Copanlisib Plus Nivolumab Demonstrates Activity in Microsatellite Stable Colorectal Cancer


Copanlisib plus nivolumab was active and met the primary end point of a phase 1/2 study in a cohort of patients with MSS CRC.

Eric Scott Christenson, MD

Eric Scott Christenson, MD

Copanlisib (Aliqopa) in combination with nivolumab (Opdivo) led to durable responses in patients with microsatellite stable (MSS) colorectal cancer (CRC), meeting the primary end point in the PIK3Ca-mutated cohort according to findings from a phase 1/2a trial (NCT03711058) presented during the 2024 AACR Annual Meeting.1

Among patients with PIK3Ca-mutated MSS CRC (n = 22), 3 achieved a partial response (PR) and 2 others achieved stable disease; the 3 responders all experienced a progression-free survival (PFS) of approximately 24 months. Additionally, in the subset of patients with PIK3Ca wild-type disease (n = 17) there was 1 PR and 4 instances of stable disease. The patient who achieved the PR had PIK31R amplification and achieved a PFS of approximately 30 months.

PIK3Ca mutations are present in about 15% to 32% of patients with CRC,” Eric S. Christenson, MD, an assistant professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, said during the presentation. “[Patients with] MSS CRC generally have very low response rates to anti–PD-1 monotherapy of less than 5%. PIK3Ca inhibitors alone or in combination with chemotherapy really don’t do much better providing very minimal benefits even in biomarker selected [patients] with PIK3Ca-mutant MSS CRC. Standard of care third-line options also leave a lot to be desired providing very limited benefit, with a median PFS of between 1.9 and 3.7 months for regorafenib [Stivarga], trifluridine/tipiracil [Lonsurf] and fruquintinib [Fruzaqla], respectively, in their landmark phase 3 trials and low response rates of less than 2%. PI3K inhibition may have more than just direct anti-tumor effects, but also [potentially] modifies anti-tumor immunity.”

The trial enrolled adult patients with relapsed/refractory solid tumors with expansion cohorts in MSS CRC. To be eligible for the study, patients needed to have received all curative treatment options and at least 2 prior lines of systemic therapy. In phase 2, patients needed to have received at least 2 lines of systemic therapy including a fluoropyrimidine, oxaliplatin, and irinotecan-containing regimen, have measurable disease per RECIST v1.1 criteria, have an ECOG performance status of 1 or less, a life expectancy greater than 3 months, and adequate organ function.2

During the phase 2 portion, patients in both cohorts received the PI3K inhibitor copanlisib via a 60-minute intravenous (IV) infusion at a dose of 45 mg to 60 mg on days 1, 8, and 15, or day 1 and 15 of each 28-day cycle. IV nivolumab was given at a dose of 480 mg via a 30-minute IV infusion on day 1 of each 28-day cycle.

The primary end point of phase 2 was objective response rate at 6 months in each cohort; the study was considered successful if at least 3 of the 21 patients within a cohort experienced a PR or complete response. Secondary end points included disease control rate, duration of response, PFS, overall survival, and safety.1,2

Additional findings from the study revealed that an increase in pro-immune cytokines was observed following treatment with copanlisib and nivolumab. There was a rise in TNFa, IL-15, and IL-5 levels from baseline after treatment of 145- (P = .012), 148- (P = .036), and 211-fold (P = .0027), respectively. Notably, an increase in cytokines was more prominent in patients who experienced disease progression.1

In terms of safety, patients in the PIK3Ca-mutated and the PIK3Ca wild-type cohort experienced adverse effects (AEs) of grade 3 or higher at rates of 48% and 67%, respectively. Patients in both cohorts experienced hypertension (43% vs 33%), maculopapular rash (10% vs 17%), gastrointestinal disorders (10% vs 8%), increased aspartate aminotransferase (0% vs 8%), and hyperglycemia (5% vs 17%).

“Combining copanlisib and nivolumab in MSS CRC produced durable responses in a subset of patients, meeting the primary end point in the PIK3Ca-mutant cohort,” Christenson said in conclusion. “Cytokine analysis revealed this combination increased TNFa, IL-5, and IL-15 levels with patients who had a benefit [also] having a drop in circulating naive T cells and a potential rise in the activated T effector cell to naive T-cell ratio following copanlisib and nivolumab treatment. Intratumoral M2 macrophages were identified as a potential mechanism of resistance. We still have some ongoing analysis to do on other immune cell components in the tumor microenvironment as well as evaluate additional patients to look for biomarkers of response and additional potential mechanisms of resistance.”

Disclosures: Dr Christenson reported being a consultant for Seres Therapeutics and SIRTex; and grant/research support from Regeneron, NextCure, Affimed Gmbh, Haystack, and Pfizer.


  1. Christenson ES, Wala JA, Parkinson R, et al. Phase 1/2 trial of copanlisib in combination with nivolumab for microsatellite stable (MSS) colorectal cancer (CRC). Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT007.
  2. Study of PI3Kinase inhibition (copanlisib) and anti-PD-1 antibody nivolumab in relapsed/​refractory solid tumors with expansions in mismatch-repair proficient (MSS) colorectal cancer. Updated January 5, 2024. Accessed April 8, 2024.
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