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Another PI3K Inhibitor Welcome For Use in Indolent Lymphoma


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“It will be interesting to see whether the intravenous schedule seen with copanlisib is viewed as favorable or unfavorable in the eyes of practitioners and patients.”
— Brad Kahl, MD

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PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) signaling is important for the proliferation and survival of malignant B cells. Copanlisib (Aliqopa) is a novel pan-class PI3K inhibitor with predominant activity against PI3K-alpha and PI3K-delta isoforms. As reviewed in this issue of The ASCO Post, a phase II experience testing copanlisib in patients with relapsed and refractory indolent lymphoma was recently reported in the Journal of Clinical Oncology by Dreyling and colleagues.1 Findings in the subgroup of patients with follicular lymphoma in the trial supported the recent accelerated approval of copanlisib in relapsed follicular lymphoma after at least two prior therapies. 

The study enrolled 142 patients with relapsed or refractory indolent lymphoma after 2 or more lines of therapy. The patients were assigned to receive copanlisib at 60 mg intravenously on days 1, 8, and 15 of an 18-day cycle. The primary endpoint of the trial was the overall response rate. Key secondary endpoints included the duration of response, progression-free survival, overall survival, and safety. The median number of prior therapies was three, with a range of two to nine. Most patients had follicular lymphoma (n = 104; 73%). There were also smaller numbers of patients with marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma. 

Toxicity and Efficacy 

OVERALL, THE THERAPY was reasonably well tolerated. Of note, unlike with other PI3K inhibitors that have been tested in this setting, the incidence of colitis and pneumonitis was quite low. Specifically, there were only 2 episodes of colitis and 10 episodes of noninfectious pneumonitis, most of which were grade 1 to 2. Patients receiving copanlisib were more likely to experience hyperglycemia and hypertension compared with those who received other PI3K inhibitors. For example, 50% of the patients experienced some degree of hyperglycemia, and 30% of the patients experienced some degree of hypertension. Of the hyperglycemia cases, 34% were grade 3, and 7% were grade 4. They tended to be transient and to resolve spontaneously within 24 to 48 hours. 

Efficacy evaluation demonstrated an objective response rate of 59%, with 12% of the patients achieving a complete response. The median duration of response was 22 months, and the median progression-free survival was 11 months. Among the patients with follicular lymphoma, the response rate was 59%, with a complete response in 14%, and the median response duration was 12.2 months. 

In Comparison With Other PI3K Inhibitors 

OVERALL, THE RESPONSE data were comparable to those with other PI3K inhibitors such as idelalisib (Zydelig), which is already approved in this setting. Idelalisib is an oral agent that is relatively well tolerated, although there are risks for colitis and pneumonitis, which can be severe and problematic. Copanlisib seems to avoid those significant toxicities, although patients treated with this newer agent are more likely to experience hyperglycemia and hypertension. With monitoring and patient education, these particular toxicities probably can be manageable. 

It will be interesting to see whether the intravenous schedule seen with copanlisib is viewed as favorable or unfavorable in the eyes of practitioners and patients. Receiving treatments on days 1, 8, and 15 of every 28-day cycle is certainly tolerable for a few months of therapy, but the copanlisib therapy is designed to be given indefinitely, and this administration schedule may become cumbersome over time. That said, having another agent available for patients with relapsed indolent lymphoma is certainly welcome. 

Dr. Kahl is Professor of Medicine and Director of the Lymphoma Program, Washington University School of Medicine in St. Louis. 

DISCLOSURE: Dr. Kahl is a consultant for Bayer and Gilead Sciences. 

REFERENCE 

1. 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.


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