Expert Highlights RESPONSE Results With Ruxolitinib in Polycythemia Vera

Ruben Mesa, MD

Four-year follow-up data suggest that the majority of patients with polycythemia vera (PV) who responded to treatment with ruxolitinib (Jakafi) maintained those responses for up to 4 years, according to an analysis from the RESPONSE trial that was presented at the 2017 ASH Annual Meeting. Additionally, there were no new safety signals compared with the previous follow-up at 80 weeks.

In the RESPONSE trial, patients with PV and hydroxyurea resistance or intolerance were randomly assigned to receive ruxolitinib or best available therapy. At 208 weeks, 41 patients (37%) originally on the ruxolitinib arm remained on treatment compared with none of the patients on the control arm. Additionally, 37 of 98 patients (38%) who crossed over from the control arm to ruxolitinib after 32 weeks remained on treatment.

Results at the 208-week follow-up showed that 19 of 25 patients who attained primary responses to ruxolitinib at 32 weeks maintained those responses. The median duration of response has yet to be reached for patients who attained a primary response at 32 weeks.

“The key takeaway message for this study is regarding durability, efficacy, and safety,” said Ruben A. Mesa, MD. “This 4-year data shows long-term durable responses. The majority of patients remain on the therapy. There are no new long-term safety signals.”

OncLive: Please provide an overview of the RESPONSE trial.

In an interview with OncLive during the 2017 ASH Annual Meeting, Mesa, director of the UT Health San Antonio Cancer Center, discussed the significance of the RESPONSE study for patients with PV.Mesa: My colleagues and I presented the 4-year follow-up data from the RESPONSE study. The RESPONSE study investigated ruxolitinib as a second-line therapy for patients with PV. We demonstrated that, at 4-years of follow-up, the majority of patients remain on the therapy.

What is the potential for ruxolitinib in the first-line setting?

Overall, there are no unexpected long-term toxicities. The efficacy in terms of phelobotomy independence, control of spleen size, and improvements in symptoms is very durable. This is a very important study. There are no long-standing data regarding therapies in PV that have risen from a randomized clinical trial.Ruxolitinib in PV is a very active drug. The decision to start looking at it in the second-line setting was appropriate to meet an unmet need. Based on the degree of efficacy, it certainly may have activity in the frontline setting.

What are the next steps following this research?

We need to see which patients would be most appropriate in terms of their risk or their degree of burden. PV is heterogeneous and ruxolitinib is active in the frontline setting. An important question is, “Which patients are more appropriate?” Is it all patients or a select group who have more predictively problematic PV from the beginning?We are wondering if we should use ruxolitinib in earlier settings of PV. Are there individuals who have higher-risk features where we should consider any combination-type approaches?

Can you give background on the Myeloproliferative Disorders-Research Consortium Protocol 111 global phase II trial?

Another agent that is active in PV is interferons. There have been some pilot studies that have shown that they are active together. There may be a benefit in progression-free survival or efficacy by using them in combination; that is another interesting area of research.The Myeloproliferative Disorders-Research Consortium is an National Cancer Institute-funded program. This was an international collaboration between myeloproliferative neoplasms (MPNs) centers focusing on research and clinical trials. The 111 study was a second-line trial on the use of interferon in high-risk patients with PV or essential thrombocythemia who are resistant to hydroxyurea.

At this meeting, we presented data showing high-rates of efficacy in the second-line setting at 65%. There was good improvement in disease-related symptoms, which we presented as a more in-depth analysis on the issues of quality of life. Also, the drug is clearly active in the second-line setting but there are low-grade toxicities that are not irrelevant in the setting of PV at interferon. That clearly came through in our analysis; local skin-site irritations, flu-like symptoms, and rare autoimmune conditions can arise with the use of interferon.

What are the next steps following this study?

In general, where do you envision the field of PV moving?

It is a good drug but dose is important. There is a dose-dependent toxicity that can occur. Not all patients tolerate this drug. In my estimation, 70% to 80% can tolerate it whereas 20% to 30% do not. Again, in the era of individualized medicine, there are certainly individuals in which this is a better fit than others.There are randomized trials ongoing that are investigating interferons in the frontline setting helping to demonstrate that it is active in the second-line setting or third-line setting. We know ruxolitinib is approved in the second-line setting in PV. In terms of the data, it clearly shows that if patients fail ruxolitinib, interferon will be an option for them.The key scientific unmet need is knowing why patients progress. If we knew why patients progress, we would be able to better understand those mechanisms and pharmacologically impact them to avoid progression, as well as potentially move for deeper remissions or curative-type strategies. That remains one of the key opportunities.

There was an interesting drug for PV, a nutlin inhibitor, presented in a study from Mount Sinai Hospital that showed good in-depth activity for patients who had failed multiple therapies. That will be tested further in an ongoing phase II study.

Kiladjian JJ, Verstovsek S, Griesshammer M, et al. Results from the 208-week (4-year) follow-up of RESPONSE trial, a phase 3 study comparing ruxolitinib (rux) with best available therapy (BAT) for the treatment of polycythemia vera (PV). In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 322.