Ivosidenib plus venetoclax with or without azacitidine safe, effective for AML subset
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Ivosidenib and venetoclax with or without azacitidine appeared safe and effective for the treatment of IDH1-positive myeloid malignancies, according to phase 1B/phase 2 study results presented during the ASCO20 Virtual Scientific Program.
Eighty percent of patients in the study achieved some form of complete response to therapy, according to the investigators.
Ivosidenib (Tibsovo, Agios Pharmaceuticals) is a small molecule IDH1 inhibitor, whereas venetoclax (Venclexta; AbbVie, Genentech) selectively binds and inhibits the BCL-2 protein.
“The idea was that if we combined these two agents, we may get synergistic efficacy and improve responses,” Curtis Lachowiez, MD, hematology/medical oncology fellow at The University of Texas MD Anderson Cancer Center, told Healio.
Lachowiez’s group conducted the study among an older population with heavily pretreated disease, “so a lot of these patients are unable to tolerate the intensive chemotherapies that have been the standard of care for the last 30 years,” he said.
“The aim was to develop a more effective, targeted therapy with a more favorable toxicity profile that would provide a new option for this patient population,” he added.
Lachowiez said the two-drug combination has produced some “very nice responses” but they are not as durable, and patients are susceptible to relapse. Researchers sought to determine whether the addition of azacitidine to the regimen added durability to patients’ responses.
The study included 20 adults (median age, 67 years; range, 37-84; 60% men) with IDH1-positive myeloid malignancies (acute myeloid leukemia or high-risk myelodysplastic syndrome) assigned to one of three treatment cohorts. Cohort 1 included six patients who received 500 mg ivosidenib and 400 mg venetoclax on days 1 to 14 of each 28-day treatment cycle, cohort 2 included six patients who received 500 mg ivosidenib and 800 mg venetoclax on days 1 to 14 of each 28-day cycle, and cohort 3 included eight patients who received the cohort 1 regimen plus 75 mg/m2 azacitidine on days 1 to 7 of each cycle.
The study’s key objectives included determining the safety and tolerability of the both the doublet and triplet regimens, in addition to the maximum tolerated dose, overall response rate, time to adverse events and minimal residual disease (MRD) by flow cytometry.
Eight patients (40%) had relapsed or refractory AML and four patients (20%) had myelodysplastic syndrome.
Median follow-up was 7 months.
The safety analysis showed 75% of patients experienced grade 1 or grade 2 diarrhea. The most common grade 3 or grade 4 adverse events included pneumonia (70%) and febrile neutropenia (50%).
One patient experienced a dose-limiting toxicity (tumor lysis syndrome) and another patient died within 30 days of study discontinuation due to febrile neutropenia.
The prevalence of febrile neutropenia and pneumonia in this study were “as expected” among this patient population with pretreated disease, according to Lachowiez.
“The pneumonia rate in our study was a bit higher than I would have expected, but that may be more reflective of the patient population as opposed to the combination therapy,” he told Healio.
“We are still working to find the recommended phase 2 dose for the triplet combination, so there will need to be more dose optimization because there appears to be more myelotoxicity with the three-drug regimen,” he added. “We will want to be mindful of this going forward so we don’t put forward a regimen that’s too toxic for the patient.”
The efficacy analysis showed an ORR of 90% across all three cohorts, 100% in cohorts 2 and 3, and 60% in cohort 1.
The composite complete response rate, including complete response with or without complete hematologic recovery, was 80% overall, 67% for cohort 1, 100% for cohort 2 and 75% for cohort 3. The complete response rate was 40% across all cohorts (50% for cohorts 1 and 2 and 25% for cohort 3).
Ten percent of patients had no response to therapy.
Half of evaluable patients across all cohorts were MRD-negative at follow-up, including 67% (n = 4) of those evaluable in cohort 3.
Patients with relapsed or refractory AML had a 75% ORR, compared with a 100% ORR for all other disease subgroups in the study.
Median OS was not reached by median follow-up. Median EFS was 2.4 months (95% CI, 0-20) for cohort 1, 9.4 months (95% CI, 5-14) for cohort 2 and not reached for cohort 3.
Lachowiez acknowledged that his group’s study is difficult to interpret due to the small sample size. He noted that a lot of the patients had relapsed or refractory AML or secondary AML.
“This group of diseases is historically difficult to treat,” he told Healio. “Compared with historical controls, we saw a marked improvement in response rates in this patient population.”
Responses in this ongoing study have been clinically meaningful, according to Lachowiez. “Ideally we would like all of our patients to have some form of complete response to this therapy, and one of the most impressive aspects of this study was that 16 of the 20 patients were able to have some form of complete response,” he said.
“We can achieve a complete response in many patients with AML — perhaps upwards of 80% to 90% — but the trick is keeping them in remission because a lot of these patients will relapse. Hopefully, this triple-combination therapy will allow us to keep these patients in remission.”
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Lachowiez CA, et al. Abstract 7500. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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