Indirect Treatment Comparison of Ivosidenib and Other Therapies in Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction: The combination of ivosidenib (IVO) (an inhibitor of mutant isocitrate dehydrogenase 1 [IDH1]) and azacitidine (AZA) has recently shown significant clinical benefit, compared with placebo and AZA, in a Phase III trial in patients with newly diagnosed IDH1-mutated (IDH1m) acute myeloid leukemia (AML) who were ineligible for intensive induction chemotherapy (iCI) (AGILE; ClinicalTrials.gov number, NCT03173248). Several other treatments are currently available in this difficult-to-treat population, which have not been investigated in head-to-head randomized controlled trials (RCTs) with IVO + AZA. The objective of this study was to identify studies describing the clinical efficacy of therapies for AML in newly diagnosed IDH1m patients ineligible for iCI, and to estimate the relative efficacy of IVO + AZA versus existing therapies through an indirect treatment comparison (ITC).

Methods: A systematic literature review (SLR) was conducted to identify evidence from studies assessing the clinical efficacy of therapies in the population of interest. Searches were performed in MEDLINE^®, Embase^®, and EBM reviews up to October 2023. A comprehensive feasibility assessment was conducted to verify the transitivity assumption, i.e. the similarity of study designs and patient populations across included studies. The relative efficacy of IVO + AZA versus existing therapies was therefore estimated for adults with previously untreated AML ineligible for iCI irrespective of mutation status, using a Bayesian network meta-analysis (NMA) for the outcomes overall survival (OS) and event-free survival (EFS). In addition, an anchored matching-adjusted indirect comparison (MAIC) of OS for IVO + AZA versus the venetoclax + AZA arm from the VIALE-A IDH1m subgroup was conducted to account for population imbalances.

Results: Following the SLR and feasibility assessment, six studies were considered eligible for inclusion in the NMA, which reported outcomes for the treatments IVO + AZA, AZA, low-dose cytarabine (LDAC), decitabine, venetoclax + AZA, venetoclax + LDAC and glasdegib + LDAC. AGILE is the first and only study comparing treatments exclusively in patients with IDH1m. The feasibility assessment identified heterogeneity in the analysis populations arising from a lack of published subgroup data for patients with IDH1m, modest heterogeneity in other patient demographic and disease characteristics (gender, type of AML diagnosis, cytogenic risk, ECOG performance status and median bone marrow blast), differences in placebo arm rates across placebo-controlled studies, and differences in the definition of EFS. Based on results from the NMA, IVO + AZA showed a statistically significant increase for OS versus LDAC (hazard ratio [HR], 0.38; 95% credible interval [CrI], 0.24-0.63), AZA (HR, 0.43; 95% CrI, 0.28-0.65) and decitabine (HR, 0.47; 95% CrI, 0.28-0.79). In addition, a greater numerical effect for OS was observed in IVO + AZA versus venetoclax + AZA (HR, 0.74; 95% CrI, 0.46, 1.18), venetoclax + LDAC (HR, 0.55; 95% CrI, 0.30-1.00) and glasdegib + LDAC (HR, 0.78; 95% CrI: 0.41-1.49). The results demonstrate clinically meaningful survival benefit (HR: ≤0.8) for IVO relative to all comparators. Similarly, IVO + AZA was estimated to statistically significant increase EFS versus LDAC (HR, 0.34; 95% CrI, 0.20-0.57) and AZA (HR, 0.39; 95% CrI, 0.24-0.64). IVO + AZA presented a greater magnitude of effect for EFS versus venetoclax + AZA (HR, 0.62; 95% CrI, 0.36-1.07) and venetoclax + LDAC (HR, 0.56; 95% CrI, 0.30-1.03). Results from the anchored MAIC demonstrated consistent survival benefit with the NMA, for the comparison of IVO + AZA compared to venetoclax + AZA (HR 0.71; 95% CI 0.43-1.19).

Conclusions: ITCs using both NMA and MAIC methods generated consistent results, demonstrating a benefit of IVO + AZA versus other therapies for the treatment of newly diagnosed IDH1m AML in patients who are ineligible for iCI.