A combination of copanlisib (Aliqopa®; Bayer; previously known as BAY 80-6946), a highly selective and intravenous pan-class I PI3K inhibitor with sub-nanomolar IC50s against PI3Kα and PI3Kδ, approved as monotherapy for relapsed follicular lymphoma (FL) in patients who have had ≥2 prior systemic therapies, and rituximab (Rituxan®; Genentech/Biogen), the standard for patients with relapsed or advanced indolent non-Hodgkin lymphoma (iNHL)*, led to a 48% reduction in the risk of disease progression or death compared with placebo and rituximab in patients with relapsed indolent non-Hodgkin lymphoma. 

The conclusion is based on data from the phase III trial CHRONOS-3, s study sponsored by Bayer AG. The results were presented during Week 1 of the virtual AACR Annual Meeting 2021, held April 10-15, 2021, and concurrently published in The Lancet Oncology.[1][2][3]

“We are glad to see that copanlisib could be safely combined with rituximab for the long-term treatment of patients with relapsed indolent non-Hodgkin lymphoma,” said Matthew J. Matasar, MD, an associate member of Lymphoma Service at Memorial Sloan Kettering Cancer Center (MSK).

“The CHRONOS-3 trial met its primary endpoint of progression-free survival (PFS), with improved outcomes seen in several subtypes of indolent lymphoma included in the study. To my knowledge, this is the first study to report such a broad benefit in patients with relapsed indolent non-Hodgkin lymphoma,” Matasar added.

Rituximab given as monotherapy is a standard of care in patients with relapsed indolent lymphomas of many subtypes, Matasar said. “However, it does not work as frequently, or for as long, as we would like,” he added.

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Cell-signaling pathway
Preclinical studies have shown that lymphoma cells rely on a cell-signaling pathway called the PI3K pathway for survival, and activation of PI3K plays a role in the resistance to rituximab, Matasar explained. Copanlisib is a potent PI3K inhibitor approved as monotherapy for patients with follicular lymphoma, a common indolent lymphoma, whose disease has relapsed after at least two courses of prior treatment.

In CHRONOS-3, patients with relapsed indolent non-Hodgkin lymphoma were randomly assigned to copanlisib plus rituximab (307 patients) or to placebo plus rituximab (151 patients). Of them, 60% had follicular lymphoma, 20.7% had marginal zone lymphoma, 10.9% had small lymphocytic lymphoma, and 8.3% had lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

Matthew J. Matasar, MD, Medical Oncologist at the Regional Care Network Medical Site Director, MSK Bergen. Matasar focuses on Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Autologous Stem Cell Transplantation, and Cancer Survivorship.

After a median follow-up of 19.2 months, the study met its primary endpoint of PFS with a 48 percent reduction in the risk of lymphoma progression or death in the copanlisib-rituximab arm. Significant reductions were seen for follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma. Median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm (95% CI 17·8–33·0) and 13.8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p<0·0001) in the placebo-rituximab arm.

Overall response rate (ORR) was 80% in the copanlisib-rituximab arm, versus 47.7% in the placebo-rituximab arm. Complete response rate (CRR) was 33.9% in the copanlisib-rituximab arm, versus 14.6% in the placebo-rituximab arm. Median overall survival could not be estimated at the time of assessment.

The study results also showed a reduction in risk of progression/death across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]

The most common adverse events with copanlisib treatment were increases in blood glucose and blood pressure. These effects are temporary and generally do not require treatment, Matasar noted.

The primary endpoint of Progression Free Survival (PFS) in all patients with iNHL (© 2021 AACR; Used with permission)

“Very few patients had to stop receiving treatment because of these side effects (3% and 1%, respectively). Lung inflammation was an adverse event we watched for, but was reported in only 3% of patients receiving copanlisib plus rituximab,” he said.

Earlier studies using the daily orally administered PI3K inhibitors idelalisib and duvelisib resulted in severe toxicity, including deaths, leading to early termination of clinical trials. Copanlisib is administered intravenously on an intermittent schedule, and has lower rates of such side effects compared with these oral PI3K inhibitors, Matasar said.

“Thus, the overall results shown here with CHRONOS-3 are essentially a long-awaited proof of concept for combining a PI3K inhibitor with rituximab, and hopefully offer insight into ongoing and future studies of copanlisib and other investigational PI3K inhibitors in development,” Matasar noted.

The primary analysis for this study was triggered when a pre-specified number of events (deaths or progressive disease) was seen, Matasar said. The median follow-up for this primary endpoint was 19 months, and many patients were still on treatment at the time of the analysis.

“Differences in overall survival, a secondary endpoint of the study, were not seen between arms, and longer follow-up will be required to determine whether copanlisib plus rituximab improves the expected lifespan on average,” Matasar concluded.


* Indolent non-Hodgkin lymphoma (iNHL), also known low-grade lymphoma, is a group of slow-growing non-Hodgkin Lymphomas (NHL).  They make up about 40% of all NHL cases in the United States. Indolent non-Hodgkin Lymphoma subtypes include:

  • Cutaneous T-cell lymphoma (Mycosis Fungoides and Sézary syndrome)
  • Follicular lymphoma (FL)
  • Lymphoplasmacytic lymphoma and Waldenström macroglobulinemia
  • Marginal zone lymphoma
  • Small cell lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL)

Because indolent lymphoma is usually very slow-growing and slow to spread, it generally tends to have fewer signs and symptoms when first diagnosed and may not require treatment straight away. Overall, treatment options range from observation with careful monitoring (also known as the watch-and-wait approach) to aggressive therapy. However, management of the disease is highly individual and depends on prognostic factors, the stage of disease, the patient’s age, and comorbidities.

Clinical trial
Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin’s Lymphoma (iNHL) (CHRONOS-3) – NCT02367040

Highlights of prescribing information
Copanlisib (Aliqopa®; Bayer) [Prescribing Information]
Rituximab (Rituxan®; Genentech/Biogen) [Prescribing Information]

[1] Liu N, Rowley BR, Bull CO, Schneider C, Haegebarth A, Schatz CA, Fracasso PR, Wilkie DP, Hentemann M, Wilhelm SM, Scott WJ, Mumberg D, Ziegelbauer K. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013 Nov;12(11):2319-30. doi: 10.1158/1535-7163.MCT-12-0993-T. Epub 2013 Oct 29. PMID: 24170767.
[2] Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor Á, Bouabdallah K, Galiulin R, Uchida T, Soler LM, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. 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. 2021 Apr 9:S1470-2045(21)00145-5. doi: 10.1016/S1470-2045(21)00145-5. Epub ahead of print. PMID: 33848462.
[3] Matasar MJ, Capra M, Özcan M, Lv F, Wei Li, Yañez E, Sapunarova K, Lin T. CHRONOS-3: Randomized Phase III study of copanlisib plus rituximab vs rituximab/placebo in relapsed indolent non-Hodgkin lymphoma (iNHL). Presented at: AACR Annual Meeting 2021; April 9-14; Virtual. Abstract: #CT001

Featured image: The American Association for Cancer Research (AACR) Annual Meeting in pre-COVID19 Days: New Orleans, LA – The AACR 2016 Annual Meeting. Photo courtesy AACR/Scott Morgan.

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