Cost-Effectiveness of Azacitidine and Ivosidenib in Newly Diagnosed Older, Intensive Chemotherapy-Ineligible Patients with IDH1-Mutant Acute Myeloid Leukemia

Introduction Ivosidenib (IVO) is an oral inhibitor of mIDH1 that is approved in the USA as monotherapy for pts with mIDH1AML, either relapsed/refractory or newly diagnosed, but older/unfit for intensive therapy. The recent AGILE trial (Montesinos et al. NEJM 2022) randomized newly diagnosed, older/intensive chemotherapy-ineligible mIDH1 AML pts to IVO + AZA vs placebo + AZA and showed improved event-free survival (EFS) and overall survival (OS) in the intervention arm. We sought to understand the health economic implications by conducting a cost-effectiveness analysis.

Methods Pts with newly diagnosed mIDH1 AML entered our partitioned survival model at age 75 years and received either IVO/AZA or AZA monotherapy. We used recreated pt-level data derived from the Kaplan-Meier curves and at-risk tables for EFS and OS from the AGILE trial for the IVO/AZA arm to fit loglogistic parametric survival distributions. Hazard ratios (HRs) for EFS and OS were used to derive the EFS and OS curves for the AZA arm, respectively.

Medication costs were derived from the average sales price (ASP) for AZA and cytarabine listed by the Centers for Medicare and Medicaid Services or the average wholesale price (AWP) for IVO and venetoclax (Ven), respectively. As ASP ranges between 26-30% below the AWP, we used a 28% discount off the AWP for the base-case scenario and varied this discount during sensitivity analyses between 18% and 38%. Costs and practice patterns of treatment discontinuation or treatment interruption due to adverse events, subsequent treatments, supportive and terminal care, and incidence of complications were derived from the original trial or published literature (Table 1). Costs were adjusted for inflation to 2021 US dollars using the personal consumption expenditure health index. Utilities were derived from the literature and were assumed to be equal between treatment arms for the base case scenario as the quality-of-life assessment were not statistically significantly different for IVO/AZA vs AZA in the AGILE trial at most timepoints. Costs and utilities were modeled over a 30-year time horizon and discounted by 3% annually.

Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) for IVO/AZA, which represents the cost in 2021 US dollars (USD) of each additional quality adjusted life-year (QALY) gained compared to AZA. One-way sensitivity analyses were performed to evaluate the impact of individual parameters on the overall model. Utility values were varied with a 10% range and all other variables were varied across a 50% range. We also performed probabilistic sensitivity analyses, in which we described each parameter using a distribution and performed 10,000 Monte Carlo simulations, each time randomly sampling from the distributions of model inputs.

Results In the base case scenario, IVO/AZA and AZA resulted in life-time costs of $652,088 and $242,828, respectively, for an incremental cost of $409,260 with IVO/AZA. With an incremental gain of 2.21 QALYs with IVO/AZA (IVO/AZA: 3.10 QALYs; AZA: 0.89 QALYs), the ICER of IVO/AZA compared to AZA was $185,024/QALY.

In one-way sensitivity analyses, only a reduction in the AWP of IVO by 32.4% (from $33,693 to $22,788 per 28-day cycle) would yield a reduction in the ICER to below the conventional willingness-to-pay (WTP) threshold of $150,000/QALY. Figure 1 shows the ten variables with the greatest influence on the ICER demonstrating that variations in any of the variables would not achieve an ICER of less than $150,000/QALY.

Probabilistic sensitivity analysis yielded a median ICER of $205,124/QALY (95% CI: $129,344 - $346,479) with AZA favored in 91.2% of 10,000 iterations at a WTP threshold of $150,000/QALY.

Conclusion Even in the best-case scenario in favor of the IVO arm following AGILE trial assumptions, we calculated an ICER of $185,024/QALY, which makes IVO/AZA unlikely to be cost-effective compared to AZA alone when applying the traditional WTP threshold of $150,000/QALY in patients with newly diagnosed mIDH1 AML. Only a reduction in the price of IVO by 32.4% lowered the ICER to below $150,000/QALY. The influence of more frequent use of 2^nd line IVO in the control arm, comparison against an AZA-Ven control arm, differences in utilities, and extended duration of follow up in the prematurely terminated trial on the ICER warrant additional analyses but are likely to further worsen the cost effectiveness of IVO.

Shallis:Bristol Myers Squibb and Gilead Sciences, Inc: Honoraria; Gilead Sciences, Inc.: Honoraria. Podoltsev:CTI BioPharma: Honoraria; PharmaEssentia: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Blueprint Medicines: Honoraria; Cogent Biosciences: Other: Independent Data Review Committee ; Agios Pharmaceuticals: Honoraria; AbbVie: Honoraria; Constellation Pharmaceuticals: Honoraria. Stahl:Boston Consulting: Consultancy; Novartis: Other: Advisory Board; Curis Oncology: Consultancy. Stein:Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Auron Therapeutics: Current equity holder in private company; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Bayer: Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy. Huntington:Janssen: Consultancy; FlatonIron Health: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Epizyme: Consultancy, Honoraria; Beigene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy, Honoraria; Merck: Consultancy; Seattle Genetics: Consultancy, Honoraria; Tyme: Consultancy; Agios: Research Funding; Debiopharm Group: Research Funding; TG Therapeutics: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria; AstraZeneca: Consultancy; Arvinas, Novartis, Servier, Bayer, SeaGen: Consultancy; Celgene: Research Funding. Zeidan:Celgene/BMS, AbbVie, Pfizer, Boeringer-Ingelheim, Trovagene, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, Otsuka: Consultancy, Honoraria, Research Funding; Astex, Medimmune, Astrazeneca, ADC Therapeutics: Research Funding; Celgene/BMS, Novartis, AbbVie, Gilead, Kura, Loxo Oncology, Geron: Other: Clinical Trial Committee; Novartis, Cardiff Oncology, Pfizer: Other: Travel Support; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie: Consultancy, Honoraria, Other: Advisory Board; Celgene/BMS, Novartis, Cardiff Oncology, AbbVie, Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Astex, Pfizer, Medimmune/AstraZeneca, ADC Therapeutics: Research Funding; Gilead, Kura, Loxo Oncology: Consultancy, Honoraria, Other: Clinical Trial Committee; Pfizer, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Amgen, Aprea, Gilead, Kura, Loxo Oncology, Otsuka, Jazz, Agios, Acceleron, Astellas, Daiichi-Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Ionis, Epizyme, Janssen, Syndax, Genentec: Consultancy, Honoraria, Other: Advisory Boards; Jazz, Agios, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, Beyondspring, Gilead, Kura, Tyme, Janssen, Syndax, Geron, Ionis, Epizyme: Consultancy, Honoraria.