Results of a new phase Ib trial of voxtalisib in combination with chemoimmunotherapy

Prof Farrukh Awan - Ohio State University, Columbus, USA

Can you tell me a bit about what led you to research this topic?

In the field of CLL there has been a huge change in the last couple of years, specifically with the approval of newer, less toxic therapies. But over the last decade things have significantly improved in terms of therapeutic options for patients with CLL, therapies less toxic, more specific, outcomes are getting better and better. So people who originally did not have the option of getting prolonged remissions or prolonged survivals can now have those options without having a lot of toxicity, without having a lot of side effects. Along those lines, some of the most successful molecules have been that target a specific molecule in the CLL, the BTK inhibitors primarily, and also the PI3 kinase inhibitors. So the attempt is now how can we improve on the responses and one of the ways that we can inhibit the pathways much more effectively is to inhibit multiple pathways that drive the cancer cells simultaneously. So that was the molecule that we worked with, it’s called voxtalisib and it’s a dual kinase inhibitor. It targets PI3 kinase and it also targets mTOR. This was primarily based on the preclinical work that showed that inhibiting mTOR by itself may not be enough and the cells may be able to escape, so mTOR inhibitors haven’t been as successful. An early phase trial that was done that showed some promising responses in patients with lymphomas, so our trial was primarily designed to test a larger population with this drug and combine it with therapies that we already have approved – immunotherapy like rituximab and also chemo-immunotherapy like bendamustine and rituximab, which is commonly used.

So we treated patients with indolent non-Hodgkin’s lymphomas, mantle cell lymphomas and CLL with these combinations in two arms. One arm got no chemotherapy, they just got the kinase inhibitor along with rituximab, and the other arm got chemotherapy with rituximab and our kinase inhibitor voxtalisib. Therapy was generally fairly well tolerated, we saw some issues with nausea, diarrhoea but it wasn’t significant, it was less than 20%. We saw a few rashes but there was only one patient in each group that had a significant rash that required us to stop the drug. Most of the side effects that we saw in both the groups were primarily because of the effect of the drug and especially the chemotherapy on the counts. So we saw some thrombocytopenia, we saw some anaemia, but for the most part the drug was very well tolerated. PI3 kinase inhibitors also are known to cause pneumonitis, colitis and transaminitis. When we looked at those three specifically we don’t see any evidence of transaminitis, we didn’t see any evidence of significant pneumonitis but that again is hard to classify because there were a few patients with pneumonias in a patient population which is relapsed refractory and hard to treat, these guys get infections anyway, so that’s a harder to assess side effect. Then we didn’t see a lot of colitis, actually we didn’t see any colitis. So, for the most part, the drug was fairly well tolerated in combination with immunotherapy and chemo-immunotherapy in patients with relapsed and refractory disease. Something we don’t expect in this cohort of patients, we saw response rates in excess of 50% in the CLL group when bendamustine rituximab was combined with voxtalisib. One thing to note is that the vast majority of patients, almost 60% of the patients, had had prior bendamustine. So this was their second exposure to bendamustine-based chemotherapies. The median number of prior therapies in both the groups, the ones without chemotherapy and the ones who got chemotherapy, was three. So this was a fairly heavily pre-treated patient population who got this therapy and actually did really well. For the most part therapy was well tolerated.

Now, there are a couple of issues that remain unanswered – what’s going to be the long-term use issue with this particular drug and, primarily, that issue is true for all kinase inhibitors. We don’t know when to stop, we don’t know when to transition patients off of therapy. That’s something that we would have to design new trials that address that question. The second issue is what is the role of this particular compound in this rapidly evolving landscape of CLL? We have idelalisib that’s already approved, duvelisib is looking very promising, ibrutinib is already approved and there are multiple other kinase inhibitors in the pipeline. So the market is shrinking and there is a lot of competition. So it really now remains to be seen how this drug can be positioned in the market and whether or not it will be used in the up-front setting or in the relapsed setting or would that be an option that maybe we can leave it on the shelf and use it maybe a few years from now when we really need it? So all of these questions are being addressed right now and being debated right now. Ultimately it’s going to be a commercial or a marketing decision to whether or not to develop this drug further but clinically the drug is promising and we feel that there is an option for patients who have failed conventional therapies in the past.

So that’s a summarised version of what we did specifically regarding this project.