Hagop M. , Stone Richard M. , Quek Lynn , Konteatis Zenon , Dang Lenny , Zhang Vickie , Liu Hua , Attar Eyal C. , Wu Bin 
Published: February 2020

Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple solid and hematologic tumors and drive tumorigenesis via production of the oncometabolite D-2-hydroxyglutarate (2-HG). The mutant IDH1 (mIDH1) inhibitor ivosidenib is approved in the US for the treatment of adults with mIDH1 newly diagnosed acute myeloid leukemia (AML) in patients ≥75 years old or with comorbidities that preclude induction chemotherapy, and mIDH1 relapsed or refractory (R/R) AML. In patients with R/R AML who were enrolled in a phase 1 study (NCT02074839), ivosidenib was associated with an overall response rate of 42%, a complete remission (CR) rate of 24%, and a CR plus CR with partial hematologic response (CR+CRh) rate of 32%, with durable responses and additional clinical benefits observed (Pollyea et al. J Clin Oncol 2018 Abs). Baseline co-occurring mutations in receptor tyrosine kinase (RTK) pathway genes were shown to be associated with primary resistance to ivosidenib (DiNardo et al. N Engl J Med 2018). Case studies of secondary resistance to ivosidenib monotherapy have revealed examples of 2-HG restoring mechanisms at relapse, including IDH2 isoform switching and the emergence of mIDH1-S280F (Harding et al. Cancer Discov 2018; Intlekofer et al. Nature 2018).
Aim: To characterize the mechanisms of response and relapse to ivosidenib monotherapy via a comprehensive genomic analysis of samples from a large cohort of patients with mIDH1 R/R AML enrolled in the pivotal phase 1 study whose starting dose was 500 mg daily (approved dose).
Methods: Baseline and longitudinal co-occurring mutation profiling was performed on whole bone marrow, bone marrow mononuclear cell, and peripheral blood mononuclear cell samples by next generation sequencing (NGS; detection sensitivity 1-5%). 3D modelling of second-site IDH1 mutations was performed with an ivosidenib analog using Molecular Operating Environment 10.0 software. Enzymatic assays were performed with mIDH1 as previously reported. The clinical response data cut-off was Nov 10, 2018.
Results: In 167 patients with baseline NGS data from whole bone marrow, the genes with most frequent co-occurring mutations were DNMT3A (35%), NPM1 (26%), SRSF2 (24%), ASXL1 (18%), RUNX1 (18%), NRAS (14%), and TP53 (13%). RTK pathway mutations, and mutations in the individual genes NRAS and PTPN11, were significantly associated with a lack of CR or CRh response to ivosidenib (p&lt;0.001 [RTK], p=0.004 [NRAS], and p=0.016 [PTPN11], Fisher's exact test). Investigation of clonal hierarchy at baseline showed that neither subclonal nor clonal status of mIDH1 was associated with clinical response (p=0.4, Fisher's exact test). To characterize mechanisms of secondary resistance to ivosidenib, longitudinal NGS profiling was performed for 129 patients, 74 of whom had data at both baseline and relapse or disease progression. Mutations not detected at baseline but identified at the time of relapse/progression were categorized into canonical biological pathways. Mutations in RTK pathway genes were identified at relapse/progression in 20 of 74 (27%) patients, with IDH1/2 mutations detected at a comparable rate (17 [23%]; Table). IDH2-R140Q mutations were newly detected during treatment in 9 of 74 patients (12%). IDH1 second-site mutations emerged in 10 of 74 patients (14%), including previously unreported mutations at 5 amino acid positions. Detection of these IDH1 second-site mutations was concurrent with an increase in plasma 2-HG. Five patients acquired both RTK pathway mutations and 2-HG restoring mutations (IDH1 and/or IDH2) at relapse/progression. All identified second-site IDH1 mutations were clustered into two sub-regions and were predicted by 3D modeling to impact ivosidenib and/or co-factor (NADPH) binding either directly or indirectly. Biochemical characterization of two of these mutations confirmed loss of ivosidenib inhibitory potency.
Conclusions: Relapse to ivosidenib monotherapy is mediated by diverse mechanisms that include emergent mutations, most frequently in RTK pathway genes and IDH1/IDH2. The observation of frequent 2-HG restoration at relapse underscores the key role of 2-HG production in mIDH AML disease. These results are important for the rational design of combination treatment strategies in mIDH1 AML, and to understand whether these patterns are replicated in ongoing combination trials.

Disclosures
Choe: Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria. Stein:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees. De Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Tallman:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Cellerant: Research Funding; Cellerant: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Biosight: Research Funding; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; UpToDate: Patents & Royalties; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Kantarjian:Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Novartis, Agios, Arog: Research Funding; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: . Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. Konteatis:Agios: Employment, Equity Ownership. Dang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership.