Ivosidenib/Venetoclax/Azacitidine Proves Tolerable, Strengthens Survival in AML

Ivosidenib (Tibsovo) plus venetoclax (Venclexta) with or without azacitidine (Onureg) showed an expected and tolerable safety profile with durable responses and a prolonged survival rate across acute myeloid leukemia (AML) disease groups, according to findings from a phase 1b/2 study (NCT03471260) that were presented at the 10th Annual Society of Hematologic Oncology Annual Meeting.¹ In particular, high minimal residual disease (MRD)–negative clinical complete response (cCR) rates were observed with the triplet.

In total, 100% of patients with de novo AML (n = 9) and myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN; n = 9) responded to the study treatment, with 100% in each achieving a cCR, as did 100% of patients with secondary AML or treated secondary AML (n = 5), 80% of whom achieved cCR. Of the patients with relapsed/refractory AML (n = 8), 75% responded, including 63% who achieved cCR.

Patients were eligible to enroll in the trial if they had an ECOG performance score of 2 or less; an IDH1 R132 mutation; advanced MDS or MPN, defined as having at least 10% blasts; newly diagnosed or relapsed/refractory AML, and adequate hepatic and renal function. Patients were excluded if they had received prior ivosidenib or venetoclax; if they had received CYP3A4 inducers or inhibitors within 72 hours prior to the initiation of study treatment if they had active graft-vs-host disease; and if they had a gastrointestinal or metabolic disorder with altered absorption.

This trial included 2 doublet cohorts and 2 triplet cohorts. The Dose Level #1 (DL#1) cohort was a doublet cohort consisting of 6 patients: 4 with relapsed/refractory AML, and 1 each with newly diagnosed AML and MDS/MPN. These patients received venetoclax at 400 mg on days 1 through 14 of each 28-day cycle and ivosidenib at 500 mg beginning on day 15 of cycle 1 and on each day thereafter throughout all subsequent cycles.

The Dose Level #2 (DL#2) cohort was a doublet cohort consisting of 6 patients: 2 with relapsed/refractory AML, 3 with newly diagnosed AML, and 1 with MDS/MPN. These patients received venetoclax at 800 mg on days 1 through 14 of each 28-day cycle and ivosidenib at 500 mg beginning on day 15 of cycle 1 and on each day thereafter throughout all subsequent cycles.

The Dose Level #3 (DL#3) cohort was a triplet cohort consisting of 13 patients: 2 with relapsed/refractory AML, 9 with newly diagnosed AML, and 2 with MDS/MPN. These patients received venetoclax at 400 mg on days 1 through 14 of each 28-day cycle, ivosidenib at 500 mg beginning on day 15 of cycle 1 and on each day thereafter throughout all subsequent cycles, and azacitidine at 75 mg/m² on days 1 through 7 of each cycle.

The Dose Level #4 (DL#4) cohort was a triplet cohort consisting of 6 patients: 1 with newly diagnosed AML and 5 with MDS/MPN. These patients received venetoclax at 800 mg on days 1 through 14 of each 28-day cycle, ivosidenib at 500 mg beginning on day 15 of cycle 1 and on each day thereafter throughout all subsequent cycles, and azacitidine at 75 mg/m² on days 1 through 7 of each cycle.

In the DL#1 cohort, 2 patients had received 1 prior treatment and 1 patient each had received 2, 3, and 4 prior treatments. In the DL#2 cohort, 2 patients had received 1 prior treatment, and 1 patient had received 4 prior treatments. In the DL#3 cohort, 2 patients had received 1 prior treatment and 2 patients had received 3 prior treatments. In the DL#4 cohort, 1 patient had received 1 prior treatment. Two patients in the DL#1 cohort and 1 patient in the DL#2 cohort had received prior IDH inhibitors.

The primary end points of this trial were safety, tolerability, and overall response rate, including complete response (CR), CR with incomplete hematologic recovery, CR with partial hematologic recovery, partial response, and morphological leukemia-free state. In addition, this trial sought to determine the maximum tolerated dose and a recommended phase 2 dose. Secondary end points included a pharmacokinetic analysis of the ivosidenib and venetoclax combination, the identification of cellular or molecular predictive biomarkers, duration of response, overall survival (OS), and event-free survival (EFS).

When responses were stratified by dose level, 67% of the DL#1 cohort achieved a cCR. Additionally, 100% of the DL#2 and DL#4 cohorts responded, with 100% in each achieving a cCR, and 100% of the DL#3 cohort responded, with 85% of patients achieving a cCR. 

