Copanlisib/Rituximab Prolongs PFS in Relapsed Indolent Non-Hodgkin Lymphoma

Copanlisib (Aliqopa) in combination with rituximab (Rituxan) prolonged progression-free survival (PFS) in patients with non-Hodgkin lymphoma who relapsed following 1 or more previous lines of rituximab-based therapy, meeting the primary end point of the phase 3 CHRONOS-3 trial (NCT02367040).¹

Additionally, the safety profile of the combination proved to be consistent with findings on the individual agents that had previously been published; no new safety signals were reported. The data from the trial will be presented at an upcoming medical meeting. Bayer Pharmaceuticals also announced that they will be discussing the findings from CHRONOS-3 with health authorities on a global scale.

“Indolent forms of non-Hodgkin lymphoma are a heterogenous group of malignancies characterized by a chronic pattern of remissions and recurrences. For [patients with] indolent non-Hodgkin lymphoma with disease progression who are in need of treatment, there are few approved treatment options,” said Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer.¹ “The positive results from CHRONOS-3 demonstrate the potential clinical benefit of copanlisib in combination with rituximab, to address the unmet medical need in these patients.”

In the randomized, double-blind, placebo-controlled, phase 3 trial, investigators examined whether copanlisib plus rituximab would result in superior prolongation of PFS compared with placebo plus rituximab patients with relapsed non-Hodgkin lymphoma who received 1 or more lines of previous rituximab-based therapy.

Patients with follicular lymphoma, small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LHL)/Waldenström macroglobulinemia, and marginal zone lymphoma (MZL) were included. To be eligible for participation, patients had to have relapsed following their last rituximab-containing therapy. Additionally, they had to have experienced a treatment-free interval of 12 months or longer following the completion of their last rituximab-containing treatment, they had to be unwilling to receive chemotherapy, or chemotherapy had to have been contraindicated because of age, comorbidities, or residual toxicity.

A total of 458 patients were enrolled on CHRONOS-3. The primary end point of the trial was PFS, while key secondary end points included objective tumor response, duration of response (DOR), complete response (CR), time to progression, overall survival (OS), and safety, among others.²

Participants who were randomized to the copanlisib/rituximab arm received copanlisib as lyophilized preparation in a 6-mL injection on days 1, 8, and 15 of each 28-day treatment cycle prior to rituximab, which was given at a dose of 375 mg/m² body surface weekly during cycle 1 on days 1, 8, 15, and 22, followed by day 1 of cycles 3, 5, 7, and 9. Those in the control arm received placebo and rituximab at the same dose and schedule as the experimental arm.

In September 2017, copanlisib was granted an accelerated approval from the FDA for use in patients with relapsed follicular lymphoma who received at least 2 previous systemic therapies based on data from the phase 2 CHRONOS-1 trial (NCT01660451). Results from the study showed that copanlisib elicited an objective response rate (ORR) of 59.2% in patients with multiple types of lymphoma and these responses proved to be durable.³

CHRONOS-1 enrolled patients with follicular lymphoma (grades 1-3a), MZL, SLL, and LHL/Waldenström macroglobulinemia. To be eligible for inclusion, patients had to have relapsed/refractory disease and progressed on at least 2 previous lines of treatment.

In the phase 2 trial, participants were given copanlisib at a dose of 60 mg on days 1, 8, and 15 every 28 days until progressive disease or intolerable toxicity. The primary objective of the trial was objective response per central review following a minimum of 16 weeks of treatment. Key secondary end points of the trial comprised PFS, DOR, OS, safety, and quality of life.

A total of 142 patients were analyzed on the trial. The median age of participants was 63 years and the median time since the most recent disease progression was 8.3 months. Participants had received a median of 3 previous regimens and all had previously been exposed to rituximab and 1 or more alkylating agents. Just over half, or 60.6%, had disease that was considered to be refractory to the last therapeutic regimen they had been given.

Across the subgroups of patients analyzed, the majority (80.3%) had advanced disease at the time of enrollment; 73.2% of patients had follicular lymphoma. Participants continued to receive treatment for a median duration of 22 weeks; they were administered a median of 5.5 cycles and 96% of planned doses of the study drug.

Additional results showed that the majority of patients experienced target lesion shrinkage to some degree with copanlisib; patients with all lymphoma subtypes experienced lesion shrinkage.

Twelve percent of patients achieved a CR with copanlisib, while 47.2% experienced partial responses; 29.6% of patients achieved stable disease. The disease control rate was 85.9%. Notably, ORRs were 59% or higher across all the lymphoma subtypes with the exception of LHL/Waldenström macroglobulinemia. The median PFS experienced with copanlisib was 11.2 months (95% CI, 8.1-24.2). Those in the follicular lymphoma subgroup achieved the same median PFS, at 11.2 months.

Updated results at 2 years showed that copanlisib resulted in an ORR of 60.6%.⁴ The median DOR with the agent was 14.1 months (median follow-up of 16.1 months), while the median PFS was 12.5 months (median follow-up of 14.0 months). Additionally, the median OS with copanlisib was 42.6 months (median follow-up of 31.5 months).

The median safety follow-up was 6.7 months and 26% of participants received treatment for over 1 year. The most commonly reported all-grade treatment-emergent toxicities included transient hyperglycemia (50.0%), diarrhea (35.2%), transient hypertension (29.6%), and neutropenia (28.9%). None of these events demonstrated evidence of increased incidence or worsening after longer exposure in patients who received treatment with copanlisib for over 1 year.

Continued approval for copanlisib for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial, according to Bayer.

References

1. Aliqopa (copanlisib) in combination with rituximab meets primary endpoint in patients with relapsed indolent non-Hodgkin’s lymphoma. News release. Bayer. October 14, 2020. Accessed October 14, 2020. https://bit.ly/3dqGE2m.
2. Copanlisib and rituximab in relapsed indolent B-cell non-Hodgkin’s lymphoma (iNHL) (CHRONOS-3). ClinicalTrials.gov. Updated September 10, 2020. Accessed October 14, 2020. https://clinicaltrials.gov/ct2/show/NCT02367040.
3. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; San Washington, DC. Abstract CT149.
4. Dreyling M, Santoro A, Mollica L, et al. Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study. Am J. Hematol. Published online December 23, 2019. doi:10.1002/ajh.25711