PIK3CA is one of the most common tumor gene mutation involved in cancer development and occurs across multiple tumor types. Although frequent, PIK3CA mutations tend to vary across patients and cancer type. Moreover, PIK3CA mutations often co-exist with other molecular abnormalities, especially KRAS and PTEN loss, affecting clinical response.
There has been high interest in finding new drugs to target the PIK3CA mutation for quite some time. However, these efforts have yielded mixed results.
"Initial efforts targeting PIK3CA mutations have yielded mixed results because of lack of isoform specificity of inhibitors and dose-limiting toxicities," said lead researcher Senthil Damodaran, MD, PhD, a medical oncologist at The University of Texas MD Anderson Cancer Center.
Now, the first published results of a platform trial of PIK3CA mutations across multiple tumor types appear in the Journal of Clinical Oncology. The data evaluate treatment with copanlisib, an intravenous cancer drug, and delve into the genomic features of PIK3CA across more than 20 cancer types. The data are from Arm Z1F of the NCI-MATCH trial.
"In NCI-MATCH's Arm Z1F, the PI3K inhibitor copanlisib showed clinical activity in select tumors with PIK3CA mutation in the late-line refractory setting," said Dr. Damodaran.
NCI-MATCH is a signal-finding study for adult patients with refractory cancers, both common and rare. Patients in the trial receive targeted therapies based on matching genomic alterations. With nearly 40 single-arm phase II studies, NCI-MATCH is the largest precision medicine cancer trial. The ECOG-ACRIN Cancer Research Group and the National Cancer Institute (NCI), part of the National Institutes of Health, are co-leading NCI-MATCH.
Copanlisib is a targeted cancer drug that inhibits the P13K signaling pathway regulating cell growth and survival. NCI-MATCH trial leaders selected it based on evidence of clinical effectiveness in early phase trials
In Arm Z1F, 28 patients were eligible and treated after being identified through standard-of-care assay results performed by NCI-MATCH designated laboratories. After patients started treatment, the central trial assay confirmed the commercial and academic lab results. There was a high degree of concordance between the two assays. However, the primary analysis of 25 patients excludes three cases not able to be confirmed due to issues with specimens.
Patients received copanlisib intravenously at a dose of 60 mg on days 1, 8, and 15 in 28-day cycles until progression or toxicity. The primary measure of clinical benefit was the objective response rate, which was 16% (4/25).
"Arm Z1F met its primary endpoint with an objective response rate of 16 percent," said Dr. Damodaran.
Six-month progression-free survival (PFS) was 38%, with a median PFS of 3.4 months. The estimated 6-month overall (OS) rate was 50%, with a median OS of 5.9 months.
The clinical benefit rate was 36% (9/25). Clinical benefit was defined as complete response (CR), partial response (PR), or stable disease (SD) for ≥6 months. There were no complete responses.
"The treatment resulted in nine of 25 patients having clinical benefit, which included four patients with a partial response and five with stable disease for six or more months," said Dr. Damodaran.
The tumor types among the four patients with partial responses (PR) were all rare:
Patients with MLS and ameloblastoma of the mandible were still on study treatment and had received 28 and 29 cycles, respectively, at the time of data cut-off on January 6, 2021.
The tumor types among the five patients with stable disease were mostly rare:
The publication, Phase 2 Study of Copanlisib in Patients with Tumors with PIK3CA Mutations: Results from the NCI-MATCH ECOG-ACRIN trial (EAY131) Sub-protocol Z1F, is available here (subscription required).