Senthil Damodaran1, Fengmin Zhao2, Dustin A Deming3, Edith P Mitchell4, John J Wright5, Robert J Gray2, Victoria Wang2, Lisa M McShane6, Larry V Rubinstein6, David R Patton7, P Mickey Williams8, Stanley R Hamilton9, Jennifer M Suga10, Barbara A Conley11, Carlos L Arteaga12, Lyndsay N Harris11, Peter J O'Dwyer13, Alice P Chen14, Keith T Flaherty15. 1. The University of Texas MD Anderson Cancer Center, Houston, TX. 2. Dana-Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA. 3. University of Wisconsin Carbone Cancer Center, Madison, WI. 4. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. 5. Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. 6. Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. 7. National Cancer Institute/Center for Biomedical Informatics & Information Technology, Rockville, MD. 8. Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD. 9. City of Hope Comprehensive Cancer Center, Duarte, CA. 10. Kaiser Permanente, Vallejo, CA. 11. Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. 12. UT Southwestern Medical Center, Dallas, TX. 13. University of Pennsylvania Abramson Cancer Center, Division of Medical Oncology, Philadelphia, PA. 14. Developmental Therapeutics Clinic/Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. 15. Dana-Farber Cancer Institute/Harvard Medical School/Massachusetts General Hospital, Boston, MA.
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.
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.
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