Acute myeloid leukemia (AML) is a disease of high unmet need with a generally poor prognosis. This is especially true in the elderly population, with only approximately 45% of these patients receiving aggressive therapy with curative intent (Kantar Health, CancerMPact Treatment Architecture, 2012). Dacogen (decitabine, Eisai /Astex) was recently approved in Europe for use in elderly AML patients (but was rejected by the FDA in the same indication), and Phase III trials of both sapacitabine (Cyclacel) and Vidaza (azacytidine, Celgene) are ongoing in newly diagnosed elderly AML patients. Presentations of positive Phase II data in elderly AML patients at ASH 2012 suggest that two new targeted agents – quizartinib (AC220, Ambit Biosciences/Astellas) and volasertib (BI6727, Boehringer Ingelheim) – may be efficacious in this population and are poised to enter Phase III development within the next year.
Volasertib in an inhibitor of Polo-like kinase 1 (Plk1), which is involved in spindle assembly during mitosis. Preliminary results from the randomized Phase II portion of a Phase I/II study were presented at ASH 2012 (Maertens, Abstract 411). Eighty-six newly diagnosed AML patients ineligible for intensive therapy were randomized to treatment with either low-dose cytarabine (LoDAC) alone or LoDAC plus volasertib. Significantly more patients in the volasertib plus LoDAC arm achieved an objective response (p<0.0523, CR: 19.0%, CRi: 12.0%) compared with the control arm (CR: 6.7%, CRi: 6.7%). Also, the addition of volasertib to LoDAC significantly extended event-free survival (5.6 months versus 2.3 months, HR: 0.56, p<0.0237), and there was a statistical trend toward an increase in overall survival (8.0 months versus 5.2 months, HR: 0.66, p=0.0996). However, this efficacy was accompanied by an increase in adverse events, with patients in the volasertib plus LoDAC arm experiencing a higher incidence of Grade 3+ gastrointestinal adverse events (21% versus 7%), infections (Grade 3: 48% versus 23%), metabolism-related adverse events (Grade 3: 15% versus 7%) and respiratory adverse events (Grade 3: 23% versus 13%). Based on the promising Phase II results, the speaker announced that Boehringer Ingelheim plans to initiate a Phase III trial of volasertib in the first quarter of 2013. The POLO-AML-2 trial will randomize 660 previously untreated AML patients aged 65 and older who are ineligible for high-intensity therapy to be treated with either LoDAC alone or LoDAC plus volasertib.
Fms-like tyrosine kinase 3 (FLT3) is commonly overexpressed in AML, and approximately 30-35% of AML patients have FLT3 internal tandem duplications (FLT3-ITD), which confer a poor prognosis compared with FLT3 wild-type patients (Gale, Blood, 2008, 11(5): 2776-2784). Midostaurin (PKC-412, Novartis) is currently the only FLT3 inhibitor in Phase III development, but its pivotal RATIFY trial is focused on younger patients, evaluating the addition of midostaurin to standard 7 + 3 daunorubicin and cytarabine induction in newly diagnosed AML patients aged 60 years or younger. Quizartinib is a selective FLT3 inhibitor with a low plasma IC50 of 18 nM (compared to ~1000 nM for midostaurin). Final results were presented from a single-arm Phase II study of quizartinib in 333 AML patients who were FLT3-ITD-positive and FLT3-ITD-negative (Cortes, Abstract 48). The study was divided into two cohorts. The first cohort included second-line patients at least 60 years of age, and data from this cohort are discussed here. The second cohort included third-line patients at least 18 years of age, and data from this cohort will be presented late Monday afternoon at ASH 2012. In the 90 FLT3-ITD-positive elderly patients treated with quizartinib, 3% achieved a complete remission (CR) + CRp, and 50% achieved a CRi. In the 42 FLT3-ITD-negative elderly patients treated with quizartinib, 5% achieve a CR + CRp, and 31% achieved a CRi. The ability to achieved a CR is something that wasn’t observed with midostaurin in its Phase IIB study, suggesting that quizartinib’s higher selectivity may translate into greater clinical activity. Overall survival with quizartinib was similar regardless of FLT3-ITD status, with a median survival of 25.3 weeks for FLT3-ITD-positive patients and 19.0 weeks for FLT3-ITD-negative patients. As expected from previous investigation of quizartinib, the most common Grade 3/4 adverse events were hematological (anemia: 33% for FLT3+ and 20% for FLT3-, febrile neutropenia: 33% for FLT3+ and 48% for FLT3-thrombocytopenia: 29% for FLT3+ and 19% for FLT3-), asthenia (12% for FLT3+ and 5% for FLT3-), and QT prolongation (10% for FLT3+ and 12% for FLT3-). The speaker announced that Phase III randomized trials are planned for the end of 2013, but details were not provided.
Compared with Dacogen, which was recently approved in Europe for newly diagnosed elderly patients, both quizartinib and volasertib (plus LoDAC) produce higher overall response rates. Volasertib plus LoDAC also appears to result in a survival benefit similar to Dacogen. In the case of quizartinib, however, it is currently unclear whether the extremely high response rate will translate into a meaningful survival benefit in a randomized setting. Considering the fact that Dacogen was rejected by the FDA primarily because the survival benefit was perceived to lack clinical meaningfulness, it will be important for each of these new agents to show a clear statistical increase in overall survival in their Phase III studies to gain approval in the United States. In addition, each new agent has its own unique toxicity profile. Quizartinib has consistently resulted in QT prolongation in addition to causing hematologic toxicities similar to Dacogen. In contrast, volasertib primarily results in increased gastrointestinal and respiratory adverse events as well as infection (including febrile neutropenia). However, considering the poor prognosis and lack of options for elderly patients newly diagnosed with AML, further development of new therapeutic options is a welcome development indeed!
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Cory Blaiss, PhD, Analyst, Kantar Health
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