CHRONOS-3: Addition of Copanlisib to Rituximab Extends Progression-Free Survival in Relapsed Indolent NHL

Get Permission

The combination of the PI3K inhibitor copanlisib plus the monoclonal antibody rituximab reduced the risk of disease progression or death by 48% compared with placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (NHL), according to the results of the phase III CHRONOS-3 trial presented at the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021 by Matthew J. Matasar, MD, attending physician at Memorial Sloan Kettering Cancer Center, New York.1 Trial results were also published in The Lancet Oncology to coincide with the presentation.2

Another notable finding favoring the addition of copanlisib to rituximab was a consistent improvement in progression-free survival across all subtypes of indolent NHL, including follicular lymphoma (FL), marginal zone lymphoma (MZL), and small lymphocytic lymphoma (SLL). In addition, the centrally assessed objective response rate was significantly higher with copanlisib plus rituximab than with placebo plus rituximab: 81% vs 48% (P < .0001). The combination of copanlisib plus rituximab reportedly had a manageable safety profile consistent with previous reports of both agents when used as monotherapy.

Matthew J. Matasar, MD

Matthew J. Matasar, MD

“Copanlisib is the first PIK3 inhibitor to be safely combined with rituximab and the first to demonstrate broad and superior efficacy in combination with rituximab across all histologic subtypes. Overall, copanlisib plus rituximab represents a potential new treatment option for patients with relapsed indolent NHL disease across all subtypes,” stated Dr. Matasar. “To my knowledge, this is the first study to report such a broad benefit in patients with indolent NHL,” he added.

Rituximab monotherapy is a standard of care in patients with relapsed indolent NHL who have had a long remission after rituximab-based therapy or who are unwilling or unfit for chemotherapy. “However, the clinical benefit of rituximab [in this setting] can be short-lived,” Dr. Matasar noted.

Copanlisib is a selective, potent, intravenous pan-class PI3K inhibitor with predominant on-target activity against the PI3K alpha and delta isoforms. It is approved as monotherapy for relapsed FL in patients treated with at least two prior therapies.

Study Details

Patients with relapsed indolent NHL were randomly assigned in a 2:1 ratio to receive copanlisib plus rituximab (n = 307) or placebo plus rituximab (n = 149). All participants had CD20-positive B-cell lymphoma (including FL, MZL, SLL, and Waldenström’s macroglobulinemia) and relapsed after receiving rituximab- or other anti-CD20 monoclonal antibody–containing therapy. Participants had to be progression-free and treatment-free for at least 12 months since their last rituximab-containing therapy or for more than 6 months and unwilling to undergo or unfit for chemotherapy.

Copanlisib (or placebo) was given at a dose of 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. Standard-dose rituximab was given in both arms. Participants were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival by central review. Secondary endpoints included objective response rate, disease control rate, duration of response, complete response rate, time to disease progression, overall survival, safety, and patient-reported outcomes. Tertiary endpoints included pharmacokinetics, biomarkers, and additional patient-reported outcomes.

Both treatment arms were well balanced at baseline. The median patient age was about 62. Approximately 15% of patients had a history of diabetes, and approximately 35% had a history of hypertension. The median time from last systemic therapy was 25 months.

Approximately 60% of participants had FL; about 20% had MZL; and nearly 10% each had small B-cell lymphocytic lymphoma and Waldenström’s macroglobulinemia. About 80% were more than 12 months from the previous rituximab-containing therapy and 20% between 6 and 12 months. About 50% had one prior line of therapy; 25% had two or more prior lines of therapy; and 25% had three or more prior lines of therapy.

Study Results

The study met the primary endpoint of progression-free survival. At a median follow-up of 19.2 months, median progression-free survival was 21.5 months with copanlisib plus rituximab vs 13.8 months with placebo plus rituximab (P < .0001). This significant benefit in progression-free survival was evident across histologic subtypes. A numerical trend favored copanlisib plus rituximab in Waldenstrom’s macroglobulinemia, but it did not reach statistical significance, possibly due to the small numbers of patients.

