Home World News Copanlisib Could Be a Viable Therapeutic Option for Select PIK3CA-Mutated Cancers

World News

Copanlisib Could Be a Viable Therapeutic Option for Select PIK3CA-Mutated Cancers

May 25, 2022

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The National Cancer Institute—Molecular Analysis for Therapy Choice (NCI-MATCH) is a tumour-agnostic platform that enrols patients based on matching genomic alterations. Copanlisib is an α and δ isoform–specific phosphoinositide 3-kinase (PI3K) inhibitor. Arm Z1F of the NCI-MATCH study run by ECOG-ACRIN met a primary endpoint with copanlisib, showing promising clinical activity in select PIK3CA–mutated cancers in the late-line, refractory setting. The findings are published by Dr. Senthil Damodaran of The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues in the Journal of Clinical Oncology.

PIK3CA mutations are frequently observed across multiple cancers including breast, endometrial, ovarian, and colon cancers. However, targeting PIK3CA has been hampered because of lack of selectivity of inhibitors and dose-limiting toxicities. PIK3CA mutations are also very heterogeneous, and their oncogenicity depends on the location of mutation in the gene. PIK3CA mutations often coexist with other pathway alterations (e.g. KRAS), which can affect clinical response.

Recently, alpelisib, an α-selective PI3K inhibitor, was approved by US Food and Drug Administration (FDA) for PIK3CA-mutated, hormone receptor–positive, metastatic breast cancers in combination with fulvestrant. Copanlisib is approved by FDA for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.

Launched in 2015, the NCI-MATCH is a signal-finding, molecularly matched study for patients with refractory cancers. The primary aim was to establish whether patients with advanced cancer would derive clinical benefit from treatments selected on the basis of their tumour molecular profile regardless of histology. Patients with actionable molecular alterations of interest are treated with matching therapies in independent subprotocols. Subprotocol Z1F evaluated copanlisib, an α and δ isoform–specific PI3K inhibitor in patients with PIK3CA-mutated cancers with or without PTEN loss.

Patients received copanlisib 60 mg intravenously once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, HER2–positive breast cancers, and lymphomas were excluded. Patients with uncontrolled type I or II diabetes mellitus (HbA1c > 8.5%) and those who received prior copanlisib or other PI3K, Akt, or mTOR inhibitors were excluded. The primary endpoint was centrally assessed objective response rate (ORR). Secondary endpoints included progression-free survival, 6-month progression-free survival, and overall survival.

In total, 35 patients were enroled and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. Multiple histologies were enroled, with gynaecologic (6 patients) and gastrointestinal (6 patients) being the most common. Majority of patients (68%) received at least 3 lines of prior treatment. The most frequent co-occurring mutations were TP53, PTEN, and ARID1A. The median number of genomic alterations was 3 (range, 1-9) and 9 patients had ≥ 4 genomic alterations in their tumours.

The ORR was 16% (4 of 25 patients, 90% confidence interval 6 to 33) with p = 0.0341 against a null rate of 5%. Clinical benefit rate, defined as complete response, partial response, or stable disease for at least 6 months was 36% (9 of 25, 90% CI 20 to 54). The most common reason for protocol discontinuation was disease progression in 17 patients (68%).

Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition with 16 patients (53%) having grade 3 toxicities and 1 patient (3%) had grade 4 toxicity according CTCAE v5.0. Most common toxicities include hyperglycaemia, fatigue, diarrhoea, hypertension, and nausea.

The authors commented that considering the observed clinical activity, PI3K inhibitors could be a potential targeted therapy option for patients with myxoid liposarcoma. Furthermore, considering the prolonged clinical activity of copanlisib in ameloblastomas, PI3K inhibition in these rare tumours could potentially be clinically meaningful, notwithstanding the presence of BRAF driver mutation. The clinical activity of copanlisib in patients with coexistent PIK3CA mutation and ARID1A loss has led to a proposed study of PI3K inhibitor in patients with coexisting PIK3CA and ARID1A mutations. Prolonged tumour response observed in the study in patients with coexistent PTEN loss suggests that the clinical activity of copanlisib is not limited by PTEN loss, in contrast to PI3Kα-specific inhibitors.

The authors concluded that the study met its primary endpoint with an ORR of 16% with copanlisib showing clinical activity in select PIK3CA–mutated cancers in the refractory setting. Further study of copanlisib in rational combinations is warranted.

This study was coordinated by the ECOG-ACRIN Cancer Research Group and supported by the US National Cancer Institute of the National Institutes of Health.