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Arog Pharma Moving FLT3 Inhibitor Crenolanib Into Head-to-Head AML Trial Against First-Gen Rydapt


NEW YORK – After a positive Phase II trial, Arog Pharmaceuticals is advancing crenolanib into a Phase III study in which it will pair the next-generation FLT3 inhibitor with chemotherapy and compare the combination's activity against Novartis' first-generation FLT3 inhibitor Rydapt (midostaurin) plus chemo in newly diagnosed FLT3-mutant acute myeloid leukemia patients.

According to a Journal of Clinical Oncology paper detailing the Phase II results earlier this month, treatment with crenolanib plus intensive chemotherapy led to high response rates and durable responses in FLT3-mutated AML patients. Those 60 years old or younger appeared to fare better on the crenolanib-chemo combo compared to those older than 60, prompting the firm to launch the latest Phase III trial in the younger group.

Eunice Wang, first author of the study and chief of the leukemia service at Roswell Park Comprehensive Cancer Center, noted that the results emphasize the importance of precision medicine for newly diagnosed AML.

"We've known for the last few years with the approval in 2017 of the first targeted therapy for AML, midostaurin, that it is beneficial, and we can improve outcomes by adding the targeted therapy to frontline chemotherapy," Wang said. "This [trial] is just further along the therapeutic road from midostaurin and where we now have more potent and specific newer generation FLT3 inhibitors like crenolanib."

Most AML patients are screened for FLT3 mutations now, Wang said, due to the increasing market availability of these targeted agents. But she underscored the importance of not only looking for the mutation but also establishing the specific type of mutation: an FLT3 internal tandem duplication (ITD) versus tyrosine kinase domain (TKD) mutation. "It's pretty much standard of care now to wait for those results before starting treatment, as long as the patient is clinically stable," she noted.

In the crenolanib Phase II trial, across the entire cohort of 44 patients, 86 percent achieved a complete response. At a median follow-up of 45 months, the median overall survival was not reached, and the estimated three-year overall survival rate was 58 percent. The cumulative incidence of relapse among 38 patients who achieved a complete response was 31.5 percent.

The younger group of patients had better outcomes, with higher complete response and three-year overall survival rates at 90 percent and 71.4 percent, respectively, and a lower cumulative incidence of relapse at 15.3 percent. With a median follow-up of 45 months, the median overall survival was not reached in the younger group. Meanwhile, the over-60 group had a complete response rate of 80 percent, median overall survival of 19.8 months, a three-year survival rate of 33.3 percent, and a cumulative incidence of relapse of more than 60 percent.

Wang noted that younger AML patients tend to have better outcomes because they can receive allogenic hematopoietic stem cell transplantation, while many older patients cannot. She added that the older group in this study experienced more toxicities and needed more dose reductions or interruptions.

"Even older patients going to transplant did better than those that didn't go to transplant," Wang pointed out. "Crenolanib looks like it particularly benefits those people because, potentially, we think that the addition of the FLT3 inhibitor results in better disease control as reflected in high [measurable residual disease]-negative rates at the time that they're going to transplant."

The researchers assessed measurable residual disease (MRD) by multiparameter flow cytometry in 29 patients who responded to crenolanib plus chemo and found that 89 percent of younger patients and 45 percent of older patients achieved an MRD-negative complete response. Event-free survival was also better among the younger patients, in whom a median event-free survival was not established at 45 months compared to 7.9 months median event-free survival in older patients.

The trial also included an assessment of patients' tumor mutational profiles. The study included patients with several types of FLT3 mutations, with three quarters of patients having the more common FLT3-ITD mutations, 18 percent having FLT3-TKD mutations, and 7 percent having both. Compared to other FLT3 inhibitors, crenolanib is able to inhibit different types of FLT3 mutations. First-generation FLT3 inhibitor Rydapt, which was approved in 2017, Daiichi Sankyo's recently approved agent in this class, Vanflyta (quizartinib), and Astellas' Xospata (gilteritinib) can only inhibit FLT3-ITD mutations in AML patients.

Among 41 patients whose tumor mutational profiles were assessed, the researchers found lower response rates among those who had only FLT3-TKD mutations and those who had TP53 co-mutations. Patients with co-occurring mutations that are historically associated with poor outcomes on chemo — DNMT3A, NPM1, transcription factor, WT1, and spliceosome mutations — experienced high response rates to the crenolanib-chemo combination, the researchers noted.

The researchers also tracked subsequent therapies and outcomes for patients who relapsed. After the initial crenolanib and chemo cycles, patients who achieved remission could go on to receive allogenic hematopoietic stem cell transplantation, with or without high-dose cytarabine chemotherapy. After that, patients could go back on crenolanib as a maintenance treatment. They found that those who got allogenic hematopoietic stem cell transplantation versus just chemotherapy had better outcomes, as did those who received subsequent maintenance treatment with crenolanib.

While this study did not compare crenolanib head-to-head to other FLT3 inhibitors, the researchers noted that the 86 percent and 90 percent response rates in the overall and younger cohorts, respectively, were higher than in other trials of drugs in this class in newly diagnosed FLT3-mutant AML. The Phase III QuANTUM-First trial, for example, which led to the approval of Vanflyta plus chemo in this setting, demonstrated a 71.6 percent complete response rate and median overall survival of 31.9 months. A Phase III trial of Rydapt plus chemo showed a complete response rate of 59 percent and a median overall survival of 74.7 months. Overall survival in the crenolanib trial was not yet reached with 45 months of follow-up.

Wang also noted that the toxicity profile of crenolanib is different than other FLT3 inhibitors. Vanflyta, a second-generation FLT3 inhibitor like crenolanib, can cause changes in heart function, which led the US Food and Drug Administration to set up a risk evaluation and mitigation strategy program for monitoring and managing these toxicities. Crenolanib does not affect heart function, and the serious adverse events reported in the Phase II trial included febrile neutropenia, diarrhea, and nausea.

In the upcoming Phase III trial, sponsor Arog will pit crenolanib head-to-head against the first-generation FLT3 inhibitor Rydapt. Researchers are currently recruiting patients with newly diagnosed FLT3-mutant AML into this study and will compare crenolanib plus intensive chemo against Rydapt plus intensive chemo. Arog did not respond to a request for comment about its regulatory plans for crenolanib.

Previous randomized Phase III trials of FLT3 inhibitors Rydapt, Xospata, and Vanflyta compared them against standard chemotherapy, but Wang noted that this isn't the standard of care anymore for this subset of patients. "Having an array of options that are all clearly providing benefit [over chemotherapy] is important," she said. "All of the second-generation FLT3 inhibitors have improved efficacy for these patients."

She recognized that the development and approval of these personalized drugs have changed the prognosis for AML patients with FLT3 mutations. Prior to these targeted therapies, patients with FLT3 mutations were typically considered to have a poor prognosis and aggressive disease that was often chemo-resistant, Wang said.

"Now, with the advent of multiple FLT3 inhibitors in the upfront setting, we see [that according to] the 2022 European LeukemiaNet classification, FLT3 is no longer considered a poor prognostic indicator for newly diagnosed AML," she said. FLT3 mutations currently denote intermediate prognostic risk in the classification scheme, which, to Wang, reflects "the fact that over the last seven years or so, we have been able to make a poor prognosis leukemia into one that we think we have a really good chance of beating."