In an interview with Targeted Oncology, Srdan Verstovsek, MD, PhD, discussed the data from the MANIFEST trial, which evaluated the use of CPI-0610 as treatment of patients with myelofibrosis.
Myelofibrosis (MF) has very limited treatment options, and the only curative option for patients with MF remains transplantation. However, not all patients are able to go on to receive transplant and are treated with the FDA-approved JAK inhibitor ruxolitinib (Jakafi). The phase 2 MANIFEST study (NCT02158858) demonstrated that the addition of CPI-0610, a novel BET inhibitor, induced clinical activity in patients with JAK inhibitor-naïve, -exposed, or -intolerant MF.
In this clinical trial, 43 patients with advanced MF who were refractory to, intolerant of, or ineligible for ruxolitinib were enrolled in arm 1, while 70 patients who had a suboptimal response to ruxolitinib were enrolled to arm 2, as well as patients who developed disease progression on a JAK inhibitor. Arm 3 enrolled patients with JAK inhibitor-naïve MF.
The study evaluated CPI-0610 as a monotherapy in arm 1, as an add-on to ruxolitinib in arm 2, and in combination with ruxolitinib in the arm 3. Overall, the use of CPI-0610 induced a significant reduction in spleen volume of at least 35% and total symptom score reduction of at least 50%.
In an interview with Targeted Oncology, Srdan Verstovsek, MD, PhD, medical oncologist and professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, discussed the data from the MANIFEST trial, which evaluated the use of CPI-0610 as treatment of patients with MF.
TARGETED ONCOLOGY: What does the current treatment landscape for patients with MF look like?
Verstovsek: MF is 1 of the myeloproliferative neoplasms that is the most aggressive and shortens life expectancy to an average of 5 to 7 years. Now we believe that there is actually potential to extend life for a little bit with ruxolitinib, the first agent approved therapy for MF on the basis of improving the spleen size and decreasing the symptoms, or overall improving the quality of life. With that activity, you also get the anti-inflammatory potential, meaning people gain weight, have less symptoms, walk more, metabolize in the body, and improves the organ function. With the development of the tumor, which has big spleen, you get people to live longer, so it's indicated for people with spleen and symptoms.
Fedratinib was also approved in September last year. This is another JAK inhibitor with a similar quality, and this complements ruxolitinib very well. Perhaps we can even be used after ruxolitinib in the second line. This is all we have on the market so far. You would expect that up to three-quarters of the patients with MF potentially could be candidates for JAK inhibitors, but I don't think that's a reality because it is gauged based on how bad the quality of life is or how symptomatic or large the spleen is. I would say that the minority of patients are actually exposed to JAK inhibitors, maybe 30% to 40%.
The third problem is anemia, and we don't have anything for anemia. Transplant is the only curative potential we have, but less than 10% [receive] the transplant. We are left with medications that are prescribed and off label use of many other medications to improve the anemia and boost the response to JAK inhibitors.
TARGETED ONCOLOGY: What was the rationale for adding CPI-0610 to ruxolitinib in this study?
Verstovsek: CPI-0610 is a BET inhibitor, which is 1 of the epigenetic modifiers. We know that the epigenetic abnormalities are quite often present in patients with M, and that can be associated with the loss of response to JAK inhibitors or progression on JAK inhibitors, and this can certainly shorten the life expectancy of the patients when you progress. The idea of utilizing epigenetic modifiers is not new. We tried with hypomthylating agents (HMAs) like azatadine and decitabine, among others, but they all modify the genetic expression in a different way.
CPI-0610 is being studied in multiple different ways. In MF patients, there are multiple studies from a single-agent arm in this phase 2 study in the second-line setting, then adding it to ruxolitinib while patients are on a stable dose of ruxolitinib, and combining it from the very beginning, This study is kind of 3 sets of patients, including second-line, first-line or in the middle, which we call an add-on approach. There are separations, again, in subgroups based on what the goal of the therapy would be or what the problem is and why the patients would be going on to study. One aspect would be including the anemia, and another aspect will be improving the quality of life.
TARGETED ONCOLOGY: What were the methods of design for this study, and what did the patient population look like in the trial?
Verstovsek: The difference is you would have, in a second-line setting after ruxolitinib, patients with more advanced features with lower platelets with more anemia. They will still have a big spleen, and they might be more genetically complex. They certainly are in a difficult situation where their life expectancy is somewhere between a year and 2 to 2.5 years. In that setting, you would expect the medications to work because of the acquisition of epigenetic abnormalities, so that was the initial intent.
TARGETED ONCOLOGY: What were the findings?
