Reference Detail

Ref Type

abstract

PMID

Authors

Eric S. Christenson; Jeremiah A. Wala; Rose Parkinson; Natalie B. Collins; Christopher Jakubowski; Jea-Ren Lin; Hao Wang; Won Jin Ho; Sabrina Chan; Rachel Klein; Yvette Cetasaan; Emma Johnson; Maureen Berg; Jeffrey Meyerhardt; Benjamin Schlechter; Harshabad Singh; Peter K. Sorger; Marios Giannakis; Nilofer Azad

Title

Abstract CT007: Phase 1/2 trial of copanlisib in combination with nivolumab for microsatellite stable (MSS) colorectal cancer (CRC)

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	84	7_Supplement	April 1, 2024

URL

https://aacrjournals.org/cancerres/article/84/7_Supplement/CT007/742273/Abstract-CT007-Phase-1-2-trial-of-copanlisib-in

Abstract Text

Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) is frequently mutated in CRC, leading to constitutive activation and enhanced cellular growth. PI3K also regulates immunity; inhibition of this pathway suppresses Tregs and myeloid derived suppressor cells resulting in enhanced anti-tumor immune responses. Murine experiments combining PD-1 and PI3K inhibition showed an increased CD8+ T cell:Treg ratio and improved survival compared to either alone. We launched a multicenter phase I/II investigation of copanlisib (PI3K inhibitor) and nivolumab (anti-PD-1) in 2 cohorts of patients with metastatic MSS CRC, Cohort 1: PIK3CA mutant (PI3KCAm) and Cohort 2: PIK3CA wild type (PIK3CAwt). From 2/2019 to 4/2022, 39 patients were enrolled: 6 in the phase 1 portion and 33 in phase 2 (22 PIK3CAm/17 PIK3CAwt). All patients had received at least 2 lines of prior therapy. Patient demographics and best treatment responses are in Table 1. There were no dose-limiting toxicities; toxicities were as expected and tolerable, most commonly hypertension in 16 (41%) patients and maculopapular rash in 4 (10%) patients. 3 patients in cohort 1 (14%) had partial responses (PR) and 3 had stable disease (SD): (range 1.7-4.7 mo.). One patient in Cohort 2 (6%) had a PR and 4 had SD: (range 3.8-7.4 mo.). Notably, all 4 responses have lasted more than 2 years. The trial incorporated robust translational correlates for mechanism interrogation with serial biopsies and blood draws. We will report circulating cytokine profiling, mass cytometry on PBMCs, and highly multiplexed immunofluorescence imaging (CyCIF) on paired pre- and on-treatment tissue specimens to i) dissect immune and PI3K pathway changes with treatment ii) correlate these to clinical responses and iii) determine baseline biomarkers of response and mechanism of effect. Overall copanlisib/nivolumab was well tolerated. The PIK3CAm CRC cohort met the primary endpoint for objective response rate but later than 6 months as responses were evolving.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA mutant	colorectal cancer	predicted - sensitive	Copanlisib + Nivolumab	Phase Ib/II	Actionable	In a Phase I/II trial, treatment with the combination of Aliqopa (copanlisib) and Opdivo (nivolumab) was well tolerated and resulted in 3 partial responses in 22 patients with microsatellite stable colorectal cancer harboring PIK3CA mutations (Cancer Res (2024) 84 (7_Supplement): CT007; NCT03711058).	detail...