The NCI-MATCH is a tumour-agnostic platform that enrols patients on the basis of matching genomic alterations. The NCI-MATCH ECOG-ACRIN study (EAY131) subprotocol Z1F evaluated copanlisib, an α and δ isoform–specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations. The study met its primary endpoint with an objective response rate (ORR) of 16% with copanlisib, showing promising clinical activity in select tumours with PIK3CA mutation in the late-line, refractory setting. The study fundings suggest that copanlisib could be a viable therapeutic option for select tumours with PIK3CA mutations. The results are published by Dr. Senthil Damodaran of The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 8 February 2022 in the Journal of Clinical Oncology.

Activation of the PI3K/AKT/mTOR pathway through PIK3CA mutations or PTEN loss is observed in many human cancers. PIK3CA is the most commonly mutated oncogene with alterations observed across multiple tumour types including breast, ovarian, and colon. Consequently, targeting PIK3CA has been of major clinical interest. However, initial clinical efforts targeting PIK3CA mutations yielded mixed results because of lack of isoform specificity of inhibitors and poor therapeutic index. Recently, alpelisib, an α-selective PI3K inhibitor, was approved by the US Food and Drug Administration (FDA) for PIK3CA-mutated, hormone receptor–positive, metastatic breast cancers in combination with fulvestrant.

Copanlisib is a class I inhibitor of PI3K with inhibitory activity predominantly against PI3Kα and PI3Kδ isoforms. Copanlisib (Aliqopa) was approved by FDA for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.

Arm Z1F of the NCI-MATCH (EAY131) study evaluated copanlisib in patients with PIK3CA mutations 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. The primary endpoint was centrally assessed ORR. Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS).

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 (n = 6) and gastrointestinal (n = 6) being the most common. Most (68%) of patients had ≥3 lines of prior therapy.

The ORR was 16% (4 of 25, 90% confidence interval 6 to 33) with p = 0.0341 against a null rate of 5%.

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. In total, 16 patients (53%) had grade 3 toxicities, and 1 patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycaemia, fatigue, diarrhoea, hypertension, and nausea.

The authors concluded that the Z1F study met its primary endpoint with copanlisib, showing promising clinical activity in select tumours with PIK3CA mutation in the late-line, 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 multiple grants of the US National Cancer Institute of the National Institutes of Health.


Damodaran S, Zhao F, Deming DA, et al. Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F. Journal of Clinical Oncology; Published online 8 February 2022. DOI: 10.1200/JCO.21.01648