PI3K Inhibition With Copanlisib in Relapsed or Refractory Indolent Lymphoma

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Martin Dreyling, MD, PhD

Martin Dreyling, MD, PhD

AS REPORTED in the Journal of Clinical Oncology by Martin Dreyling, MD, PhD, of University Hospital, Ludwig Maximilians University of Munich, and colleagues, the phase II CHRONOS-1 trial has shown a high response rate and durable responses with the phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib (Aliqopa) in adult patients with relapsed or refractory indolent lymphoma who had received at least two previous lines of therapy.1 Data in the subgroup of patients with follicular lymphoma in the trial supported the recent accelerated approval of copanlisib in relapsed follicular lymphoma after at least two prior therapies. Copanlisib is a pan-class I PI3K inhibitor that exhibits predominant activity against PI3K-α and -δ isoforms. 

Study Details 

IN THE STUDY, 142 patients from 81 sites in Europe, Asia, the United States, Australia, and New Zealand were enrolled between November 2013 and February 2016 and received copanlisib at 60 mg intravenously on days 1, 8, and 15 of 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on a blinded independent review. 

The median age of patients was 63 years, 50% were female, and 85% were white and 11% were Asian. Tumor histology was follicular lymphoma in 104 patients (73%; grade 1, 2, and 3a in 21%, 50%, and 26%, respectively), marginal zone lymphoma in 23 patients (16%), small lymphocytic lymphoma in 8 eights (6%), and others in 7 patients (5%). Ann Arbor stage was I, II, III, and IV in 2%, 18%, 23%, and 58%, respectively. Patients had received a median of three prior therapies (range = 2–9), with 100% receiving prior rituximab (Rituxan) and alkylating agents. The median time to most recent disease progression was 8 weeks. Overall, 61% of patients were refractory to their last regimen, including rituximab in 56%, alkylating agents in 42%, and both in 43%. 

Response Rates 

AMONG ALL PATIENTS, objective response was achieved in 84 patients (59%), with a complete response in 12%. The median time to response was 53 days. Stable disease was observed in 30% of patients. The median duration of response was 22.6 months, the median progression-free survival was 11.2 months, and the median overall survival had not yet been reached. 


  • Copanlisib produced an objective response rate of 59% in heavily pretreated patients with indolent lymphoma.
  • The response rate was 59% among patients with follicular lymphoma, the largest subgroup.

Objective response rates were 59% (14% complete response) in patients with follicular lymphoma, 70% (9% complete response) in those with marginal zone lymphoma, 75% among 8 patients with small lymphocytic lymphoma, 60% among those with disease refractory to their last treatment, and 57% among those with disease responsive to their last treatment. The median response duration was 12.2 months in patients with follicular lymphoma. A waterfall plot of best response in target lesions according to investigator assessment showed that 74 of 125 patients (59%) assessed had lesion reduction of at least 50%. 

Among evaluated patients, high expression of PI3K/B-cell receptor pathway genes was found in 33 of 44 (75%) with an objective response, including 6 of 8 with a complete response. High expression levels were found in 25 of 33 (76%) evaluable patients with follicular lymphoma with an objective response and in 5 of 6 with a complete response. 

Adverse Events 

THE MOST COMMON adverse events of any grade were hyperglycemia (50%), diarrhea (34%), fatigue (30%), hypertension (30%), and neutropenia (30%). Grade 3 or 4 adverse events occurred in 80%, with the most common being hyperglycemia (41%), hypertension (24%), neutropenia (24%), and lung infection (15%). Noninfectious pneumonitis occurred in 11 patients (8%; 1% grade 3). Abnormal laboratory tests of interest included increased alanine transaminase (23%; 19% grade 1) and aspartate transaminase levels (28%; 25% grade 1). 

“PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.”
— Martin Dreyling, MD, PhD, and colleagues

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Serious grade ≥ 3 adverse events occurring in at least three patients consisted of lung infection (13%), hyperglycemia (5%), decreased neutrophil count (4%), fever (3%), and diarrhea (2%); grade 3 pneumonitis occurred in two patients, and grade 4 colitis occurred in one. Adverse events led to treatment discontinuation in 25% of patients and were considered drug-related in 16%, including noninfectious pneumonitis in five patients (4%), lung infection in four patients (3%), and hyperglycemia in three patients (2%). Adverse events led to death in five patients (4%) during or within 35 days after treatment; death was considered treatment-related in three patients, due to lung infection in one patient, respiratory failure in one patient, and a cerebral thromboembolic event in one patient. 

The investigators concluded: “PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.” 

DISCLOSURE: The study was supported by Bayer AG. For full disclosures of the study authors, visit www.jco.ascopubs.org. 


1. Dreyling M, Santoro A, Mollica L, et al: Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 35:3898-3905, 2017.

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