Copanlisib Plus Rituximab Extends Progression-Free Survival in Indolent NHL

Primary results from the phase 3 CHRONOS-3 study (NCT02367040) showed that copanlisib (Aliqopa) in combination with rituximab (Rituxan) achieved a 48% reduction in the risk of disease progression or death compared with rituximab plus placebo in patients with relapsed indolent non-Hodgkin lymphoma (NHL), according to a presentation given in a press briefing ahead of Week 1 of the virtual AACR Annual Meeting 2021.

At a median follow-up of 19.2 months, findings showed that the median progression-free survival (PFS) with copanlisib/rituximab was 21.5 months (95% CI, 17.8-33.0) compared with 13.8 months (95% CI, 10.2-17.5) with rituximab/placebo (HR, 0.520; 95% CI, 0.393-0.688; P <.0001).

Moreover, the combination of copanlisib/rituximab demonstrated a manageable safety profile that was consistent with prior reports of copanlisib and rituximab as single agents.

“Copanlisib represents the first PI3K inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combination with rituximab across indolent histologic subtypes,” Matthew J. Matasar, MD, associate member of Lymphoma Service, Department of Medicine, at Memorial Sloan Kettering Cancer Center, said in a virtual presentation of the data. “Overall, this combination of copanlisib plus rituximab represents a potential new treatment option for patients with relapsed disease across all subtypes of indolent B-cell lymphoma.”

Single-agent rituximab is a standard treatment for patients with relapsed indolent NHL who have had a long remission following rituximab-based treatment, or who are unwilling, or unfit, to undergo chemotherapy. However, the benefit of this approach is short-lived, Matasar said.

Copanlisib, which is currently indicated for the treatment of patients with relapsed follicular lymphoma who have previously received 2 or more systemic therapies, is a potent, pan-class I PI3K inhibitor that has selective activity against the α and δ isoforms.

The phase 3 CHRONOS-3 study enrolled patients with CD20-positive indolent B-cell lymphoma; this included those eith grades 1 to 3a follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). These patients had relapsed following rituximab, a rituximab biosimilar, or an anti-CD20 antibody. Patients also needed to be progression and treatment free for at least 12 months since the last rituximab-containing regimen, or for at least 6 months and unwilling or unfit to receive chemotherapy.

Patients were treated with either copanlisib/rituximab (n = 307) or placebo/rituximab (n = 151). Copanlisib was administered intravenously (IV) at 60 mg on days 1, 8, and 15 of a 28-day cycle; rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. In the control arm, placebo was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle.

The primary end point of the trial was PFS by central review; secondary end points were objective response rate (ORR)/disease control rate, duration of response, complete response rate, time to progression, overall survival, safety, and patient-reported outcomes (PROs). Tertiary end points included pharmacokinetics, biomarkers, and additional PROs.

Baseline characteristics were similar between the 2 arms. The median age of study participants was 63 years (range, 28-91) and 52.0% were male. Additionally, 14.6% of patients had a medical history of diabetes and 36.5% had history of hypertension. When broken down by histology, 60.0% of patients had FL; of these patients, 19.0% had grade 1 disease, 27.9% had grade 2 disease, and 13.1% had grade 3 disease. Moreover, 20.7% had MZL, 10.9% had SLL, and 8.3% had LPL/WM.

The median time since the last systemic therapy received was 25.2 months (range, 0.8-192.5), and the median time since initial diagnosis was 63.2 months (range, 10.3-349.2). Additionally, 80.3% of patients were progression and treatment free for at least 12 months since their last rituximab-containing regimen, and 19.7% of patients were unwilling/unfit to receive chemotherapy. Moreover, 48.3% of patients had undergone at least 1 prior line of systemic therapy, 25.1% had received 2 prior lines, and 26.6% had 3 prior lines.

The primary efficacy data also showed that the PFS benefit was observed across all histologies, including FL (HR, 0.58); MZL (HR, 0.48); SLL (HR, 0.24), and LPL/WM (HR, 0.44).

Additionally, the centrally assessed ORR was significantly higher with copanlisib/rituximab vs placebo/rituximab, at 81.0% vs 48.0%, respectively (P <.0001).

Regarding safety, all-grade treatment-emergent adverse effects (TEAEs) occurred in 100% and 91.8% of patients on copanlisib/rituximab and rituximab/placebo, respectively; grade 3 TEAEs were reported in 53.4% and 43.2% of patients, respectively, and grade 4 TEAEs were experienced by 35.8% and 13.0% of patients, respectively.

All-grade serious TEAEs occurred in 47.2% and 18.5% of patients on copanlisib/rituximab and placebo/rituximab, respectively. Grade 3 serious TEAEs occurred in 26.7% and 13.0% of patients, respectively; grade 4 TEAEs were in 13.0% and 0.7%, respectively.

The most common all-grade TEAEs on the copanlisib/rituximab arm were hyperglycemia (69.4%) and hypertension (49.2%), which Matasar noted were toxicities that are associated with copanlisib. Grade 3 and 4 hyperglycemia occurred in 48.2% and 8.1% of patients, respectively. Grade 3 and 4 hypertension occurred in 39.7% and 0% of patients, respectively. Grade 4 neutropenia occurred in 8.8% of patients on copanlisib/rituximab.

Pneumonitis was an AE of special interest, and it was noted in 6.8% (grade 3, 2.0%; grade 4, 0.7%) of patients on copanlisib compared with 1.4% (grade 3, 0.7%) of those on placebo/rituximab.

Grade 5 TEAEs were reported in 6 patients (2.0%) who were treated with copanlisib/rituximab; 1 of these effects, pneumonitis, was considered to be related to study treatment. One patient on rituximab/placebo died.

Program chair Charles Swanton, MBPhD, FRCP, FMedSci, FRS, FAACR, commented on the findings during the press briefing.

“In summary, this is a potential new treatment option for relapsed disease, across all subtypes of indolent non-Hodgkin lymphoma, for patients with a longer remission after first-line therapy, or who are unfit for chemotherapy,” Swanton said. “However, one should also bear in mind the toxicities associated with the addition of the [pan-]class I PI3K inhibitor.

_Reference:

_{Matasar MJ, Capra M, Ozcan M, et al. CHRONOS-3: randomized phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT001.}