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Phase II Study of Copanlisib in Patients With PTEN Loss: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131)
Mohamed A Gouda1, Zihan Wei2, Jordi Rodon1
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Purpose:
Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial.
Methods:
Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of PTEN mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the PTEN gene and retained expression of PTEN were included in subprotocol Z1H. Copanlisib was given intravenously over 1 hour at a dose of 60 mg on days 1, 8, and 15 in a 21-day-on and 7-day-off schedule in 28-day cycles. Patients continued treatment until disease progression or unacceptable toxicity.
Results:
Overall, 49 patients (20 patients in Z1G and 29 in Z1H) were included in the primary efficacy analyses. The objective response rates in both cohorts were 0% (Z1G; 90% CI, 0 to 13.9) and 3.4% (Z1H; 90% CI, 0.2 to 15.3), respectively. The median progression-free and overall survival durations were 1.8 months (90% CI, 1.4 to 3.9 months) and 13.7 months (90% CI, 6.8 to 18.3 months) for the Z1G cohort and 1.8 months (90% CI, 1.8 to 2.1 months) and 9.0 months (90% CI, 5.4 to 13.3 months) for the Z1H cohort, respectively.
Conclusion:
Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.
Insights
Single-agent copanlisib did not demonstrate antitumor activity in patients with PTEN loss, irrespective of PTEN mutation or deletion status. This study evaluated copanlisib in PI3K-targeted therapy for PTEN-deficient tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Phosphatidylinositol 3-kinase (PI3K) pathway dysregulation is common in cancer.
- PTEN loss is a frequent event in various malignancies, often leading to PI3K pathway activation.
- Copanlisib is a potent inhibitor of PI3K isoforms, particularly PI3K-alpha and PI3K-delta.
Purpose of the Study:
- To evaluate the efficacy and safety of copanlisib in patients with PTEN loss.
- To assess copanlisib activity in tumors with complete PTEN loss (Z1G) and PTEN deleterious mutations with retained expression (Z1H).
Main Methods:
- Patients with PTEN loss (immunohistochemistry) or PTEN deleterious mutations (Z1G and Z1H cohorts) were enrolled in the NCI Molecular Analysis for Therapy Choice trial.
- Copanlisib was administered intravenously at 60 mg on days 1, 8, and 15 of 28-day cycles.
- Treatment continued until disease progression or unacceptable toxicity.
Main Results:
- 49 patients were included in efficacy analyses (20 in Z1G, 29 in Z1H).
- Objective response rates were 0% in Z1G and 3.4% in Z1H.
- Median progression-free survival was 1.8 months for both cohorts; median overall survival was 13.7 months (Z1G) and 9.0 months (Z1H).
Conclusions:
- Single-agent copanlisib does not show significant antitumor activity in tumors with PTEN loss.
- The findings do not support copanlisib as a monotherapy for PTEN-altered cancers.
- Further investigation into combination therapies or different patient selection criteria may be warranted.
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