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Preliminary Data for Duvelisib in Indolent NHL

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School;Ian W. Flinn, MD, Sarah Cannon Center for Blood Cancer
Published: Wednesday, Aug 10, 2016


Transcript:

Ian W. Flinn, MD:
Duvelisib is a PI3 kinase inhibitor. It’s both a delta and gamma isoform-specific inhibitor. This is an important distinction from idelalisib, which is a pure delta inhibitor. In this instance, we think that inhibiting the gamma isoform is important as it gets to the microenvironment and perhaps also improving the efficacy by targeting the microenvironment, not just with a delta isoform. So, there’s a phase I trial that was conducted with duvelisib, and in that study where we analyze the patients who were treated with low-grade lymphoma, there was a greater than 70% overall response rate. And, importantly, nearly one-third of these patients had a complete remission rate with single-agent duvelisib in this phase I trial.

The DYNAMO trial is a single-arm study looking at duvelisib as a single agent in patients with double refractory low-grade and follicular lymphoma. In this instance, by double refractory I mean those patients were refractory both to rituximab as well as to chemotherapy, such as an alkylating agent. This study has fully accrued, and we expect to see the results soon in terms of its efficacy in overall response rate, complete remission rate, as well as full understanding of the toxicity profile. There’s also a trial known as the DYNAMO-R trial, and this is a study that is looking at rituximab with duvelisib versus rituximab alone in patients with low-grade lymphoma. It will be a little bit longer before we know the results of that study.

Duvelisib is being studied widely in low-grade lymphoma as well as in chronic lymphocytic leukemia. There are studies looking at duvelisib in combination with rituximab versus standard chemotherapy, such as R-CHOP or against bendamustine/rituximab. There are some really interesting trials looking at duvelisib in combination with venetoclax. Of course, venetoclax is a BCL-2 inhibitor and in this instance, we’re looking at trying to treat the lymphoma with inhibiting two different pathways. So, I think there’s going to be some very exciting results coming out, perhaps at EHA (European Hematological Association) this year, looking at that combination. Finally, there is a study looking at duvelisib in combination with either obinutuzumab or Rituxan in frontline therapy. And we really look forward to seeing the results of this, at least initial safety cohort of patients on this trial. One of the problems that has been seen with other PI3 kinase inhibitors is that they’re very difficult to use as frontline therapy because of some of the problems with hepatotoxicity. For instance, there was some concern about using idelalisib as a frontline therapy in patients with low-grade lymphoma. It’s going to be interesting to see whether that holds true with duvelisib when it’s used as a frontline therapy, or perhaps by also inhibiting the gamma isoform, whether that makes it easier to use as a frontline therapy.

There are many promising therapies that are currently under development for patients with relapsed and refractory low-grade lymphoma. Most prominently, I think about the so-called R2 regimen. R2 is the combination of lenalidomide and rituximab for patients, not only for the relapsed and refractory but also for frontline therapy. But it has high overall response rates in both settings, both in the relapsed and refractory setting. And so this is a regimen that has great promise for that setting. Now, there are a variety of other therapies that are also being developed. We know that venetoclax, which is approved for the treatment of patients with chronic lymphocytic leukemia, has also been tested in patients with follicular lymphoma. And there are both single-agent studies and combination studies with rituximab that have been conducted and are being conducted in that setting. It makes a lot of sense. We know that in low-grade lymphoma, one of the major issues—just like in chronic lymphocytic leukemia—is the failure of these cells to undergo apoptosis by removing the blockade for apoptosis. With venetoclax, we hope that there’s increased efficacy and that it’s probably best suited in combination for that.

There’s also a number of other drugs that are further back in the developmental pipeline. Some of the immunotherapies are exciting in this arena from the bispecific antibodies to the checkpoint inhibitors. I think there’s a lot that will be coming down the pike soon.

Transcript Edited for Clarity
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Transcript:

Ian W. Flinn, MD:
Duvelisib is a PI3 kinase inhibitor. It’s both a delta and gamma isoform-specific inhibitor. This is an important distinction from idelalisib, which is a pure delta inhibitor. In this instance, we think that inhibiting the gamma isoform is important as it gets to the microenvironment and perhaps also improving the efficacy by targeting the microenvironment, not just with a delta isoform. So, there’s a phase I trial that was conducted with duvelisib, and in that study where we analyze the patients who were treated with low-grade lymphoma, there was a greater than 70% overall response rate. And, importantly, nearly one-third of these patients had a complete remission rate with single-agent duvelisib in this phase I trial.

The DYNAMO trial is a single-arm study looking at duvelisib as a single agent in patients with double refractory low-grade and follicular lymphoma. In this instance, by double refractory I mean those patients were refractory both to rituximab as well as to chemotherapy, such as an alkylating agent. This study has fully accrued, and we expect to see the results soon in terms of its efficacy in overall response rate, complete remission rate, as well as full understanding of the toxicity profile. There’s also a trial known as the DYNAMO-R trial, and this is a study that is looking at rituximab with duvelisib versus rituximab alone in patients with low-grade lymphoma. It will be a little bit longer before we know the results of that study.

Duvelisib is being studied widely in low-grade lymphoma as well as in chronic lymphocytic leukemia. There are studies looking at duvelisib in combination with rituximab versus standard chemotherapy, such as R-CHOP or against bendamustine/rituximab. There are some really interesting trials looking at duvelisib in combination with venetoclax. Of course, venetoclax is a BCL-2 inhibitor and in this instance, we’re looking at trying to treat the lymphoma with inhibiting two different pathways. So, I think there’s going to be some very exciting results coming out, perhaps at EHA (European Hematological Association) this year, looking at that combination. Finally, there is a study looking at duvelisib in combination with either obinutuzumab or Rituxan in frontline therapy. And we really look forward to seeing the results of this, at least initial safety cohort of patients on this trial. One of the problems that has been seen with other PI3 kinase inhibitors is that they’re very difficult to use as frontline therapy because of some of the problems with hepatotoxicity. For instance, there was some concern about using idelalisib as a frontline therapy in patients with low-grade lymphoma. It’s going to be interesting to see whether that holds true with duvelisib when it’s used as a frontline therapy, or perhaps by also inhibiting the gamma isoform, whether that makes it easier to use as a frontline therapy.

There are many promising therapies that are currently under development for patients with relapsed and refractory low-grade lymphoma. Most prominently, I think about the so-called R2 regimen. R2 is the combination of lenalidomide and rituximab for patients, not only for the relapsed and refractory but also for frontline therapy. But it has high overall response rates in both settings, both in the relapsed and refractory setting. And so this is a regimen that has great promise for that setting. Now, there are a variety of other therapies that are also being developed. We know that venetoclax, which is approved for the treatment of patients with chronic lymphocytic leukemia, has also been tested in patients with follicular lymphoma. And there are both single-agent studies and combination studies with rituximab that have been conducted and are being conducted in that setting. It makes a lot of sense. We know that in low-grade lymphoma, one of the major issues—just like in chronic lymphocytic leukemia—is the failure of these cells to undergo apoptosis by removing the blockade for apoptosis. With venetoclax, we hope that there’s increased efficacy and that it’s probably best suited in combination for that.

There’s also a number of other drugs that are further back in the developmental pipeline. Some of the immunotherapies are exciting in this arena from the bispecific antibodies to the checkpoint inhibitors. I think there’s a lot that will be coming down the pike soon.

Transcript Edited for Clarity
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