When survival was stratified by dose level, the median EFS was 7.9 months (95% CI, 0-not reached [NR]), 8.7 months (95% CI, 7-NR), NR (95% CI, 23-NR), and NR in the DL#1, DL#2, DL#3, and DL#4 cohorts, respectively. The 12-month EFS rates were 50% (standard error, 20%) in the DL#1 and DL#2 cohorts, 77% (standard error, 12%) in the DL#3 cohort, and not applicable (NA) in the DL#4 cohort.

The median OS was 26 months (95% CI, 3-NR), NR (95% CI, 5-NR), NR (95% CI, 21-NR), and NR in the DL#1, DL#2, DL#3, and DL#4 cohorts, respectively. The 12-month OS rates were 50% (standard error, 20%), 67% (standard error, 19%), 85% (standard error, 10%), and NA in the DL#1, DL#2, DL#3, and DL#4 cohorts, respectively.

When stratified by disease, the median EFS was NR (95% CI, 14-NR), 36.4 months (95% CI, 23-NR), and 6 months (95% CI, 2-NR) in the MDS/MPN, newly diagnosed AML, and relapsed/refractory AML populations, respectively. The 12-month EFS rates were 89% (standard error, 11%), 71% (standard error, 12%), and 50% (standard error, 18%) in the MDS/MPN, newly diagnosed AML, and relapsed/refractory AML populations, respectively.

Additionally, the median OS was 42.1 months (95% CI, NR-NR), NR (95% CI, 21-NR), and 9 months (95% CI, 8-NR) in the MDS/MPN, newly diagnosed AML, and relapsed/refractory AML populations, respectively. The 12-month OS rates were 100% (standard error, NR), 79% (standard error, 11%), and 50% (standard error, 18%) in the MDS/MPN, newly diagnosed AML, and relapsed/refractory AML populations, respectively.

In terms of IDH1 clearance by digital droplet polymerase chain reaction (sensitivity, 0.25%-0.1%), of the patients who received less than 5 cycles of study treatment (n = 13), 92% (n = 12) did not have clearance, and 1 patient did. Of the patients who received at least 5 cycles of study treatment (n = 14), 36% (n = 5) did not have clearance, and 64% (n = 9) did.

MRD was measured using multiparameter flow cytometry (sensitivity, 0.1%-0.01%). Of the 8 patients in the doublet cohorts tested for MRD, 50% (n = 4) were MRD negative. Of the 8 patients in the triplet cohorts tested for MRD, 75% (n = 6) were MRD negative. Of the 7 patients in the doublet cohorts tested for IDH1, 43% (n = 3) achieved clearance. Of the 7 patients in the triplet cohorts tested for IDH1, 86% (n = 6) achieved clearance. In the overall population, of 8 patients tested for both MRD negativity and IDH1, 63% (n = 5) were MRD negative with undetected IDH1. The MRD-negative median survival was NR, with a 24-month OS rate of 100%. The MRD-positive median survival was 8 months.

The molecular and cellular correlates of relapse are currently being defined. Molecular drivers of relapse are being measured by single-cell DNA sequencing. An outgrowth of TP53-mutated clones occurred with the elimination of an IDH1-containing clone. Furthermore, when NRAS G12A clones were eliminated, KRAS and NRAS G13R signaling mutations developed. Cellular mechanisms of relapse are being measured by mass cytometry. The emergence of a CD34-positive cell population was observed with increased MCL1 expression following treatment cycle 7 in patients with newly diagnosed AML.

Regarding safety in the overall population, the recorded adverse effects (AEs) included febrile neutropenia (29%; n = 9), lung infection (19%; n = 6), abdominal pain (10%; n = 3), musculoskeletal pain (10%; n = 3), and otitis media (6.5%; n = 2). All AEs were grade 3, except for 1 patient who experienced grade 5 febrile neutropenia.

AEs of special interest included tumor lysis syndrome and differentiation syndrome. Two patients experienced grade 3 tumor lysis syndrome with a median onset of 14 days (range, 0-27), 1 of which was a dose-limiting toxicity. Differentiation syndrome appeared as grade 2 in 1 patient and grade 3 in 3 patients, with a median onset of 39 days (range, 17-95).

Based on the findings from this phase 1b/2 trial, Dose Level #3 has been selected as the recommended phase 2 dose.²

References

1. Lachowiez CA, Zeng Z, Loghavi S, et al. A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1 mutated myeloid malignancies. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster AML-348.
2. Lachowiez CA, Garcia JS, Borthakur G, et al. A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol. 2022;40(suppl 16):7018.doi:10.1200/JCO.2022.40.16_suppl.7018