Matthew J. Matasar, MD
As reported in The Lancet Oncology by Matthew J. Matasar, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, the phase III CHRONOS-3 trial has shown that the addition of the pan-class I PI3K inhibitor copanlisib to rituximab significantly improved progression-free survival vs rituximab alone in patients with relapsed indolent non-Hodgkin lymphoma.1
Copanlisib received accelerated approval for treatment of relapsed follicular lymphoma in September 2017.
In the double-blind trial, 458 patients from sites in Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America were randomly assigned 2:1 between August 2015 and December 2019 to receive copanlisib plus rituximab (n = 307) or placebo plus rituximab (n = 151). Patients had to have confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody–containing therapy and have been progression-free and treatment-free for at least 12 months or for at least 6 months for patients unwilling or unfit to receive chemotherapy. Randomization stratification factors included histology and progression-free and treatment-free intervals. Copanlisib was given at 60 mg via intravenous infusion on days 1, 8, and 15 in a 28-day cycle, and rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9.
For copanlisib or placebo administration, patients were required to have a fasting blood glucose level of ≤ 125 mg/dL (≤ 160 mg/dL for patients with diabetes) before the first infusion and a fasting blood glucose level of < 160 g/dL or a nonfasting blood glucose level of < 200 mg/dL for subsequent infusions. Blood pressure was required to be ≤ 150/90 mm Hg before infusion; antihypertensive medication was permitted to control arterial hypertension.
Treatment with copanlisib or placebo continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in all randomly assigned patients, according to masked central review.
For the combination vs rituximab groups, median patient age was 63 years (range = 54–70 years) vs 62 years (range = 53–70 years) and 50% vs 56% were male. The disease stage was I in 7% vs 7%, II in 12% vs 9%, III in 28% vs 21%, and IV in 52% vs 60%; 80% vs 80% were progression-free and treatment-free for at least 12 months since their last rituximab-containing regimen and 20% vs 20% were unwilling or unfit to receive chemotherapy; 99% in both groups had prior rituximab treatment; and the number of previous anticancer therapy lines was one in 49% vs 47%, two in 24% vs 26%, three in 12% vs 15%, and at least four in 14% vs 11%.
The median follow-up was 19.2 months (interquartile range [IQR] = 7.4–28.8 months). Median progression-free survival was 21.5 months (95% confidence interval [CI] = 17.8–33.0 months) in the copanlisib/rituximab group vs 13.8 months (95% CI = 10.2–17.5 months) in the placebo/rituximab group (hazard ratio [HR] = 0.52, 95% CI = 0.39–0.69, P < .0001), with estimated 2-year rates of 46% vs 27%.
Hazard ratios according to histologic groups were 0.58 (95% CI = 0.40–0.83) for follicular lymphoma and 0.44 (95% CI = 0.29–0.69) for other indolent non-Hodgkin lymphoma combined, including 0.48 (95% CI = 0.25–0.92) for marginal zone lymphoma, 0.24 (95% CI = 0.11–0.53) for small lymphocytic lymphoma, and 0.44 (95% CI = 0.16–1.23) for lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. Hazard ratios were 0.51 (95% CI = 0.37–0.69) among patients with a treatment-free interval of at least 12 months and 0.63 (95% CI = 0.32–1.22) among those unwilling or unfit to receive chemotherapy.
The median time to disease progression was 22.3 months (95% CI = 19.4–33.2 months) in the combination group vs 13.8 months (95% CI = 10.8–18.7 months) in the rituximab group (HR = 0.48, 95% CI = 0.36–0.64). An objective response was observed in 81% vs 48% of patients, with a complete response in 34% vs 15%. The median duration of response was 20.4 months (95% CI = 17.0–30.8 months) vs 17.3 months (95% CI = 11.8–25.3 months; HR = 0.70, 95% CI = 0.48–1.02).
At the data cutoff, with a median follow-up of 30.1 months (IQR = 17.4–39.7 months), death from any cause had occurred in 14% vs 13% of patients. No differences between groups were observed for estimated overall survival at 24 months (86% vs 91%) or 36 months (83% vs 81%; HR = 1.07, 95% CI = 0.63–1.82).
Grade ≥ 3 adverse events occurred in 91% of the combination group vs 57% of the rituximab group, with the most common in the combination group being hyperglycemia (56% vs 8%) and hypertension (40% vs 9%). At least one insulin treatment and at least one blood glucose–lowering treatment were required for a hyperglycemia adverse event in 36% and 28% of patients in the combination group; 37% received antihypertensive medication for a hypertension adverse event. Serious adverse events occurred in 47% vs 18% of patients, with the most common in the combination group being hyperglycemia (7%) and pneumonia (6%). Copanlisib-related adverse events led to permanent discontinuation of the agent in 25% of patients, with the most common cause being pneumonitis (6%). Treatment-related death occurred in one patient in the combination group (< 1%; due to pneumonitis) and in no patients in the rituximab group.
The investigators concluded: “Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.”
DISCLOSURE: The study was funded by Bayer. Dr. Matasar holds stock or other ownership interests in Merck; has received honoraria from Bayer, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Roche, Seattle Genetics, and Takeda; has served as a consultant or advisor to Bayer, Daiichi Sankyo, Genentech, Juno Therapeutics, Merck, Roche, Rocket Medical, Seattle Genetics, Takeda, and Teva; has received research funding from Bayer, Genentech, GlaxoSmithKline, IGM Biosciences, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Roche, Rocket Medical, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by Bayer, Genentech, Roche, and Seattle Genetics.
1. Matasar MJ, Capra M, Özcan M, et al: Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 22:678-689, 2021.
Better understanding of the mechanism behind the malignant transformation of B cells has led to an explosion of “targeted” therapy. With the growing knowledge of the role of the B-cell receptor and its downstream kinases, it appeared that we were entering a new era in the management of patients...