EMERGING THERAPIES
ment for high-risk patients with AML and FLT3 mutations. Patients and physicians have waited for new drugs for AML since the 1990s, so the results of the CALGB 10603/ RATIFY trial were greeted with enthu siasm at ASH 2015. The study was an undertaking of the Alliance for Clinical Trials in Oncology. At a median follow-up of 57 months, midostaurin reduced mortality risk by 23% compared with placebo plus che motherapy. The median OS was 74.7 months for the group receiving midos taurin versus 26 months for the place bo group (P = .007), representing a 23% reduction in the risk for death favoring midostaurin. “This represents a new standard of care for FLT3-mutat ed AML,” said Richard M. Stone, MD, Director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston. “These results…represent a long- awaited advance for hematologists and the AML community,” Dr Stone told attendees. “This is the first step in ap plying the theories of personalized med icine to patients with AML, specifically those patients with AML who have a FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard therapy.” Approximately 30% of patients with
© Rodney White 2015. All rights reserved.
Midostaurin the First Targeted Therapy to Improve...
“This represents a new standard of care for FLT3mutated AML.”
“The study does have the potential to be practice-changing.”
—Richard M. Stone, MD
—Mark R. Litzow, MD
AML carry the FLT3 mutation, which is associated with aggressive disease, with poor prognosis and a high risk for relapse. Among the FLT3 inhibitors under development, midostaurin is the first to demonstrate improved survival in patients with an FLT3 mutation in a phase 3 clinical trial. RATIFY randomized 717 adults with AML and an FLT3 mutation to oral midostaurin or to placebo in addition to standard induction with daunorubicin plus cytarabine and consolidation che motherapy (high-dose cytarabine). The patients who achieved a complete re mission (CR) after consolidation che motherapy continued treatment with
single-agent midostaurin or with place bo as maintenance therapy for 1 year. Midostaurin significantly improved event-free survival compared with pla cebo, with a median event-free surviv al of 8 months for midostaurin versus 3.6 months for placebo (P = .003), a 21% reduction in risk for events favor ing midostaurin. The patients were prestratified ac cording to the 3 mutation subtypes of FLT3, including tyrosine kinase domain (TKD), internal tandem duplications (ITD) high, and ITD low. ITD FLT3 mutations carry a worse prognosis, and prognosis is less uncertain with TKD FLT3 mutations. Midostaurin improved
Continued from the cover
OS and event-free survival in all 3 FLT3 subtypes versus placebo. The patients who achieve a CR with midostaurin benefit from continued mi dostaurin therapy, with 25.9 months of disease-free survival with midostaurin versus 14 months with placebo in pa tients who achieved a CR. Overall, 57% of the patients went on to undergo allogeneic stem-cell trans plantation at first remission (28% in the midostaurin group and 22% in the pla cebo group); midostaurin achieved a survival benefit in patients who did and did not have a transplant. Midostaurin had acceptable safety. No significant differences were observed in the overall rates of grade ≥3 hema tologic and nonhematologic adverse events. A total of 37 deaths occurred, with no difference in treatment-related deaths between the 2 groups. “The study does have the potential to be practice-changing, and midostau rin should be considered as part of the control arm of future studies. ECOGACRIN is now discussing the design of future trials,” said Mark R. Litzow, MD, Head of the Acute Leukemia Group, Mayo Clinic, Rochester, MN, regarding the RATIFY trial. “But it may turn out that other drugs out there prove to be better FLT3 inhibitors,” he added. s
Venetoclax Shows Strong Activity in CLL By Phoebe Starr
T
