Better understanding of the mechanism behind the malignant transformation of B cells has led to an explosion of “targeted” therapy. With the growing knowledge of the role of the B-cell receptor and its downstream kinases, it appeared that we were entering a new era in the management of patients afflicted with B-cell non-Hodgkin lymphoma (NHL). One of the targets that was identified was the phosphoinositide 3-kinase (PI3K) pathway.
An initial study by Gopal et al,1 based on impressive results, appeared to mark a turning point in the treatment of patients with indolent NHL. This study evaluated the oral agent idelalisib in a heavily pretreated population of patients who had the following indolent NHL subtypes: follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma. This study reported a remarkable overall response rate of 57% across all enrolled patients.
“Class-specific side effects have prevented the long-term use of [PI3K inhibitors] in most patients and complicated studies looking to combine these agents with other drugs.”— Tycel J. Phillips, MD
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Although it has been almost a decade since the initial studies demonstrated the benefit of inhibitors of the PI3K pathway, and specifically inhibition of the delta isoform in B-cell malignancies, actual implementation of these drugs into our treatment armamentarium has been complicated. This has been directly related to the adverse-event profile of these agents, highlighting the off-target effects of such “targeted” therapy. Class-specific side effects have prevented the long-term use of these drugs in most patients and complicated studies looking to combine these agents with other drugs. Some of these issues have been resolved with second-generation agents, which have, in most cases, demonstrated an improved safety profile, either through structural changes or alteration in dosing schedules.
CHRONOS-3 Trial: Closer Look at Copanlisib
The CHRONOS-3trial, recently reported by Matasar et al2 and reviewed in this issue of The ASCO Post, assessed the second-generation agent copanlisib, a PI3K inhibitor that hits all four PI3K isoforms but mainly inhibits the alpha and delta isoforms. Copanlisib is the only approved agent in this class to be given intravenously and on a noncontinuous schedule. It is the schedule that is believed to be behind the improved adverse-event profile noted with this agent compared with the other drugs initially approved. Consequently, of the currently approved agents, copanlisib is an ideal candidate to combine with other agents to see whether any improvement in efficacy could be obtained.
In CHRONOS-3, the combination of copanlisib and rituximab was compared with rituximab and placebo in patients with relapsed or refractory low-grade lymphoma. Copanlisib was given at the standard dose of 60 mg intravenously on days 1, 8, and 15 every 28 days, and rituximab was given weekly during cycle 1 then on day 1 of cycles 3, 5, 7, and 9 in both arms. The study enrolled patients who had received at least one prior line of therapy, which is a less pretreated population than in the original study that led to the U.S. Food and Drug Administration approval of this agent.3
In this patient population, the authors reported that the combination had an overall response rate of 81% and a complete response rate of 34%, compared with 48% and 15%, respectively, with single-agent rituximab. In the individual subgroups, while still consistently favoring the combination, there was some disparity between the groups. This was evident in the differences between follicular lymphoma, which had the highest overall response rate for the combination (85% vs 54% for single-agent rituximab), vs Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma, which reported an overall response rate of 68% vs 56% for the combination vs single agent, respectively. The most impressive result of the study was the primary endpoint of progression-free survival: median progression-free survival with the combination was 21.5 months vs 13.8 months for single-agent rituximab. This improvement was documented across the varying subtypes enrolled in the study.
The most common adverse events in the combination arm were consistent with single-agent use of copanlisib and included transient hypertension and hyperglycemia due to inhibition of the alpha isoform of PI3K. Adverse events more commonly associated with the class due to inhibition of the delta isoform were noted as well, including diarrhea/colitis, pneumonitis, transaminitis, neutropenia, and upper respiratory infections. Of these side effects, diarrhea/colitis and pneumonitis seem to be the most problematic for the class, and pneumonitis was the most common reasons for drug discontinuation in the study.
Challenges Ahead
Although thecombination of copanlisib and rituximab was superior to single-agent rituximab in this patient population, without any new safety signals noted, the study still highlights some of the challenges with the use of delta isoform inhibitors. The combination still had a high rate of treatment discontinuation, with the most common reason being drug-related adverse events, compared with disease progression in the rituximab/placebo arm. As such, this study adds to the growing evidence of progress that we have made in refining treatments utilizing PI3K delta inhibitors. However, it also continues to highlight some of the major challenges we have moving forward with these drugs due to class-specific adverse events. How best to avoid or mitigate these adverse events will be essential to fully maximize the full potential of this still promising class of drugs in the indolent NHL space.
Dr. Phillips works in the Division of Hematology and Oncology at the Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor.
DISCLOSURE: Dr. Phillips has received honoraria from Bayer, Genentech, Gilead Sciences, Incyte, Pharmacyclics, and Seattle Genetics; has served as a consultant or advisor to Bayer, Celgene, Curis, Genentech, Genmab, Gilead Sciences, Incyte, Kite/Gilead, Pharmacyclics, and Seattle Genetics; and has received research funding from AbbVie, Bayer, and Pharmacyclics/Janssen.
REFERENCES
1. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.
2. Matasar MJ, Capra M, Özcan M, et al: Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 22:678-689, 2021.
3. Dreyling M, Santoro A, Mollica L, et al: Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 35:3898-3905, 2017.
