Jordyn Sava 

Findings from the phase 3 AGILE trial showed significant benefit with Tibsovo (ivosidenib) plus Vidaza (azacytidine) compared to placebo in patients who had newly diagnosed 

Results from AGILE supported the recent Food and Drug Administration

(FDA) approval of Tibsovo in combination with Vidaza as a treatment option for patients with previously untreated IDH1-mutated AML

 aged 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy. The supplemental new drug application was reviewed as part of the FDA's Real-Time Oncology Review (RTOR) pilot program, which gets safe and effective therapies to patients sooner.

Earlier findings AGILE findings showed the median survival for patients who received the combination of Tibsovo and Vidaza to be 24 months compared to placebo. Improvements were also seen in event free survival (time from treatment until any complications or events that the therapy was meant to delay) and complete remission plus complete remission with partial hematologic recovery rates was 52.8% compared to17.6% with placebo.

“Approximately 6% to 10% of patients with acute myeloid leukemia have somatic mutations in the 

 gene. (Tibsovo) is a potent oral targeted inhibitor of mIDH1. And the AGILE study showed benefits of (Tibsovo) plus (Vidaza) compared with placebo plus (Vidaza) in patients with newly diagnosed 

-mutated AML,” Dr. Hartmut Dohner, medical director, deputy director, professor, principle investigator at Ulm, Baden-Wurttemberg in Germany, stated during a presentation of the poster during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

The multicenter, double-blind (meaning neither patients nor their clinicians knew which treatment was being administered), randomized, placebo-controlled, phase 3 AGILE trial aimed to evaluate the efficacy and safety of Tibsovo plus Vidaza compared with placebo plus Vidaza in adult patients with newly diagnosed, previously untreated 

m AML who were ineligible for intensive induction chemotherapy.

Enrollment within the trial was open to patients aged 18 years who met at least 1 of the following criteria: an ECOG performance status score of 2 (which indicates some degree of impairment to perform daily functions), severe cardiac disorder, severe pulmonary disorder, creatinine clearance less than 45 mL/minute, bilirubin greater than 1.5 times the upper limit of normal, or had another comorbidity judged incompatible with intensive IC by the investigators.

Along with this, patients must have had previously untreated AML with 20% or more leukemic blasts in the bone marrow, an 

 mutation and adequate hepatic and renal function.

Patients were randomly assigned to receive the combination of oral Tibsovo at 500 mg plus subcutaneous or intravenous Vidaza at 75 mg/m2 (72 patients), or a matching placebo (74 patients). Patients were assessed for red blood cell and/or platelet transfusion history at the time of screening and follow-up. Further, bone marrow and peripheral blood samples were obtained at the time of screening, weeks nine, 17, 25, 33, 41, 53, every 24 weeks after, as well as at the end of treatment and during event-free survival follow-up.

The primary end point of the trial was EFS with key secondary end points including overall survival (time from treatment until death of any cause), rate of complete remission (no signs of cancer left after treatment), rate of complete remission and complete remission with partial hematologic recovery (CRh), and overall response rate (percentage of patients whose disease shrinks as a result of treatment).

Results from the sub-analysis of the trial demonstrated that in the Tibsovo plus Vidaza and placebo plus Vidaza arms, a total of 4.2% and 5.5% of patients received concomitant granulocyte colony-stimulating factor.

The combination of Tibsovo plus Vidaza demonstrated rapidly increased mean neutrophil counts from baseline (0.99 x 109/L) (2.05 x 109/L) and week five (4.07 x 109/L), before generally stabilizing to a normal range by the end of the study (last available cycle value; ̃2.0 x 109/L), showing that they recovered more rapidly compared with the placebo combination.

Along with increased blood counts, there was a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week nine and 17 in the Tibsovo plus Vidaza treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the patients who were administered placebo plus Vidaza (53.7%, 34.6% and 19.6% at baseline, week nine and week 17, respectively).

The mean platelet count recovered from baseline values in the Tibsovo plus Vidaza and placebo plus Vidaza arms (71.0 and 92.6 x 109/L, respectively) as early as week nine of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population.

Additionally, there was a reduced dependence on red blood cell and/or platelet transfusion. Febrile neutropenia and infection rates also were reduced when patients were administered Tibsovo and Vidaza, and within the placebo plus Vidaza arm, the mean neutrophil counts initially declined before recovering to near-normal levels after 36-40 weeks at a slow pace.

Of the patients who at baseline were red blood cell/platelet transfusion-dependent, a total of 54.0% in both groups, 46.2% of patients within the Tibsovo plus Vidaza arm vs 17.5% in the placebo plus Vidaza arm achieved red blood cell/platelet transfusion independence compared.