he oral, investigational, small- molecule BCL-2 inhibitor vene toclax has shown excellent and durable responses in patients with re lapsed or refractory chronic lymphocyt ic leukemia (CLL). All patients in the trial harbored the 17p deletion (del 17p), which signals poor prognosis. In the pivotal phase 2 trial reported at ASH 2015, nearly 80% of high-risk patients with relapsed or refractory CLL had a response to venetoclax monother apy, approximately 10% had a complete response and partial response, and more than 20% had minimal residual disease; the responses were durable. So far, 3 other new drugs have been approved by the FDA for the treatment of patients with CLL, including the Bruton’s kinase inhibitor ibrutinib (Im bruvica), the PI3K inhibitor idelalisib (Zydelig), and the anti-CD20 obinu tuzumab (Gazyva), which is a more po tent version of rituximab (Rituxan). Venetoclax attacks CLL by a differ ent mechanism, inhibiting the BCL-2 protein that prevents cell death, mak ing it an attractive partner with other
CLL drugs that have a complementary mechanism of action. Venetoclax has such strong antitu mor activity that tumor lysis syndrome (TLS) emerged as a major concern in preliminary studies. This led AbbVie (one of the study’s sponsors) and the investigators to adjust the dosing sched ule of venetoclax, initiating treatment at 20 mg daily and increasing the dose slowly over 4 weeks to a target dose of 400 mg daily. The new dosing schedule has not led to any clinical TLS, but there has been laboratory evidence of TLS in approximately 20% of patients in various trials. “We saw deep responses and accept able toxicity with venetoclax mono therapy in a relapsed/refractory popula tion. Investigator-confirmed complete response was 7.5% and nodular partial response was 2.8%, with minimal dis ease negativity in greater than 20%,” said Stephan Stilgenbauer, MD, PhD, Department of Internal Medicine III, University of Ulm, Germany. “In this study, venetoclax had a fa vorable risk–benefit profile. The risk of
“We saw deep responses and acceptable toxicity with venetoclax mono therapy in a relapsed/ refractory population.” —Stephan Stilgenbauer, MD, PhD
tumor lysis syndrome was effectively mitigated by our careful dosing strategy, and we saw no clinical tumor lysis syn drome,” Dr Stilgenbauer said. Study Details
This pivotal study enrolled 107 pa tients with relapsed or refractory CLL and del 17p confirmed by a central labo ratory. The median progression-free sur vival (PFS) with frontline chemotherapy is
ment for high-risk patients with AML and FLT3 mutations. Patients and physicians have waited for new drugs for AML since the 1990s, so the results of the CALGB 10603/ RATIFY trial were greeted with enthu siasm at ASH 2015. The study was an undertaking of the Alliance for Clinical Trials in Oncology. At a median follow-up of 57 months, midostaurin reduced mortality risk by 23% compared with placebo plus che motherapy. The median OS was 74.7 months for the group receiving midos taurin versus 26 months for the place bo group (P = .007), representing a 23% reduction in the risk for death favoring midostaurin. “This represents a new standard of care for FLT3-mutat ed AML,” said Richard M. Stone, MD, Director, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston. “These results…represent a long- awaited advance for hematologists and the AML community,” Dr Stone told attendees. “This is the first step in ap plying the theories of personalized med icine to patients with AML, specifically those patients with AML who have a FLT3 mutation, who we have shown are likely to benefit from the addition of this targeted agent, midostaurin, to standard therapy.” Approximately 30% of patients with
© Rodney White 2015. All rights reserved.
Midostaurin the First Targeted Therapy to Improve...
“This represents a new standard of care for FLT3mutated AML.”
“The study does have the potential to be practice-changing.”
