Copanlisib-rituximab combination extends PFS in relapsed indolent non-Hodgkin lymphoma
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The addition of copanlisib to rituximab increased response rates and significantly extended PFS among patients with relapsed indolent non-Hodgkin lymphoma, according to study results.
The findings, presented during the virtual American Association for Cancer Research Annual Meeting and simultaneously published in The Lancet Oncology, also showed the combination of copanlisib (Aliqopa, Bayer) and rituximab (Rituxan; Genentech, Biogen) had a manageable safety profile consistent with previously reported data on each agent alone.
“Copanlisib plus rituximab represents a relative therapeutic option for this population of patients,” Matthew J. Matasar, MD, associate member of lymphoma service at Memorial Sloan Kettering Cancer Center, told Healio. “Patients with relapsed indolent B-cell lymphoma lack effective and tolerable treatment options. Rituximab monotherapy remains a standard treatment, but not all patients will respond to the treatment and responses are not durable.”
For this reason, Matasar and colleagues conducted the randomized phase 3 CHRONOS-3 trial, in which they assessed the safety and efficacy of the intermittently administered phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in combination with rituximab among 458 patients (median age, 63 years; range, 28-91; 52% men) with relapsed indolent B-cell lymphoma.
The researchers randomly assigned patients to 375 mg/m2 rituximab via IV on days 1, 8, 15 and 22 of the first 28-day treatment cycle and on day 1 of cycles 3, 5, 7 and 9, plus either 60 mg copanlisib (n = 307) or placebo (n = 151) via IV on days 1, 8 and 15 of each cycle.
Most patients (60%) had follicular lymphoma, whereas 20.7% had marginal zone lymphoma, 10.9% had small lymphocytic lymphoma and 8.3% had lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Median follow-up was 19.2 months.
Centrally assessed PFS served as the primary endpoint. Secondary endpoints included objective response rate, duration of response, complete response rate, OS and treatment-emergent adverse events
Results showed patients assigned the copanlisib-rituximab combination achieved significantly longer median PFS than those assigned placebo and rituximab (21.5 months vs. 13.8 months; HR = 0.52; 95% CI, 0.39-0.69).
Researchers observed reductions in risk for progression or death among patients with all histologic subtypes analyzed, including follicular lymphoma (22.2 months vs. 18.7 months; HR = 0.58; 95% CI, 0.4-0.83), marginal zone lymphoma (22.1 months vs. 11.5 months; HR = 0.48; 95% CI, 0.25-0.92), small lymphocytic lymphoma (14.2 months vs. 5.7 months; HR = 0.24; 95% CI, 0.11-0.53) and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (33.4 months vs. 16.6 months; HR = 0.44; 95% CI, 0.16-1.23).
Researchers reported ORRs of 80.8% with copanlisib-rituximab vs. 47.7% with placebo-rituximab and complete response rates of 33.9% vs. 14.6%.
Median OS was not available at the time of assessment.
Common grade 3 adverse events in the copanlisib-rituximab group included hyperglycemia (48.2%), hypertension (39.7%) and diarrhea (4.9%). Immune-related adverse events were rare. Six patients in the copanlisib group (2%) experienced grade 5 treatment-emergent adverse events, including one case of pneumonitis that was considered treatment-related, compared with one patient (0.7%) in the placebo group.
“The development of copanlisib is ongoing as we continue to understand how best to use this agent,” Matasar said. “The CHRONOS-4 trial, evaluating the combination of copanlisib with chemoimmunotherapy, both with R-CHOP and bendamustine plus rituximab, has completed accrual and we now await these results.”
References:
Matasar M, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
Matasar M, et al. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00145-5.
Perspective
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Felipe Samaniego, MD
Copanlisib is a pan-class I PI3K inhibitor with activity against PI3K-delta and PI3K-alpha that received FDA approval for treatment of patients with follicular lymphoma who previously received two lines of systemic therapy.
Several PI3K inhibitors have demonstrated clinical benefit in lymphoma both as monotherapy and in combination with other agents. One of the goals in lymphoma treatment has been to transition to targeted and immune-based therapies, with perhaps an improved clinical benefit. PI3K inhibitors combined with other agents are expected to improve efficacy and maintain low toxicity.
In the CHRONOS-3 study, patients with indolent lymphoma who had relapsed after at least one prior systemic therapy were randomly assigned to receive either copanlisib or placebo in combination with rituximab. Their results demonstrate a 48% reduction in the risk for disease progression or death. The efficacy seen with this combination still appears lower than the results seen with axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) and tisagenlecleucel (Kymriah, Novartis) in the third-line setting for follicular lymphoma.
The improved efficacy of copanlisib plus rituximab with no new safety signals shows it is promising therapeutic approach that would offer patients with indolent lymphoma an additional therapeutic option that does not involve chemotherapy. This is particularly relevant, as some patients may not be eligible for or may have developed resistance to specific therapies.
References:
- Fowler NH, et al. Abstract 1149. ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
- Jacobsen C, et al. Abstract 700. ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Collapse
Matasar M, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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