Response rates and complete response rates were higher in the experimental arm across all subtypes of indolent NHL. The median duration of response was 20.4 months with copanlisib plus rituximab vs 17.3 months with placebo plus rituximab. Overall survival was not statistically different between the two arms at a median follow-up of 30.1 months, but survival data are immature.

“The most commonly observed adverse events were hyperglycemia and hypertension, in keeping with the known toxicity profile of copanlisib,” Dr. Matasar told listeners. These side effects were reported to be transient and generally did not require treatment. Hyperglycemia was reported in 56% of patients in the copanlisib-containing arm vs 8% of those given placebo plus rituximab; the rate of hypertension was 40% and 9%, respectively. Treatment discontinuation due to these adverse events occurred in 3% and 1% of patients, respectively.

Pneumonitis, an adverse event of special interest, was reported in 6.8% of patients who received the PI3K inhibitor; grade 3 or higher pneumonitis was seen in 3%. Treatment-emergent adverse events leading to discontinuation of treatment were reported in 31% of the experimental arm and 8% of the placebo-plus-rituximab arm. “Twelve percent of treatment discontinuations were due to a grade 1 or 2 adverse event, and 18% were due to grade 3 or 4 events,” related Dr. Matasar.

Additional Commentary

Charles Swanton, MBPhD, FRCP, FMedSci, FRS, FAACR

Charles Swanton, MBPhD, FRCP, FMedSci, FRS, FAACR

Charles Swanton, MBPhD, FRCP, FMedSci, FRS, FAACR, of the Francis Crick Institute and UCL Cancer Research; Chief Clinician, Cancer Research UK, London; and Program Chair of the virtual AACR Annual Meeting 2021, commended the CHRONOS-3 investigators for a well-designed study with such encouraging results. “The arms of the trial were well balanced. Results were strongly positive for progression-free survival across all histologies, with a 7.7-month absolute improvement in patients who received copanlisib plus rituximab. The response rates were 81% for the experimental arm vs 48% for placebo plus rituximab,” Dr. Swanton noted.

These findings should be balanced by the toxicity profile of copanlisib. “It is important to state that there were also more toxicities in the combination arm, as expected for the known toxicity profile of PI3K inhibitors, and grade 3 and 4 toxicities were more common,” he added. All things considered, Dr. Swanton continued, “copanlisib plus rituximab is a potential new treatment option for relapsed indolent NHL for patients unfit for chemotherapy. One should also bear in mind the toxicity of a PI3K inhibitor.” 


DISCLOSURE: The study was funded by Bayer AG. Dr. Matasar holds stock or other ownership interests in Merck; has received honoraria from Bayer, Genentech, GlaxoSmithKline, IGM Biosciences, 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. Dr. Swanton holds stock or other ownership interests in Achilles Therapeutics, Apogen Biotechnologies, Epic Sciences, and GRAIL; has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Illumina, Lilly, MSD Oncology, Novartis, Ono Pharmaceutical, Pfizer, and Roche; has served as a consultant or advisor to Bicycle Therapeutics, Genentech/Roche, Medicxi, and Sarah Cannon Research Institute; has received research funding from Archer Dx, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, and Roche-Ventana; holds intellectual property in Achilles Therapeutics, “immune checkpoint intervention in cancer,” “method for determining whether an HLA allele is lost in a tumor,” “method for identifying responders to cancer treatment,” “method for treating cancer,” “method for treating cancer based on identification of clonal neoantigens,” “method of detecting tumor recurrence,” “method of identifying insertion/deletion mutation targets,” “method of predicting survival rates for cancer patients,” “method of treating cancer by targeting insertion/deletion mutations,” and “methods for lung cancer detection”; and has held uncompensated relationships with AstraZeneca.


1. Matasar MJ, Capra M, Özcan M, et al: CHRONOS-3: Randomized phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma. AACR Annual Meeting 2021. Abstract CT001. Presented April 10, 2021.

2. 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). Lancet Oncol. April 10, 2021 (early release online).

Related Articles

Expert Point of View: Peter Martin, MD

“With current therapies, the median survival for people with follicular lymphoma [FL] is about 20 years. Most people with FL will live as long as the general population, as it is a disease of morbidity more than mortality. That said, there is still room for improvement,” said formal CHRONOS-3...