Five-Year Data Confirm Benefit of Jakafi in Myelofibrosis

The JAK-2 inhibitor Jakafi (ruxolitinib) has a significant benefit for patients with with intermediate-2 and high-risk myelofibrosis, according to final five-year efficacy and safety data from the phase 3 COMFORT-I trial. The treatment 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. These data were presented at the 2016 European Hematology Association (EHA) Congress, a gathering of thousands of hematology and oncology professionals from around the world.

Among patients originally randomized to Jakafi, 59 percent had at least a 35 percent reduction in spleen volume at any time on study, which was the study’s primary endpoint. The median duration of response was 168 weeks.

Overall survival (OS) at a median follow-up of 268.4 weeks was not reached in the Jakafi randomized arm and was 200 weeks in the placebo arm.

These long-term findings reaffirm the primary endpoint and support longer term use of the drug, said Ruben A. Mesa, 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 Jakafi compared to the control arm.”

COMFORT-I randomized patients aged 18 years or older with intermediate-2 or high-risk myelofibrosis and splenomegaly to a twice-daily regimen of either Jakafi (155 patients) or placebo (154 patients). 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 was more than 200 × 10⁹/L received 20 mg. Crossover to Jakafi was permitted before week 24 for patients experiencing protocol-defined increasing splenomegaly and following the primary analysis. The preplanned five-year analysis occurred when all patients reached the five-year visit or discontinued therapy.

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

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

All patients completed week 24, and more than 50 percent completed week 36 of treatment. This is particularly exciting, said Mesa, as the life expectancy of the patients enrolled in this study was around three 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 Jakafi, said Mesa. “We are able to reaffirm that there were no unexpected long-term toxicities, even up through five years,” he said.

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

During the five-year follow-up, basal cell carcinoma occurred in 2.7 percent of patients receiving Jakafi, four percent in the crossover arm, and 3.9 percent of controls. The exact cause of this toxicity is unclear, said Mesa. Of the 26 patients who developed basal cell carcinoma, two in the Jakafi -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 percent of patients in the Jakafi -randomized arm and 95.5 percent in the crossover arm, with approximately 54 percent of the events grade 3/4 in both arms, versus 88 percent of controls, of which 20.5 percent were grade 3/4. All-grade thrombocytopenia occurred in 83.9 percent of patients in the Jakafi -randomized arm and 90 percent in the crossover arms (22.6 percent and 28.3 percent, grade 3/4, respectively,), compared with only 33 percent in the placebo arm (2.6 percent, grade 3/4).

Moving Forward

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

“Jakafi 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 Jakafi in myelofibrosis include investigating it in earlier or lower-risk disease. Mesa reported that agents being explored for use in combination with Jakafi 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.”