Long-Term COMFORT-I Data Confirm Ruxolitinib Survival Benefit

Ruben Mesa, MD

Final 5-year efficacy and safety data from the phase III COMFORT-I trial confirm previous findings that ruxolitinib (Jakafi) confers a significant benefit in patients with intermediate-2 and high-risk myelofibrosis. The JAK-2 inhibitor resulted in durable reductions in splenomegaly and improved overall survival, with patients experiencing no new or unexpected adverse events as a result of the long-term treatment.

Among patients originally randomized to ruxolitinib, 59% had a ≥35% reduction in spleen volume at any time on study, which was the study’s primary endpoint. The median duration of response was 168 weeks (95% CI, 107.7-NE).

Overall survival (OS) at a median follow-up of 268.4 weeks was not reached in the ruxolitinib randomized arm and was 200 weeks in the placebo arm (HR, 0.69; 95%, CI, 0.50—0.96; P = .025).

These long-term findings reaffirm the primary endpoint and support longer term use of the drug, said Ruben A. Mesa, MD, investigator on COMFORT-I and chair, Hematology, at the Mayo Clinic in Arizona, who reported the results at the 2016 European Hematology Association Congress. “We are able to see that there is a clear survival advantage for patients with ruxolitinib compared to the control arm.”

The median time to crossover in the placebo arm was 41 weeks, and a large number of patients (n = 111) crossed over. “It is noteworthy that the control arm was initially on placebo, but by 81 weeks everyone had crossed over to ruxolitinib,” said Mesa. “The trial really became ruxolitinib versus delayed ruxolitinib, and still we see a strong survival advantage.”

Reductions in spleen volume were shown to be rapid and durable in both the ruxolitinib-randomized and the crossover arms in the long-term follow-up.

All patients completed week 24, and more than 50% completed week 36 of treatment. This is particularly exciting, said Mesa, as the life expectancy of the patients enrolled in this study was around 3 years or less on average.

“This demonstrates a significant survival benefit,” he said.

Treatment-Emergent Adverse Events Remain Steady

Toxicities between the primary and follow-up analyses were consistent with the well-characterized safety profile of ruxolitinib, said Mesa. “We are able to reaffirm that there were no unexpected long-term toxicities, even up through 5 years,” he said.

Nonhematologic, all-grade AEs included fatigue, experienced by 24.3%, 18.1%, and 67.6% of patients in the ruxolitinib-randomized arm, the crossover arm, and the placebo arm, respectively. Diarrhea was reported in 18.5%, 12.7%, and 40% of patients across the three arms, respectively, and ecchymosis (12.5%, 11.9%, and 13.2%, respectively).

During the 5-year follow-up, basal cell carcinoma occurred in 2.7% of patients receiving ruxolitinib, 4% in the crossover arm, and 3.9% of controls. The exact cause of this toxicity is unclear, said Mesa. Of the 26 patients who developed basal cell carcinoma, 2 in the ruxolitinib-crossover arm had severe cases, and both had a history of skin cancer. “It is difficult to differentiate if that increased rate is because of treatment or because of their advanced age and prior hypoxic exposure,” he added.

Hematologic abnormalities included all-grade anemia, occurring in 98.7% of patients in the ruxolitinib-randomized arm and 95.5% in the crossover arm, with approximately 54% of the events grade 3/4 in both arms, versus 88% of controls, of which 20.5% were grade 3/4. All-grade thrombocytopenia occurred in 83.9% of patients in the ruxolitinib-randomized arm and 90% in the crossover arms (22.6% and 28.3%, grade 3/4, respectively,), compared with only 33% in the placebo arm (2.6%, grade 3/4).

Moving Forward

Ruxolitinib may be particularly effective in myelofibrosis because it targets multiple mutations, said Mesa.

“Ruxolitinib is a JAK2 and FLT3 inhibitor, and its an inhibitor of the native JAK2. We identified that patients with FLT3 inhibitor with myelofibrosis have an overly active JAK-STAT pathway. That can be overly activated by the JAK2 V617F mutation, the calreticulin mutation, MPL mutation, and in some patients we have not yet identified the driver mutation. However, they all feed at that same JAK2 spot, in terms of signaling, and that is the key area of inhibition. That is one of the reasons we’ve seen benefit to the therapy irrespective of an individual’s driver mutation status.”

Potential next steps for ruxolitinib in myelofibrosis include investigating it in earlier or lower-risk disease. Mesa reported that agents being explored for use in combination with ruxolitinib include cytoreductive therapies such as hypomethylating agents, other novel pathway inhibitors such as PI3K inhibitors, hedgehog inhibitors, as well as other agents that could improve anemia rates.

“Those efforts are still ongoing,” said Mesa. “There is not yet a combination that is clearly superior to single agent. At the moment there are none that we’d recommend, but those studies are being followed with great interest.”

Verstovsek S, Mesa R, Gotlib J, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 5-year final efficacy and safety analysis from COMFORT-I. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract S452

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COMFORT-I randomized patients aged ≥18 years with intermediate-2 or high-risk myelofibrosis and splenomegaly to a twice-daily regimen of either ruxolitinib (n = 155) or placebo (n = 154). Patients with a platelet (PLT) count of 100-200 × 10⁹/L) received a 15 mg dose of the study drug, and those whose PLT count >200 × 10⁹/L received 20 mg. Crossover to ruxolitinib was permitted before week 24 for patients experiencing protocol-defined increasing splenomegaly and following the primary analysis. The preplanned 5-year analysis occurred when all patients reached the 5-year visit or discontinued therapy.