The Use of Novel PI3K Inhibitors in CLL


Jennifer R. Brown, MD, PhD: A number of novel PI3-kinase inhibitors are currently under evaluation in CLL. The one that is the most advanced is a drug called duvelisib, which is an inhibitor of both the delta and gamma isoforms of PI3-kinase. And at the ASH meeting in December 2017, we saw data that can likely prove registration for this drug.

The delta isoform has been the primary target in hematologic malignancies because that particular isoform has expression limited to hematopoietic cells and has its primary physiologic function in B cells. Idelalisib, for example—the FDA-approved PI3-kinase inhibitor—is a delta inhibitor. Now, duvelisib also inhibits gamma, which is a different isoform, which is expressed in CLL cells, for example, but also is expressed in T cells and neutrophils. And so, the additional rationale for inhibiting gamma could include some antitumor activity in B-cell malignancies as well as T-cell malignancies. It may also result in modulation of the microenvironment through the effect on T cells or neutrophils or macrophages, which is work that is ongoing.

Duvelisib presented mature data from its registration trial at this meeting. This was a phase III randomized trial in relapsed/refractory CLL patients who were randomized to receive duvelisib or ofatumumab at the standard labeled dose for relapsed/refractory patients. The study has completed its full analysis at this point and was very positive for improved progression-free survival in the duvelisib-receiving arm by both the independent review committee and the investigators.

The progression-free survival in the duvelisib arm was about 14 months by the independent review committee and 18 months by the investigators. The ofatumumab arm had a median progression-free survival of about 9 months, which is actually better than usual for the ofatumumab arm, but the difference with duvelisib was still highly significant. Furthermore, we’re always concerned about the high-risk population of 17p-deleted patients, and in this study, there was no difference in the benefits of duvelisib versus ofatumumab in the 17p population; mainly that population still derived very significant benefit from duvelisib. And this is what we would expect because similar results were obtained with idelalisib in its prior registration trials.

The safety profile looks perhaps similar, maybe a bit better, with duvelisib. Just to take a step back, I’ll remind you that the safety profile with these drugs includes a pattern of autoimmune toxicity that can include diarrhea that can be severe with colitis, which tends to be a late event, and also includes infections. What was notable in this study was that although some of those events did occur, they were generally managed and patients were able to stay on duvelisib without needing to discontinue, as we’ve seen in many of the other PI3-kinase inhibitor studies. Although the rate of colitis was 10% to 15%, the discontinuation rate was only about 4% to 5%. So, it suggests that the toxicities were more manageable or that physicians are becoming more comfortable with learning how to keep people on drug while managing their toxicities.

So, the study of duvelisib versus ofatumumab was done in relapsed/refractory CLL patients, most of whom had not been exposed to ibrutinib, for example. It is likely that the niche for duvelisib, mostly because of its toxicity profile being similar to that of other PI3-kinase inhibitors, will be in patients who are not tolerating PTK inhibitors or have progressed on BTK inhibitors and/or venetoclax. So, it will provide an additional important treatment option for this growing group of patients. We do not as of yet have efficacy data in the setting of progression on ibrutinib with this drug, but that’s clearly a place where we will need to obtain such data and where we will also potentially use the drug, as those patients have limited options and there are few options that have data in that setting yet.

Oral administration, of course, is becoming quite common with our novel agents in CLL. The BTK inhibitors in investigation are orally administered. Most of the PI3-kinase inhibitors primarily developed in CLL are oral, although there was, of course, a recent approval of a pan-PI3-kinase inhibitor, copanlisib, which is IV for follicular lymphoma.

There are a number of other PI3-kinase inhibitors that may be of interest in CLL. Another drug called TGR1202, or umbralisib, is in development, and in fact has completed enrollment to registration trial, but we have not yet seen the data. This drug is relatively specific for delta, but is somewhat less potent. So, higher doses are needed. It appears to have an improved safety profile compared to some of the other PI3-kinase inhibitors. It’s unclear if this is because it may be hitting delta more gently, or if it may relate to an alternative activity that the drug has against an enzyme called casein kinase 1 epsilon. This is still under investigation. At present, we also are awaiting more mature follow-up of the long-term efficacy results with the drug, as well as awaiting the registration data. But the safety profile does look better.

Another drug, copanlisib, is an IV pan-PI3-kinase inhibitor that is somewhat selective for alpha and delta, but it’s really a pan-PI3‒kinase inhibitor that was recently approved for follicular lymphoma. And as yet, we have very limited data on that drug in CLL, but it also appears to have a different type of safety profile, and it will be of interest to test it in CLL. The IV administration results in punctuated administration rather than continuous administration, and this may have an impact on the nature of the toxicities that we observe. And so, studying it in comparison to some of the oral continuous therapies in CLL will be of interest.

The PI3-kinase inhibitor class has perhaps not been as hyped recently with the BTK inhibitors and venetoclax. But it remains a very activated, very important treatment option for our patients who are intolerant to the other drugs or progress on them. And I think in the coming years, we will continue to see more data on how best to manage the toxicities and keep patients on drugs so that they can derive the maximum benefit from this class of therapies. And duvelisib will hopefully become another option in our treatment armamentarium based on the data that we saw here from the DUO study.

Transcript Edited for Clarity

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