Incyte Medical Officer Elaborates on Ruxolitinib Benefit for Polycythemia Vera

Richard Levy, MD

In December, the FDA approved the JAK1/2 inhibitor ruxolitinib (Jakafi) for patients with polycythemia vera who are resistant or intolerant to hydroxyurea. The action made ruxolitinib the first agent with a specific indication for patients with polycythemia vera.

The FDA based its decision on the phase III RESPONSE trial, the full results of which were published today in The New England Journal of Medicine.

RESPONSE randomized 222 patients with polycythemia vera to ruxolitinib (n = 110) or best available therapy (n = 112), which included hydroxyurea, interferon, observation, and other treatments.

Hematocrit control without phlebotomy was achieved for 60% of patients treated with ruxolitinib, compared with 20% receiving best available therapy. Spleen volume was reduced by ≥35% in 38% of patients receiving ruxolitinib compared with 1% for best available therapy.

The primary endpoint of the trial looked specifically at the number of patients who achieved hematocrit control without phlebotomy from week 8 to 32 and experienced greater than a 35% reduction in spleen volume by week 32. Overall, 21% of patients in the ruxolitinib arm met this criteria compared with 1% for best available therapy (P <.001).

The rates of grade 3/4 anemia and thrombocytopenia were higher in the ruxolitinib arm compared with best available therapy (2.0% vs 0% and 5.0% vs 4.0%, respectively). Symptom improvement by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) favored ruxolitinib, with 49% of patients experiencing a ≥50% improvement from baseline compared with 5% for best available therapy.

Can you discuss the RESPONSE trial and the results?

For additional insight on the published RESPONSE data and the use of ruxolitnib to treat polycythemia vera, we reached out to Richard Levy, MD, executive vice president and chief drug development and medical officer at Incyte, the company that co-manufactures ruxolitinib with Novartis.To design the trial to get a result that was clinically meaningful and acceptable to the FDA, we focused on two things. We focused on bringing the hematocrit level down below 45% and keeping it there without phlebotomies and also reduction in spleen size. The primary endpoint was a composite of those two things in the sense that to be a responder in the primary analysis, you had to be ineligible for phlebotomies and you had to have your spleen volume reduction by at least 35%.

So in that composite analysis, which is really a regulatory endpoint and not something that someone would look at as a combination in clinical practice, there’s a big difference between the groups—around 21% response rate versus about 1%. But when you look at the individual components of that, you can see that there’s about 60% of the patients who are able to maintain hematocrit control without phlebotomies in the ruxolitinib arm and just under 20% in the control arm. And the reason why there was such a big difference overall is that only less than 1% of patients actually have the spleen size reduction in the control arm.

The other important aspect to this is the frequency of clots, which is one of the major reasons why you treat patients with polycythemia vera. There have been papers published showing that if the control of the hematocrit is below 45%, you have a lower risk of clots than if you maintain a hematocrit level between 45% and 50%. We didn’t power the study to look at clots, per say, that would require a much larger and longer study and forcing patients who were not doing well on the control arm to stay on that control arm for longer periods of time. But [reducing the frequency of clots] is the underlying medical reason why the hematocrit control is so important. It’s not simply avoiding the uncomfortable and inconvenient phlebotomies.

What is the recommended dose of ruxolitinib when treating polycythemia vera?

So these results led to the approval from the FDA. Can you discuss the specifics of this indication?

The starting recommended dose is 10 mg BID and it was clear that patients need to be titrated based on their hematocrits. What we found was that the average dose at the end of the observation period was closer to 15 mg twice a day than it was to 10 mg, but there was a range from 5 mg up to 25 mg twice a day, so it really is individualized.The indication is actually broader than the entry criteria into the RESPONSE study because the FDA and others have seen that the trial was designed around a regulatory endpoint, but the implications are greater.

So, for example, we used the ELN criteria for resistance to hydroxyurea but the indication is actually for patients who have an inadequate response, which is a broader term. But in doing a protocol, you needed a very specific set of entry criteria.

The second thing is that the indication is not limited to patients with enlarged spleens, which was done as part of the protocol in order to do this composite endpoint.

Can you discuss the significance of the JAK2 mutation in this population?

So, it’s basically for anyone who has had an inadequate response to hydroxyurea or anyone who cannot tolerate a fully active dose of hydroxyurea because of side effects.Historically, if you look at the literature, about 95% of polycythemia vera patients have the JAK2-v617F mutation, whereas in primary myelofibrosis and essential thrombocytopenia, about 50% have the mutation.

Can you discuss the toxicity of ruxolitinib?

Ruxolitinib has demonstrated in myelofibrosis that it doesn’t matter if you have the mutation or not, it works in both patients with and without the mutation and the reason for that is that the pathway through JAK is activated in all patients with these diseases, regardless of this specific mutation.So in myelofibrosis, our first approved indication for ruxolitinib, a lot of those patients already have anemia and thrombocytopenia and you’re giving a drug that by partially blocking JAK2, reduces the signaling and leads to the production of red blood cells and the production of platelets. But in polycythemia vera, you’re at a stage in this disease where you have too many red blood cells and you usually have too many platelets. So here the hematologic abnormality or side effects that were seen in patients with myelofibrosis or thrombocytopenia are actually a benefit in patients with polycythemia vera.

But that’s not to say that during the initial titration of the dose, there weren’t people who had hematocrits and platelet counts below the limited normal range, but essentially then the doses were titrated back to the right dose to keep the hematocrits and platelet counts in the normal range.

And in terms of the nonhematologic side effects, we saw a fairly similar group of things to what we have seen in myelofibrosis, which was the basis of our labeling, which included headaches and dizziness, that sort of thing.

The study was not blinded. Patients who were on their standard therapy were often on the same therapy that they came in on, which means they didn’t have anything better to switch to. So that leads to, if something doesn’t get worse taking the same drug you don’t report it as an adverse event whereas if it’s something new when you switch to the new drug you report it.

Is there any other research planned for this agent?

What should community oncologists be aware of when incorporating this treatment into practice?

So the overall frequency of adverse events was higher in the ruxolitinib arm than in the standard therapy arm, but it’s not an ideal study design to compare the safety if you were starting two different sets of drugs.So as of right now the plan is to continue this study so that all patients have a minimum of 5 years’ data if they stay on the drug. In terms of other studies, it would take a long, large study to look at the risk of thrombosis. We haven’t decided to pursue that at this time, in part because the data would make it even more difficult to maintain a control arm for long enough to look at that.Well, I think it really comes down to identifying the patients who will benefit from the drug. There are clearly a lot of polycythemia vera patients who do well on hydroxyurea for a period of time, and some for many years. But there are a number of patients out there who are not doing as well and it really comes down to identifying those patients that may still be on hydroxyurea because there previously has been nothing better, but they are really not meeting their targets. And it’s for those patients that the use of ruxolitinib needs to be considered.