Copanlisib plus Rituximab Prolongs Survival in Relapsed Indolent Non-Hodgkin Lymphoma

October 2021, Vol 12, No 5

The addition of the PI3K inhibitor copanlisib (Aliopa) to rituximab (Rituxan) reduced the risk for disease progression or death by 48% compared with placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (NHL) in the phase 3 CHRONOS-3 clinical trial. The results of this study were presented at the 2021 virtual American Association for Cancer Research (AACR) annual meeting and published simultaneously in Lancet Oncology (2021;22:678-689).

Patients treated with copanlisib plus rituximab had improved progression-free survival (PFS) regardless of indolent NHL subtype (ie, follicular lymphoma [FL], marginal zone lymphoma [MZL], and small lymphocytic lymphoma [SLL]). In addition, centrally assessed objective response rate (ORR) was significantly higher in the copanlisib plus rituximab arm versus the placebo plus rituximab arm (81% vs 48%, respectively [P <.0001]).

“Copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combo with rituximab across all histological subtypes. Overall, copanlisib plus rituximab represents a potential new treatment option for patients with relapsed indolent NHL disease across all subtypes,” stated presenting author Matthew Matasar, MD, Regional Care Network Medical Site Director and Attending Physician, Memorial Sloan Kettering Bergen, New York City. “To my knowledge, this is the first study to report such a broad benefit in patients with indolent NHL,” he added.

Although rituximab is the standard of care for patients with relapsed indolent NHL or for those who are unfit for chemotherapy, its clinical benefit in this setting is often short-lived.

Copanlisib is a selective, potent, pan-class PI3K inhibitor with predominant on-target activity against the PI3K-alpha and PI3K-gamma isoforms. It is FDA-approved as monotherapy for the treatment of patients with relapsed FL who have been treated with ≥2 previous therapies.

Study Details

In the randomized, double-blind phase 3 CHRONOS-3 study, patients with relapsed indolent NHL were randomized in a 2:1 ratio to copanlisib plus rituximab (N = 307) or to placebo plus rituximab (N = 149). The treatment arms were well balanced at baseline. All patients had CD20-positive B-cell lymphoma (including FL, MZL, SLL, and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia) and had relapsed after receiving rituximab- or anti-CD20 monoclonal antibody–containing therapy. Approximately 60% of patients had FL; approximately 20% had MZL; and approximately 10% each had either SLL or lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. Approximately 15% of patients had a history of diabetes and 35% had a history of hypertension.

At a median follow-up of 19.2 months, copanlisib plus rituximab demonstrated superior efficacy compared with placebo plus rituximab, with a median PFS of 21.5 months versus 13.8 months, respectively (P <.0001). This significant benefit in PFS was evident across histologic subtypes (ie, FL, MZL, SLL). The number of patients was too small to show significance in lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia but trended in favor of copanlisib plus rituximab.

Response rates were higher in the experimental arm across all subtypes of indolent NHL. Median duration of response was 20.4 months in the copanlisib plus rituximab group versus 17.3 months for placebo plus rituximab.

At a median follow-up of 30.1 months, no survival difference was observed.

Safety Profile

The safety profile was manageable and no new safety concerns were reported. The most common adverse events associated with copanlisib treatment were hyperglycemia and hypertension. Dr Matasar noted that these effects are transient and generally do not require treatment. A very small percentage of patients stopped treatment because of these side effects (3% for hyperglycemia and 1% for hypertension).

Pneumonitis, an adverse event of special concern, was reported in 6.8% of patients treated with copanlisib. Grade ≥3 pneumonitis was seen in 3% of patients.

Grades 3 to 5 adverse events occurred in 6 patients in the copanlisib plus rituximab arm (only 1 was treatment-related) and 1 patient in the placebo plus rituximab arm. Treatment-emergent adverse events leading to treatment discontinuation were reported in 31% of patients in the copanlisib arm and 8% of those in the placebo arm.

“All discontinuations were due to either a grade 1 or 2 adverse event,” Dr Matasar said.

Expert Commentary

“Copanlisib plus rituximab is a potential new treatment option for relapsed indolent NHL for patients unfit for chemotherapy. One should also bear in mind the toxicity of a PI3K inhibitor,” said Charles Swanton, MBPhD, FRCP, FAACR, Royal Society Napier Professor, The Frances Crick Institute and UCL Cancer Institute, Cancer Evolution and Genome Instability Lab, London, England, and Program Chair of the virtual AACR Annual Meeting 2021.

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