In regard to safety, fewer side effects of febrile neutropenia were demonstrated in the Tibsovo plus Vidaza arm (28.2%) compared to the placebo plus Vidaza arm (34.2%). Additionally, infections were found in 28.2% vs 49.3% of patients who received Tibsovo plus Vidaza compared to placebo plus Vidaza.

In the combination group, anemia of any grade occurred in 22 patients (31%) and grade 3 or higher occurred in 18 (25.4%) vs 28.8% and 26% in the placebo plus Vidaza arm. Thrombocytopenia of any grade was reported in 20 patients (28.2%) and thrombocytopenia grade 3 or higher in 17 patients (23.9%) compared with 15 (20.5%) in the placebo plus Vidaza arm.

Non-hematological side effects of any grade in the Tibsovo plus Vidaza vs placebo plus Vidaza arm included nausea (42.3% vs 38.4%), vomiting (40.8% vs 26%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), constipation (26.8% vs 52.1%), pneumonia (23.9% vs 31.5%) and more. Grade 3 or higher non-hematological in each arm included nausea (2.8% vs 4.1%), vomiting (0% vs 1.4%), diarrhea (1.4% vs 6.8%), pyrexia (1.4% vs 2.7%), constipation (0% vs 1.4%) and pneumonia (22.5% vs 28.8%).

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Articles

Tibsovo plus Vidaza led to survival benefit for patients with IDH1-mutant acute myeloid leukemia, according to findings from the AGILE clinical trial. 

Tibsovo Plus Vidaza Is Beneficial for Patients With IDH1-Mutant Acute Myeloid Leukemia

There were no major differences in outcomes for patients with previously untreated chronic lymphocytic leukemia (CLL), regardless of whether they received a fixed dose of consolidation Venclexta (venetoclax) or if their treatment was guided by their minimal residual disease status.

Consolidation therapy is given after the main line or lines of treatment to rid patients of any lingering cancer cells, known as minimal residual disease (MRD).

The data comes from the primary analysis of a phase 2 trial (HOVON 139/GiVe, NTR6043) which examined the activity and safety of 12 cycles of Venclexta consolidation after patients who were ineligible for fludarabine-based treatment was given fixed-duration Venclexta plus Gazyva (obinutuzumab). The study also aimed to see if this process could be guided by MRD status.

The open-label, multicenter, randomized trial enrolled a total of 70 patients who initially received two cycles of Gazyva given intravenously to get rid of as much cancer as possible. That was then followed by Venclexta plus Gazyva for a total of 12 cycles.

After, patients were randomly assigned and given either 12 cycles of Venclexta consolidation irrespective of MRD status or Venclexta consolidation if MRD was detected at randomization.

The main goal of the study was to see if consolidation Venclexta would lead to undetectable MRD in the bone marrow, as well as and no progressive disease three months after the end of consolidation treatment. Safety and side effects were also assessed. The analysis of the primary end point of this trial is currently ongoing.

In the study, 32 patients received fixed-dose Venclexta consolidation therapy, while 30 patients received consolidation Venclexta that was guided based on their MRD status.

At a median follow-up of 35.2 months, 16 of the 32 patients in the fixed-dose consolidation group (50%) and 16 of the 30 in the MRD-guided consolidation group (53%) met the primary endpoint of undetectable MRD in bone marrow, as well as lack of progressive disease.

Of the 32 patients in the fixed-dose Venclexta consolidation group, 22 (69%) experienced grade 2 to 4 (moderate, severe or life-threatening) side effects, compared with 11 (37%) of 30 patients in the MRD-guided consolidation group.

Overall, both methods of consolidation treatment were well-tolerated. The most common severe (grade 3 or higher) side effects were neutropenia (a decrease in a type of white blood cell), which occurred in 6% of the fixed-dose cohort and 7% in the MRD-guided group, and infection, which occurred in 6% and 3% of the fixed-dose and MRD-guided groups, respectively. There were no treatment-related deaths reported in the study.

The findings demonstrated that both maintenance treatments (fixed duration Venclexta, and MRD-guided Venclexta), were well tolerated and demonstrated high efficacy after the given cycles. MRD-guided Venclexta maintenance treatment also demonstrated slightly lower rates of side effects compared with fixed duration Venclexta.

A version of this article was originally published on Targeted Oncology as, “Venetoclax Consolidation Is Well Tolerated in Patients with Previously Untreated CLL.”

Regardless of whether it was guided by minimal residual disease status or given at a fixed dosage, consolidation Venclexta proved to be beneficial in patients with chronic lymphocytic leukemia. 

Jordyn Sava

Tibsovo Plus Vidaza Is Beneficial for Patients With IDH1-Mutant Acute Myeloid Leukemia

Post-Treatment Venclexta Improves Outcomes and Is Well-Tolerated in CLL

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