The combination of copanlisib plus rituximab reduced the risk of disease progression or death by 48% compared with placebo plus rituximab in patients with indolent non-Hodgkin lymphoma, according to results of the phase III CHRONOS-3 trial presented by Matthew J. Matasar, MD, at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract CT001). Trial results were simultaneously published in The Lancet Oncology.

Other notable findings favoring the addition of copanlisib to rituximab included a consistent improvement in progression-free survival across all subtypes of indolent non-Hodgkin lymphoma, including follicular lymphoma (FL), marginal zone lymphoma (MZL), and small lymphocytic lymphoma (SLL). The centrally assessed objective response rate was significantly higher in the copanlisib-plus-rituximab arm vs the placebo-plus-rituximab arm: 81% vs 48% (P < .0001). And the combination of copanlisib plus rituximab had a manageable safety profile consistent with previous reports of both agents when used as monotherapy.

Copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combination with rituximab across all histologic subtypes.

— Matthew J. Matasar, MD

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“Copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combination with rituximab across all histologic subtypes. Overall, copanlisib plus rituximab represents a potential new treatment option for patients with relapsed indolent non-Hodgkin lymphoma across all subtypes,” stated presenting author Dr. Matasar, an attending physician at Memorial Sloan Kettering Cancer Center, New York.

“To my knowledge, this is the first study to report such a broad benefit in patients with indolent non-Hodgkin lymphoma,” he added.

Background

Rituximab monotherapy is a standard of care in patients with relapsed indolent non-Hodgkin lymphoma who have had a long remission after rituximab-based therapy or who are unfit for chemotherapy. “However, the clinical benefit of rituximab [in this setting] can be short-lived,” Dr. Matasar noted.

Copanlisib is a selective, potent, intravenous pan-class PI3K inhibitor with predominant on-target activity against the PI3K-alpha and PI3K-gamma isoforms. It is approved as monotherapy for relapsed FL in patients treated with two or more prior therapies.

Study Details

Patients with relapsed indolent non-Hodgkin lymphoma were randomly assigned in a 2:1 ratio to receive copanlisib plus rituximab (n = 307) or placebo plus rituximab (n = 149). All participants had CD20-positive B-cell lymphoma (including FL, MZL, SLL, and Waldenström’s macroglobulinemia) and relapsed after receiving rituximab- or anti–CD20-monoclonal antibody–containing therapy. Participants had to be progression-free and treatment-free for at least 12 months since their last rituximab-containing therapy, or for more than 6 months and unwilling to undergo or unfit for chemotherapy.

Both treatment arms were well balanced at baseline: median age was about 62; approximately 15% of patients had a history of diabetes; and approximately 35% had a history of hypertension or two adverse events of interest with other PI3K inhibitors.

Approximately 60% of participants had FL; approximately 20% has MZL; and about 10% each had small B-cell lymphocytic lymphoma and Waldenström’s macroglobulinemia. About 80% were more than 12 months from the previous rituximab-containing therapy, and 20%, more than 6 months. Approximately 50% had received one prior line of therapy; 25%, two or more prior lines of therapy; and 25%, three or more prior lines of therapy.

Study Results

The study met the primary endpoint of progression-free survival. At a median follow-up of 19.2 months, median progression-free survival was 21.5 months in the copanlisib/rituximab arm vs 13.8 months in the placebo/rituximab arm (P < .0001). This significant benefit in progression-free survival was evident across histologic subtypes (ie, FL, MZL, and SLL). A numerical trend favored copanlisib plus rituximab in Waldenstrom’s macroglobulinemia, but did not reach statistical significance due to small numbers of patients.

“The most commonly observed adverse events were hyperglycemia and hypertension, in keeping with the known toxicity profile of copanlisib,” said Dr. Matasar. These were transient and generally did not require treatment, but treatment discontinuations due to these adverse events occurred in 3% and 1% of patients, respectively. Pneumonitis, an adverse event of special interest, was reported in 6.8% of patients who received the PI3K inhibitor.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.