Synergy Shown With Navitoclax/Ruxolitinib in JAK2-Resistant Myelofibrosis

Early research on overcoming resistance to JAK2 inhibitors through combined targeting of JAK2 and BCL-2/BCL-xL in JAK2-driven malignancies led to a hypothesis that the BCL-2/BCL-xL small molecule navitoclax in combination with the JAK1/2 small molecule, ruxolitinib (Jakafi) would have synergy and overcome resistance to JAK2 inhibition in patients with myelofibrosis.

A phase 2 study (NCT03222609) was executed based on the hypothesis and demonstrated clinically meaningful spleen volume reductions and better tumor symptom scores with navitoclax plus ruxolitinib when compared with ruxolitinib alone. The combination also established disease control even in patients with myelofibrosis who had prolonged exposure to ruxolitinib. Navitoclax in combination with ruxolitinib was also well-tolerated in the study subject.

Claire Harrison, MD, FRCP, FRCPath, who presented phase 2 data during the 2020 European Hematology Association (EHA 2020) Virtual Annual Congress, explained to Targeted Oncology what the results shown with navitoclax/ruxolitinib imply for future of the myelofibrosis treatment landscape “as we look for a way to improve our therapeutic landscape for patients with myelofibrosis, I think that navitoclax in combination with ruxolitinib or with another JAK inhibitor…could represent an important step forward for our patients.”

In an interview with Targeted Oncology, Harrison, professor or of hematology, Guy’s and St. Thomas’ NHS Foundation Trust, discussed the combination of navitoclax and ruxolitinib as explored in the phase 2 study.

TARGETED ONCOLOGY: Can you summarize the current treatment landscape for myelofibrosis?

Harrison: There are a range of drugs that are available to treat patients with myelofibrosis. Many of the drugs we’ve been using for a large amount of years now are principally supportive care agents. The JAK inhibitors were a major revolution in the therapeutic armamentarium for these patients. Ruxolitinib was first approved almost a decade ago now. Recently, and more recently pacratinib, a next in class JAK inhibitor with more JAK 2 than JAK 1 activity, was approved by the FDA, but is still not available in Europe.

For the majority of patients, there are not many therapeutic options, and many patients are not fit enough for a curative bone marrow transplant. Our attention is now being focused on what we can do to make the efficacy of ruxolitinib or fedratinib (Inrebic) better or what we can do the patients who don't tolerate those drugs very well. For example, patients with anemia, thrombocytopenia, or patients who progress. That’s an area of a lot of activity and research in the field.

TARGETED ONCOLOGY: Can you discuss the rationale for combining navitoclax with ruxolitinib for the treatment of these patients?

The rationale of combining and navitoclax with ruxolitinib was to see if we could get better activity, as measured by spleen volume reduction or symptom response, and over time, better durability of spleen volume.

Since we know there is a correlation between spleen volume, reduction, and survival benefit for patients, the rationale for the combination is that we do know that the apoptical cell death pathway is disrupted in patients with myelofibrosis. The venetoclax (Venclexta) target is involved in this and the abnormalities in myelofibrosis are driven by BCL-xL.

Cell line data and data from primary cells in patients with MPNs already existed, which was a good hunch to launch a study on.

The rational and the mechanism of action is on based around the ability of these two drugs and the pathways to act in an enhancing way. Ruxolitinib and its inhibition of the JAK-STAT pathway has an effect on proliferation, but navitoclax in its sequestering of anti-apoptotic factors allows the release of the pro-apoptotic pathway. In essence, you have a break on proliferation and a release of apoptosis. Theoretically, this means the two agents can work together well.

Of course, concerns about potential overlapping toxicity are certainly something that we were watching out for.

TARGETED ONCOLOGY: What results were presented during the EHA 2020?

Harrison: At EHA 2020, we presented an updated analysis, particularly focusing on week 24 for the efficacy analysis set for 30 patients who were treated with the combination. There was no withdrawal of ruxolitinib for these patients, they were just on a steady dose and then we added navitoclax. What we saw was that around one-third of patients achieved a sphingosine phosphate lyase reduction of 35% which has become the standard. These patients had already a response to ruxolitinib, so this was the added benefit of navitoclax.

The best response at any time on the study was a response from about 13 patients or 45%. That’s almost equivalent to the number of patients who responded to ruxolitinib alone in COMFORT-1 (NCT00952289) and COMFORT-2 (NCT00934544).

I'm in terms of palpable splenomegaly, just over half of patients have the complete resolution.

As we look at results with JAK inhibition, and as we're looking at patients with my life myelofibrosis we notice they have a severe symptom burden that is equivalent to those with metastatic cancer, or acute leukemia if you look at scores such as the EORTC QLQ-C30.

Also in this study, we look at something called total symptom score, which is built up with the most common symptoms that these patients have. What’s become standard practice is looking at a 50% reduction of the total symptoms score. In the data that we presented,

17 patients who were valuable for symptoms and we saw about 35% of patients having a 50% reduction in symptoms. Overall, about 2/3 of patients have some reduction in symptoms.

Interestingly, the baseline median total symptom score was 12. That is an indication to you that we were not aiming to reduce a big burden of symptoms for these patients and by week 24, the median total symptom score was 7. That demonstrates that there was quite a significant reduction. Some patients, however, did have an increase in the spleen symptom score.

TARGETED ONCOLOGY: What are the implications of this research?

Harrison: As we look for a way to improve our therapeutic landscape for patients with myelofibrosis, I think that navitoclax in combination with ruxolitinib or with another JAK inhibitor, such as fedratinib , which is now approved by the FDA, could represent an important step forward for our patients.

TARGETED ONCOLOGY: Are there any next steps with this research?

Harrison: What is planned in the coming months is a series of studies with navitoclax alone and a randomized trial, just to try to further explore this therapeutic activity.

I also think it's possible, given the tolerability of navitoclax, that this agent could be explored further in other myeloid disorders, with abnormalities of BCL-xL. Examples would be high-risk myelodysplasia and chronic monocytic leukemia, which both have very few treatment options for patients. It could also be used to treat blast phase MPN or acute myeloid leukemia.