SAN FRANCISCO – Adding vosaroxin to cytarabine chemotherapy increased overall survival in first relapsed or refractory acute myeloid leukemia in the phase III VALOR study.

The difference in this primary endpoint, however, failed to achieve statistically significance (median 7.5 months vs. 6.1 months; P = .06), lead study author Dr. Farhad Ravandi reported at the annual meeting of the American Society of Hematology.

More patients receiving vosaroxin (Qinprezo) and cytarabine than cytarabine alone achieved complete remission (CR) (30.1% vs. 16.3%; P < .0001).

The benefit was significant across all subgroups (age at least 60 years, refractory disease, early and late relapse), except in those aged younger than 60 years, he said.

Vosaroxin is an investigational, first-in-class anticancer quinolone derivative that was granted fast track designation by the Food and Drug Administration in 2011 for the potential treatment of relapsed or refractory acute myeloid leukemia (AML) in combination with cytarabine.

Despite missing its primary endpoint, Dr. Ravandi argued during a press briefing that VALOR was a positive trial and that the survival benefit with combination vosaroxin was “highly significant.” He described relapsed/refractory AML as the equivalent of metastatic cancer, with patients presenting with disease “all over their body, right from day 1.”

“In solid tumors, we are excited about a 1- or 2-month survival improvement and I don’t see why we shouldn’t be excited in AML as well,” said Dr. Ravandi of the University of Texas M.D. Anderson Cancer Center in Houston.

He suggested that the bar has been set high in AML because about 40% of patients are cured and that great leaps forward remain rare. “We should not discount the small steps forward in treating our patients and providing better treatment options,” he said.

Press briefing moderator Dr. David Steensma of the Dana-Farber Cancer Institute, Boston, agreed that change is often incremental in AML but countered that the magnitude of benefit wasn’t great.

“AML is a really difficult population, no question about it, but there’s also no question that seven and a half months is pretty crummy and we need to do better than that,” Dr. Steensma said.

VALOR randomly assigned 711 adult patients from 124 sites in 15 countries to IV cytarabine 1 g/m² on days 1-5 plus placebo or IV vosaroxin 90 mg/m² on days 1 and 4 for induction and 70 mg/m² for subsequent cycles. Patients had AML refractory to initial induction therapy or were in first relapse, defined as relapse within 90 days to 24 months after first CR or CR with incomplete platelet recovery.

In all, 30.1% of patients in the vosaroxin group and 29% in the placebo group underwent allogeneic stem cell transplantation (ASCT). In those younger than 60 years, rates were 46.2% and 45.4%.

When stratified by age, there was a significant overall survival benefit with the vosaroxin combination for patients aged 60 years and older, who accounted for two-thirds of the study population (median 7.1 months vs. 5.0 months; hazard ratio, 0.75; P = .003), Dr. Ravandi said.

There was no survival advantage in patients younger than 60 years (median 9.1 months vs. 7.9 months; HR, 1.08, P = .60).

In a preplanned analysis censored for ASCT, median overall survival was significantly better in patients receiving the vosaroxin combination versus cytarabine alone (6.7 months vs. 5.3 months; HR, 0.83; P = .02).

“The benefit may be underestimated by the high rate of [ASCT], particularly in the younger patients,” Dr. Ravandi concluded during the formal presentation of the late-breaking abstract. “These data support the use of vosaroxin in combination with cytarabine as a new standard for salvage therapy in older patients with relapsed or refractory AML.”

During the discussion following the presentation, session comoderator Dr. Jonathan Friedberg of the University of Rochester Medical Center in Rochester, N.Y., asked, “How do you reconcile the observation that the patients you wanted to get to transplant got there, and yet you’re blaming the transplant for poor outcomes?”

Dr. Ravandi responded that transplantation is an issue in all AML studies and that a much larger study would have been needed to show a survival difference regardless of transplant status.

Treatment-related adverse events were more common in patients on vosaroxin and were mostly infection related. Stomatitis was identified as a dose-limiting toxicity in previous studies and occurred at any grade in 49% of vosaroxin patients and 19% of controls and at grade 3/4 in 15% and 3%.

Other notable grade 3/4 events were febrile neutropenia (47% vs. 33%) and thrombocytopenia (24% vs. 25%). This increase in toxicity did not translate into worse all-cause mortality at either 30 or 60 days, Dr. Ravandi said.

Sunesis Pharmaceuticals funded the study. Dr. Ravandi and several coauthors reported financial ties with Sunesis. Dr Steensma reported financial ties with several companies. Dr. Friedberg reported no disclosures.

pwendling@frontlinemedcom.com

VALOR: Baby step forward or misstep in AML?