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The latest data from NCI-MATCH, the largest precision medicine cancer trial, delve into the complexities of treating PIK3CA-mutated cancers with P13K inhibitors
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.
- The objective response rate was 16%
- Clinical benefit was observed in 36% of patients
- These findings signal that the treatment warrants further investigation in select tumors
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:
- endometrial adenocarcinoma
- clear cell carcinoma of the anterior abdominal wall
- mandible ameloblastoma
- low-grade myxoid liposarcoma (MLS) of the thigh
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:
- clear cell carcinoma of the ovary
- adenocarcinoma of the lower third esophagus with mucinous features
- low-grade myxoid liposarcoma of the calf
- adenocarcinoma of the lung
- adenocarcinoma of the prostate gland
- Prolonged clinical activity of copanlisib in two patients with myxoid liposarcoma (MLS) suggest that copanlisib/PI3K inhibitors could be a potential targeted therapy option for patients with PIK3CA mutations. One patient had partial response (PR) to copanlisib, and the other had stable disease (SD) for >6 months. MLS is a rare cancer of the body's soft tissues (heart, muscles, tendons, fat, blood vessels, lymph vessels, nerves, and tissues around joints). Activation of the PI3K/AKT/mTOR signaling pathway through mutations in PIK3CA or PTEN loss have been shown to be essential in the development of MLS.
- Prolonged clinical activity of copanlisib was observed in a patient with mandibular ameloblastoma. This rare form of head and neck cancer begins in the cells in the enamel of the teeth and invades the jawbone. Gene testing for the patient found BRAF V600E and MED12 mutations with PIK3CA. This patient was not previously treated with a BRAF inhibitor. The patient achieved a partial response and was still on treatment at the time of data cut-off. PI3K inhibition in these rare tumors could potentially be clinically meaningful, notwithstanding the presence of BRAF driver mutation.
- While all known activating PIK3CA mutations were considered eligible for trial participation, the PRs and SD ≥6 months were observed only in helical and kinase domain mutations.
- In three patients with concomitant PTEN loss, SD >6 months was observed with copanlisib. Loss of PTEN has been associated with decreased clinical benefit in patients with PIK3CA mutations and treated with PI3Kalpha-specific inhibitors. Prolonged clinical activity in patients with coexistent PTEN loss suggests that the clinical activity of copanlisib is not limited by PTEN loss.
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).