Verstovsek: It didn't work out that well. We have some activity reported in the second-line setting as a single agent, about 23% to 24% spleen response, and some improvements in the quality of life as well, occasional improvement in their white blood cell count, so we saw modest improvements for a single agent in a difficult situation. Some more research needs to be pursued because the patient numbers in all the groups are small. We're talking about a small study so far, and certainly the patient characteristics would affect the delivery of the drug because it does cause some myelosuppression if it's not carefully delivered. The drug is delivered 2 weeks-on/1 week-off because of an underlying possibility of causing thrombocytopenia. We had some gastrointestinal toxicity that we learned about before we started the study at all, so careful delivery is the paramount here for success as it is usual.
The second-line group of patients is the add-on approach where the patients are divided based on a need for improvement of the spleen and symptoms or anemia. I'm quite pleased with these improvements over all the 3 aspects. If you look at the spleen responses and symptomatic improvements, and the anemia improvements, which is basically making people transfusion-dependent you have activity at all 3 levels. The best time, not surprisingly, is actually in the anemia benefit and about a third of the patients become transfusion-dependent. The spleen and symptoms are a little bit lower on the scale but still formidable activity for the add-on approach.
The frontline is quite interesting because not too many drugs have been combined recently in the frontline setting. In the past, we had a lot of combinations in the frontline, and they learned that the delivery in the frontline may harm the utility of ruxolitinib alone. If you add the medications that compromise the ruxolitinib alone by bringing additional toxicity, then nobody benefits, and you have to stop everything. These data still maintain a quite significant ability to improve the symptoms, and it's been about what you would expect with ruxolitinib. It is also delivered in a way that is pretty safe. The adjustments of the doses are necessary as described in the summary, but it gives us hope that with this combination, either with the add-on approach or in the frontline setting, we can enhance what ruxolitinib does to mostly control more symptoms.
I would say, for me, the anemia signal in the add-on approach is quite intriguing because we don't have too many anemia drugs. If I would see that in another setting as well, I would highlight that as 1 of the most [important] benefits, the most beneficial aspect of this therapy overall.
TARGETED ONCOLOGY: Can you elaborate more on these findings from the study?
Verstovsek: The number of patients and the timeframe for assessment of the benefit always affect the overall outcome. We had an 80% response rate in 15 patients after 3 months of follow-up, and now we have many more patients after this 3-month follow-up, so the response rate has decreased a little bit from 80% to 72% to 73%. That is just a function of having patients with different underlying basic characteristics or some other novel problems that we have not seen before, or just pure luck at the beginning. The difference is small, and it's not that important.
The prolongation of observation time with more patients over 6 months observation has decreased the overall response rate to 63%. That may be related again to the time frame, as we have more time maybe to lose response, maybe some patients do not respond because they have underlined different characteristics, or perhaps the loss of response happens because they have to increase the dose. These types of details would be useful to analyze in the future because we have not seen it yet. Nevertheless, 63% is still a very good response considering that in a similar situation with a similar patient population with similar characteristics, we would have about 50% to 60% response rate. So, it's still valuable, but more patients and a more diverse population will give us a better sense of the ultimate ability to deliver a significant better result than the single agent.
TARGETED ONCOLOGY: What are the implications of these data?
Verstovsek: The implication is that we have another agent that is active on multiple levels in different clinical scenarios that requires extra work for us to define which situation is the best for further development. We learned that the plan moving forward is to do a randomized study in the frontline setting, but I would not discount the ability of drug to help people who are already on ruxolitinib and still suffer from anemia, spleen, and symptoms to help them in that situation, which is quite a large group of people in need of a combination in the frontline setting. We may just start with ruxolitinib beginning, then we'll see what happens and add another agent later on if they don't do well with ruxolitinib alone, so it's a mixed bag where you combine things together. It seems that with a single agent, the results are modest, and that is the number 3 option for me.
TARGETED ONCOLOGY: Can you describe the safety profile for this combination?
Verstovsek: The safety appears to be good. The underlying gastrointestinal toxicity or myelosuppression does not appear to be a major problem, which might be a reflection of lowering the doses over 2 medications as it's known very well in a frontline setting. The dose of CPI-0610 is lower than otherwise known to be used in other clinical settings in other diseases, so cautionary approach [is recommended] to utilize the medications in a safe way, and with that, we get interesting clinical benefit without too much on the participant.
TARGETED ONCOLOGY: What are your key takeaways from this study right now?
Verstovsek: The takeaways are that the epigenetic modifiers in general have a role in the MF, but in the past, we kind of gave up on HMAs or other epigenetic modifiers mostly because of the toxicity. Other epigenetic modifiers may have a role, as in this case with CPI-0610.
It is really a balance between the safety, efficacy, and the management style in terms of how you deliver these combinations to the patients. It gives me a sense that we should pursue other agents that are epigenetic modifiers and find ones that can be delivered safely. When you have safety, you have a potential to benefit patients as well.