—Richard M. Stone, MD
—Mark R. Litzow, MD
AML carry the FLT3 mutation, which is associated with aggressive disease, with poor prognosis and a high risk for relapse. Among the FLT3 inhibitors under development, midostaurin is the first to demonstrate improved survival in patients with an FLT3 mutation in a phase 3 clinical trial. RATIFY randomized 717 adults with AML and an FLT3 mutation to oral midostaurin or to placebo in addition to standard induction with daunorubicin plus cytarabine and consolidation che motherapy (high-dose cytarabine). The patients who achieved a complete re mission (CR) after consolidation che motherapy continued treatment with
single-agent midostaurin or with place bo as maintenance therapy for 1 year. Midostaurin significantly improved event-free survival compared with pla cebo, with a median event-free surviv al of 8 months for midostaurin versus 3.6 months for placebo (P = .003), a 21% reduction in risk for events favor ing midostaurin. The patients were prestratified ac cording to the 3 mutation subtypes of FLT3, including tyrosine kinase domain (TKD), internal tandem duplications (ITD) high, and ITD low. ITD FLT3 mutations carry a worse prognosis, and prognosis is less uncertain with TKD FLT3 mutations. Midostaurin improved
Continued from the cover
OS and event-free survival in all 3 FLT3 subtypes versus placebo. The patients who achieve a CR with midostaurin benefit from continued mi dostaurin therapy, with 25.9 months of disease-free survival with midostaurin versus 14 months with placebo in pa tients who achieved a CR. Overall, 57% of the patients went on to undergo allogeneic stem-cell trans plantation at first remission (28% in the midostaurin group and 22% in the pla cebo group); midostaurin achieved a survival benefit in patients who did and did not have a transplant. Midostaurin had acceptable safety. No significant differences were observed in the overall rates of grade ≥3 hema tologic and nonhematologic adverse events. A total of 37 deaths occurred, with no difference in treatment-related deaths between the 2 groups. “The study does have the potential to be practice-changing, and midostau rin should be considered as part of the control arm of future studies. ECOGACRIN is now discussing the design of future trials,” said Mark R. Litzow, MD, Head of the Acute Leukemia Group, Mayo Clinic, Rochester, MN, regarding the RATIFY trial. “But it may turn out that other drugs out there prove to be better FLT3 inhibitors,” he added. s
Venetoclax Shows Strong Activity in CLL By Phoebe Starr
T
he oral, investigational, small- molecule BCL-2 inhibitor vene toclax has shown excellent and durable responses in patients with re lapsed or refractory chronic lymphocyt ic leukemia (CLL). All patients in the trial harbored the 17p deletion (del 17p), which signals poor prognosis. In the pivotal phase 2 trial reported at ASH 2015, nearly 80% of high-risk patients with relapsed or refractory CLL had a response to venetoclax monother apy, approximately 10% had a complete response and partial response, and more than 20% had minimal residual disease; the responses were durable. So far, 3 other new drugs have been approved by the FDA for the treatment of patients with CLL, including the Bruton’s kinase inhibitor ibrutinib (Im bruvica), the PI3K inhibitor idelalisib (Zydelig), and the anti-CD20 obinu tuzumab (Gazyva), which is a more po tent version of rituximab (Rituxan). Venetoclax attacks CLL by a differ ent mechanism, inhibiting the BCL-2 protein that prevents cell death, mak ing it an attractive partner with other
CLL drugs that have a complementary mechanism of action. Venetoclax has such strong antitu mor activity that tumor lysis syndrome (TLS) emerged as a major concern in preliminary studies. This led AbbVie (one of the study’s sponsors) and the investigators to adjust the dosing sched ule of venetoclax, initiating treatment at 20 mg daily and increasing the dose slowly over 4 weeks to a target dose of 400 mg daily. The new dosing schedule has not led to any clinical TLS, but there has been laboratory evidence of TLS in approximately 20% of patients in various trials. “We saw deep responses and accept able toxicity with venetoclax mono therapy in a relapsed/refractory popula tion. Investigator-confirmed complete response was 7.5% and nodular partial response was 2.8%, with minimal dis ease negativity in greater than 20%,” said Stephan Stilgenbauer, MD, PhD, Department of Internal Medicine III, University of Ulm, Germany. “In this study, venetoclax had a fa vorable risk–benefit profile. The risk of
“We saw deep responses and acceptable toxicity with venetoclax mono therapy in a relapsed/ refractory population.” —Stephan Stilgenbauer, MD, PhD
tumor lysis syndrome was effectively mitigated by our careful dosing strategy, and we saw no clinical tumor lysis syn drome,” Dr Stilgenbauer said. Study Details
This pivotal study enrolled 107 pa tients with relapsed or refractory CLL and del 17p confirmed by a central labo ratory. The median progression-free sur vival (PFS) with frontline chemotherapy is
