Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F.

Abstract

PURPOSE:

Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss).

PATIENTS AND METHODS:

Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2-positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival.

RESULTS:

Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10).

CONCLUSION:

The study met its primary end point with an ORR of 16% (P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

• Authors: Senthil Damodaran, Fengmin Zhao, Dustin A Deming, Edith P Mitchell, John J Wright, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, P Mickey Williams, Stanley R Hamilton, Jennifer M Suga, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 40 Issue 14 Pg. 1552-1561 (05 10 2022) ISSN: 1527-7755 [Electronic] United States
• PMID: 35133871 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Quinazolines
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• copanlisib

Topics

• Breast Neoplasms (chemically induced, drug therapy, genetics)
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Female
• Humans
• Phosphatidylinositol 3-Kinases
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Quinazolines (therapeutic use)