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.

Trial registration: ClinicalTrials.gov NCT02465060.

FIG 1.

Flowchart. Out of 35 enrolled patients, five patients did not start therapy. Among 30 that began treatment, 28 were considered evaluable for response (one patient had pretreatment creatinine clearance outside of eligibility range and the other had baseline AE greater than threshold for eligibility). Twenty-five patients were included in the primary efficacy analysis (three patients were excluded as mutational status was unable to be confirmed by the central assay). AE, adverse event; CrCl, creatinine clearance; NCI, National Cancer Institute.

FIG 2.

(A) Distributions of PIK3CA mutations across helical and kinase domains. (B) Distribution of specific variants in PIK3CA.

FIG 3.

Best percentage change from baseline. Of the 25 patients included in the primary efficacy analysis, 22 patients had lesions measurable after baseline and are included. Four patients had PR. GU, genitourinary; Gyn, gynecologic; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 4.

Duration of treatment. Twenty-five patients included in the primary efficacy analysis are shown here. Occurrence of response (*); disease progression (+); and death (#). Two patients are still on study treatment. GU, genitourinary; Gyn, gynecologic.

FIG 5.

(A) PFS and (B) OS. OS, overall survival; PFS, progression-free survival.

FIG A1.

Distributions of comutations in patients with PIK3CA mutations.

FIG A2.

Best percentage change from baseline in patient cohort (n = 28). Of the 28 evaluable patients, 24 had lesions measurable after baseline and are included (one patient without target lesion at baseline, and three patients without target lesion at baseline and without any follow-up imaging assessments were not included). GU, genitourinary; Gyn, gynecologic; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A3.

Duration of treatment in patient cohort (n = 28). Occurrence of response (*); disease progression (+); and death (#). Two patients are still on study treatment. GU, genitourinary; Gyn, gynecologic.

FIG A4.

(A) PFS and (B) OS for 28 patients (eligible and treated). OS, overall survival; PFS, progression-free survival.