Addition of Relatlimab/Nivolumab to Azacitidine/Venetoclax Shows Safety, Early Efficacy in Adverse-Risk Frontline AML

Azacitidine/Venetoclax Plus Relatlimab/Nivolumab

in AML | Image credit: © Maris – stock.adobe.com

The addition of the LAG-3 and PD-1 inhibitors relatlimab and nivolumab (Opdualag) to azacitidine (Vidaza)/venetoclax (Venclexta) was safe and generated preliminary antitumor activity in patients with frontline, adverse-risk, acute myeloid leukemia (AML) who were not fit for intensive chemotherapy, according to data from the phase 2 AARON trial (NCT04913922).1

Data from an interim analysis of evaluable patients in the frontline AML cohort (n = 10), which were presented at the 2025 AACR Annual Meeting, revealed that 80% had achieved complete remission (CR) on azacitidine/venetoclax plus relatlimab/nivolumab. The remaining 2 patients experienced a blast response and non-response to treatment, respectively. No patients achieved a partial remission (PR) or morphologic leukemia-free state (MLFS).

However, results from the relapsed/refractory AML cohort (n = 12) showed more limited efficacy with azacitidine monotherapy plus relatlimab and nivolumab, as no CRs, CRs with incomplete count recovery (CRi), PRs, or MLFS were observed. Hematologic improvements were seen in 8% of patients; however, 92% of patients did not respond to treatment.

“Despite sufficient safety of the treatment, [the] enrollment of [patients with] relapsed/refractory AML has been stopped due to moderate activity in the relapsed/refractory patient cohort,” study authors wrote in a poster presentation of the data. “Azacitidine monotherapy plus LAG-3/PD-1 inhibition in relapsed/refractory AML is of limited efficacy.”

AARON Trial Background and Design

In November 2018, the FDA granted an accelerated approval to venetoclax with azacitidine or decitabine or low-dose cytarabine for the treatment of adult patients with newly diagnosed AML who are at least 75 years of age with comorbidities that lead to ineligibility for intensive induction chemotherapy.2 The regulatory decision was supported by data from the phase 1b/2 M14-358 (NCT02203773) and M14-387 (NCT02287233) trials.

“Still, a third of patients [have] primary refractory [disease], and approximately 40% of responding patients relapse within the first year of treatment, highlighting the need for novel combinatorial treatment options,” the study authors wrote.

The AARON study enrolled patients 18 years of age or older who had relapsed/refractory AML (cohort 1) or frontline AML (cohort 2) and were ineligible for intensive induction chemotherapy and/or allogeneic stem cell transplantation (ASCT).3 Cohort 1 included patients who did not respond to first-line induction chemotherapy comprising a minimum of 2 intensive chemotherapy cycles; or patients who either relapsed after achieving a CR, CRi, or CR with incomplete platelet recovery (CRp), or did not have an adequate response to 1 prior salvage therapy. Patients in cohort 2 were required to be at least 65 years of age with previously untreated AML, and be unfit or have declined to receive standard induction therapy. An ECOG performance status of 0 to 2 was required in both cohorts.

All patients were treated with 160 mg of intravenous (IV) relatlimab plus 480 mg of IV, which was added to subcutaneous (SC) azacitidine at 75 mg/m2 and oral venetoclax at 70 mg.1 Notably, dose reduction of relatlimab to 80 mg was permitted if patients experienced dose-limiting toxicities.

“A total of 30 patients will be treated, with independent lead-in phases (including 6 to 12 patients) for relapsed/refractory AML and patients with newly diagnosed AML with wild-type NMP1 or IDH1/2,” the study authors noted.

Baseline Patient Characteristics

The median age in the relapsed/refractory AML and frontline AML cohorts was 71 years (range, 36-81) and 77 years (62-86), respectively. The respective percentages of female patients on the study were 42% and 31%. In the relapsed/refractory AML cohort, the median number of prior lines of therapy was 3 (range, 1-7). ASCT was previously received by 33% of patients, with 49% displaying blasts in bone marrow prior to cycle 1. Of note, the median absolute neutrophil count on day 1 of cycle 1 was 0.3 G/I (range < 0.1-7.2), and the median applied cycles per patient was 3 (range, 1-6).

Conversely, in cohort 2, 100% of patients had adverse-risk disease per the 2022 European Leukemia Network (ELN) recommendations. Per the 2024 ELN genetic risk factor recommendations, most patients had favorable genetic risk (62%), followed by intermediate (15%) and adverse (TP53 mutations; 23%) risk. The median percentage of blasts in bone marrow before cycle 1 was 48% (range 3%-85%), and the median applied cycles per patient was 3 (range, 1-10).

Additional Safety and Efficacy Data

The cumulative incidence of relapse or progression with the combination was higher among patients in the relapsed/refractory AML cohort vs those in the frontline AML cohort, the latter of whom had a stable incidence at approximately 7 months. At a median follow-up of 6.8 months, the median time to progression was 2.3 months vs not reached in the relapsed/refractory AML and frontline AML cohorts, respectively. The median overall survival was 3.5 months vs 8.3 months, respectively.

All patients with frontline AML (n = 13) or relapsed/refractory AML experienced an any-grade adverse effect (AE) with the regimen.

Serious AEs (SAEs) were reported in 85% of patients with frontline AML. The most common SAEs included infection (n = 9), acute kidney injury, myocarditis, and Tako-Tsubo cardiomyopathy (n = 1 each). The most common immune-related AEs (irAEs) were grade 3 transaminitis (n = 1), grade 3 rash (n = 1), grade 3 myocarditis (n = 1), and grade 1 troponin elevation (n = 4). Two patients experienced early deaths within 3 months of treatment due to septic shock and disease progression (1 each).

In patients with relapsed/refractory AML, 83% of patients experienced SAEs, of which 59% were infections. Additionally, irAEs were observed in 25% of patients, the most common of which were transaminitis (n = 2), rash or graft-vs-host-disease flare (n = 1), and colitis (n = 1).

“[Azacitidine/venetoclax] plus LAG-3/PD-1 inhibition was safe in [patients with] adverse-risk frontline AML (per ELN 2022) [who were] not fit for intensive chemotherapy and showed promising [early] efficacy,” the study authors concluded. “We have established a comprehensive accompanying immunomonitoring program to study immunological changes in the peripheral blood and bone marrow.”

References

1. Bücklein V, Magno G, Rausch C, et al. AARON: an ongoing open-label phase I/II study of reltilmab (anti-LAG-3) with nivolumab (anti-PD-1) in combination with azacitidine ± venetoclax for the treatment of patients with acute myeloid leukemia — interim analysis. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT225.
2. FDA approves venetoclax in combination for AML in adults. FDA. Updated December 14, 2018. Accessed April 29, 2025. https://www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults
3. Relatlimab with nivolumab and 5-azacytidine for the treatment of AML (AARON). ClinicalTrials.gov. Updated November 8, 2022. Accessed April 29, 2025. https://clinicaltrials.gov/study/NCT04913922