NEW YORK – Triplet combination therapy is becoming a new standard of care for acute myeloid leukemia patients at MD Anderson Cancer Center based on synergistic effects seen in ongoing studies of Genentech's Venclexta (venetoclax) with a targeted therapy and a hypomethylating agent.
In the case of IDH1-mutated AML, most patients currently receive Venclexta and azacitidine or Servier's IDH1 inhibitor Tibsovo (ivosidenib) and azacitidine. Such treatment is followed by hematopoietic stem cell transplant as consolidative therapy to improve patients' long-term cure rates. The doublets, Venclexta-azacitidine and Tibsovo-azacitidine, have not been compared head-to-head, but in previous trials, median overall survival with Venclexta-azacitidine was 15 months, and with Tibsovo-azacitidine it was 24 months. Although both regimens are efficacious, relapses are still common, and therapies with improved outcomes are needed, according to Courtney DiNardo, a hematologist at MD Anderson.
DiNardo and colleagues from Dana-Farber Cancer Institute and Oxford University published a study last month in Blood Cancer Discovery comparing a triplet regimen comprising Venclexta, Tibsovo, and azacitidine in IDH-mutated AML patients to doublet therapy with Tibsovo and Venclexta. Patients had durable responses to both regimens; the trial showed "very impressive" median event-free survival at three years in the overall study population, according to DiNardo.
There was a trend toward improved event-free survival favoring those on the triplet regimen, among whom the median was not reached, compared to a median event-free survival of 11 months for patients on the doublet. There was no statistically significant difference in median overall survival between the arms, which was not reached for Venclexta-Tibsovo-azacytidine and was 42.1 months for Venclexta-Tibsovo. Compared to the Venclexta-Tibsovo doublet, the triplet therapy had a lower rate of primary or secondary treatment failure. "We hope this triplet therapy may more effectively prevent disease relapse through … deeper remission," said DiNardo.
The overall response rate for the whole study population was 94 percent. The rate of composite complete remission was 83 percent for patients on Venclexta-Tibsovo and 90 percent on Venclexta-Tibsovo-azacitidine.
Sixty-three percent of patients evaluable for minimal residual disease were MRD-negative in the overall study population. Among patients who completed five or more cycles of Venclexta-Tibsovo-azacitidine, the rate of IDH1 clearance was 86 percent; while numerically higher, this was not a statistically significant improvement over the 43 percent IDH1 clearance rate in patients who received five or more cycles of Venclexta-Tibsovo.
DiNardo noted that not only were 90 percent of patients in the triplet therapy group achieving a composite complete response, "but they appear to be obtaining very deep responses with … MRD-negative remissions by both flow cytometry and IDH1 [clearance] by droplet digital PCR that we hope will translate into longer remissions and fewer relapses."
While there is always a concern that combination treatments will increase toxicity, the safety profile of the triplet regimen was similar to what has been previously reported for doublet treatment. For instance, a risk of differentiation syndrome has been noted with Tibsovo-azacitidine therapy and cytopenia-related risks for Venclexta-azacitidine. "While we saw all of these [same] adverse effects, they did not occur at an increased frequency than anticipated," said DiNardo.
"The safety of triplet regimens will be dependent on the safety of the third agent being added. In this case, Tibsovo is well tolerated and is not adding substantial toxicity," DiNardo added. "It will also be dependent on the dosing of the triplet therapy. In our study, all patients received 14 days of Venclexta only from the beginning to minimize cytopenias."
With the lengthy and durable responses observed in the study so far, there is a possibility that some patients may be cured and will not require stem cell transplant afterward. DiNardo noted that patients with IDH1-mutated AML tend to be older with comorbidities and may not qualify for a transplant.
"I do wonder if some of these patients with deep and durable remissions may actually be cured, although I am hesitant to use that word still," DiNardo said. "Without long-term data, I still recommend hematopoietic stem cell therapy in eligible patients, but I hope that in the future, not all of these patients will need the added toxicity of [transplant]."
Since this is the first trial to demonstrate the safety and the efficacy of triplet therapy, DiNardo believes the results will be practice changing. She noted that MD Anderson has started giving patients triplets comprising azacitidine, Venclexta, and targeted therapies in clinical trials and begun integrating these regimens as part of the standard of care. DiNardo emphasized, however, that more study is needed to confirm whether the safety and efficacy of triplet regimens warrant replacing doublets, Venclexta-azacitidine or Tibsovo-azacitidine, in treating IDH1-mutant AML.
However compelling the evidence to date, Venclexta-Tibsovo-azacitidine is not yet approved by the US Food and Drug Administration and is not part of National Comprehensive Cancer Network's guidelines, which means patients' insurers may not cover the triplet regimen. "Oral cancer therapies are incredibly expensive," said DiNardo. "This is a very important concern that needs to be addressed."
In separate studies, the cost of Venclexta-azacitidine has been estimated at $473,960 per AML patient achieving a complete response and Tibsovo-azacitidine at $652,088 over a lifetime for patients with IDH1-mutant AML.
DiNardo said this study is only the first of many testing various triplet therapies with a Venclexta-azacitidine backbone and a targeted therapy. "The safety and efficacy of this trial raises hope that this will be an effective treatment strategy to benefit our patients with various genomic drivers," DiNardo said.