Role of PI3K Inhibitors in Treatment of B-cell Malignancies

Transcript:

Ian Flinn, MD, PhD: The PI3K are a family of lipid kinases that upon activation are important in oncogenesis. There are many different activators of this pathway. We can think of the B-cell receptor pathway, but there’s also activation through other cytokine and chemokine receptors on the cell surface. One of the most important pathways that is activated is the AKT/mTOR pathway, and that makes the PI3K an attractive target for inhibition in therapies for patients with B-cell malignancies.

There are multiple different isoforms of the PI3K: the alpha, beta, delta, and gamma. Their expression is tissue specific. For instance, the delta isoform expression is limited to cells of hematopoietic origin, and it’s an attractive target for trying to target B-cell malignancies. This is because by specifically targeting that isoform, we may get inhibition and a therapeutic intent without some of the off-target toxicities that might occur with inhibiting other isoforms such as the alpha isoform, where you might have problems with glucose metabolism.

There are 3 PI3-kinase inhibitors currently available for the treatment of B-cell malignancies. The first is idelalisib. Idelalisib is a pure PI3K delta inhibitor. This was attractive in the original development of idelalisib because by inhibiting this specific isoform of the PI3K, we hope to get efficacy without some of the off-target toxicities that you might get from pan inhibition of all the different isoforms of PI3K. Idelalisib is approved for the treatment as a single agent for patients with follicular lymphoma with 2 prior therapies. It’s also approved in combination with rituximab for patients with chronic lymphocytic leukemia.

The next inhibitor that’s been approved is duvelisib. Duvelisib is both an inhibitor of the delta isoform as well as the gamma isoform. The hypothesis is that in addition to inhibiting the delta isoform, which is expressed in the malignant B cells, we’re also inhibiting the gamma isoform, which is important in the microenvironment. The thought here is that through the cellular actions, by inhibiting the gamma isoform, we may also improve the efficacy of this inhibitor over a pure delta inhibitor. Duvelisib has been approved for the treatment of chronic lymphocytic leukemia as a single agent for patients who have had 2 prior therapies, and it has been approved for patients with follicular lymphoma and small lymphocytic lymphoma who’ve also had 2 prior therapies.

Finally, copanlisib is the third PI3-kinase inhibitor that’s been approved for patients with B-cell malignancies. It’s approved for patients who have had 2 prior therapies with follicular lymphoma. Copanlisib is different from the other PI3-kinase inhibitors in that first, it’s an IV [intravenous] formulation—not an oral formulation—and its schedule is different, plus it inhibits both the delta and the alpha isoform. For the alpha isoform, while inhibiting that does bring up problems with glucose metabolism, it might be attractive in that we know in some malignancies there are data to suggest that there is means of escape that some malignancies upregulate the alpha isoform. It might be important to inhibit this along with the delta isoform, and that’s the general hypothesis behind using copanlisib.

Transcript Edited for Clarity