The primary results of the Phase 3 CHRONOS 3 study (NCT02367040) showed that copanlisib (Aliqopa) combined with rituximab (Rituxan) reduced the risk of disease progression or death compared to rituximab plus placebo in patients with relapsed Indolent Non-Hodgkin’s Lymphoma (NHL) decreased by 48%, according to a presentation at a press conference prior to Week 1 of the 2021 AACR virtual annual meeting.
With a median follow-up of 19.2 months, the results showed that the median progression-free survival (PFS) with copanlisib / rituximab was 21.5 months (95% CI, 17.8-33.0) compared to 13.8 months (95% CI, 10.2-17.5)) with rituximab / placebo (HR 0.520; 95% CI 0.393-0.688; P <0.0001).
In addition, the combination of copanlisib / rituximab demonstrated a manageable safety profile, consistent with previous reports of copanlisib and rituximab as individual agents.
“Copanlisib is the first PI3K inhibitor that can be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in indolent histological subtypes,” said Dr. 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 in all subtypes of indolent B-cell lymphoma.”
Rituximab as a single agent is a standard of care for patients with relapsed indolent NHL who have had long remission, or are unwilling or unable to undergo chemotherapy after treatment with rituximab. However, the benefits of this approach are short-lived, said Matasar.
Copanlisib, currently indicated for the treatment of patients with relapsed follicular lymphoma who previously received two or more systemic therapies, is a potent class I PI3K inhibitor that has selective activity against the α and δ isoforms.
Patients with CD20-positive indolent B-cell lymphoma were included in the Phase 3 CHRONOS 3 study. This included grade 1 to 3a follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL) and lymphoplasmacytic lymphoma (LPL) / Waldenström macroglobulinemia (WM). These patients relapsed after rituximab, a rituximab biosimilar, or an anti-CD20 antibody. Patients had to be progression-free, treatment-free and unwilling or unable to receive chemotherapy for at least 12 months since the last rituximab-containing regimen or for at least 6 months.
The patients were treated with either copanlisib / rituximab (n = 307) or placebo / rituximab (n = 151). Copanlisib was administered at 60 mg intravenously (IV) on days 1, 8 and 15 of a 28-day cycle; Rituximab was administered on days 1, 8, 15 and 22 during cycle 1 and on day 1 of cycles 3, 5, 7 and 9 at 375 mg / m². In the control arm, placebo was administered at 60 mg iv on days 1, 8 and 15 of a 28-day cycle.
The primary endpoint of the study was PFS by central review; Secondary endpoints 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 endpoints included pharmacokinetics, biomarkers, and additional PROs.
The baseline features were similar between the two arms. The mean age of the study participants was 63 years (range, 28-91) and 52.0% were male. In addition, 14.6% of the patients had a history of diabetes and 36.5% had a history of hypertension. Broken down by histology, 60.0% of the 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. In addition, 20.7% had MZL, 10.9% SLL, and 8 , 3% LPL / WM.
The median time since the last systemic therapy 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). In addition, 80.3% of patients had been progression-free and treatment-free for at least 12 months since their last rituximab-containing regimen, and 19.7% of patients were unwilling / not eligible to receive chemotherapy. In addition, 48.3% of patients had received at least one previous line of systemic therapy, 25.1% had received two previous lines of treatment, and 26.6% had three previous lines of treatment.
The primary efficacy data also indicated that 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).
In addition, the centrally assessed ORR with copanlisib / rituximab versus placebo / rituximab was significantly higher at 81.0% versus 48.0% (P <0.0001).
In terms of safety, 100% and 91.8% of patients taking copanlisib / rituximab and rituximab / placebo, respectively, experienced side effects. Grade 3 TEAEs were reported in 53.4% and 43.2% of patients, and Grade 4 TEAEs were reported in 35.8% and 13.0% of patients, respectively.
Severe TEAEs of all degrees of severity occurred in 47.2% and 18.5% of patients on copanlisib / rituximab and placebo / rituximab, respectively. Severe grade 3 TEAEs occurred in 26.7% and 13.0% of the patients, respectively; Class 4 TEAEs were 13.0% and 0.7%, respectively.
The most common all-grade TEAEs on the copanlisib / rituximab arm were hyperglycaemia (69.4%) and hypertension (49.2%), of which Matasar identified toxicities associated with copanlisib. Grade 3 and 4 hyperglycaemia 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 particular concern and was found in 6.8% (Grade 3, 2.0%; Grade 4, 0.7%) of patients on copanlisib compared with 1.4% (Grade 3, 0.7 %) of patients taking placebo / rituximab.
Grade 5 TEAEs were reported in 6 patients (2.0%) treated with copanlisib / rituximab; 1 of these effects, pneumonitis, was considered related to study treatment. One patient on rituximab / placebo died.
Program Chair Charles Swanton, MBPhD, FRCP, FMedSci, FRS and FAACR commented on the results during the press conference.
“In summary, this is a potential new treatment option for relapsed disease in all subtypes of indolent non-Hodgkin lymphoma for patients in prolonged remission after first-line therapy or who are not eligible for chemotherapy,” said Swanton. “However, one should also consider the toxicities associated with the addition of [pan-]Class I PI3K inhibitor.
Matasar MJ, Capra M., Ozcan M. et al. CHRONOS-3: randomized phase III study of copanlisib plus rituximab versus rituximab / placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). Presented at: 2021 AACR Annual Meeting 2021; 10-15 April 2021; virtual. Abstract CT001.