Copanlisib Shows Clinical Activity in PIK3CA-Mutated Tumors

Patients with tumors harboring PIK3CA mutations reported a better objective response rate when given copanlisib compared to those with the null hypothesis.

In patients with tumors harboring PIK3CA mutations, investigators for the NCI-MATCH ECOG-ACRIN trial (EAY131; NCT02465060) reported that the objective response rate (ORR) was 16% (90% CI, 6%-33%; P = .0341) in those who received copanlisib (Aliqopa), a class I inhibitor of PI3K with inhibitory activity predominantly against PI3Kα and PI3Kδ, compared with the null hypothesis ORR of 5%.

Specifically, in patients eligible for analysis (n = 25), 4 patients experienced a partial response (PR). In patients who were eligible for treatment (n = 28), the ORR was 14% (90% CI, 5%-30%; P = .0491). Findings were based on subprotocol Z1F.

In this treatment arm of the NCI-MATCH trial, investigators enrolled 35 patients. Copanlisib was administered intravenously at 60 mg doses over an hour, once weekly on days 1, 8, and 15 of a 28-day treatment cycle until progression or toxicity.

The primary end point was ORR. The study allowed for a 10% ineligibility rate and aimed to reach 31 eligible and treated patients. If fewer than 31 patients were in the primary analysis population, primary efficacy was assessed using a 5% one-sided exact binomial test of the null hypothesis. Secondary end points included the proportion of patients who were progression-free at 6 months (PFS6), progression-free survival (PFS), toxicity assessment, and evaluation of predictive biomarkers.

Patients were eligible if they were at least 18 years old with any solid tumor or myeloma who had progressed on standard treatment or were without prior therapy if no curative treatment existed. An activating PIK3CA mutation was required in patients’ tumors. Measurable disease and ECOG performance scores of 0 to 1 with acceptable organ function were also required. Investigators excluded patients with KRAS mutations, human epidermal growth factor receptor 2–positive breast cancers, and lymphomas. Other ineligibilities included uncontrolled type I or II diabetes mellitus and prior treatment copanlisib or other PI3K, Akt, or mechanistic target of rapamycin inhibitors. There was no limitation on the number of prior treatments received.

The clinical benefit rate was 36% (n = 9; 90% CI, 20%-54%) and was defined as complete response, PR, or stable disease (SD). Eleven patients (44%) had progressive disease (PD). The estimated PFS6 rate was 38% (90% CI, 22%-53%), with a median PFS of 3.4 months (90% CI, 1.8-6.6). The estimated 6-month overall survival (OS) rate was 50% (90% CI, 32%-65%), and the median OS was 5.9 (90% CI, 4.9-13.7) months.

Among patients in the primary analysis, the median age was 61 years (range, 42-78) and 64% were female. Most patients in this population were White (88%) and non-Hispanic (92%). Four patients (16%) received 0 or 1 prior therapy, 4 patients (16%) received 2 prior therapies, 6 (24%) received 3 prior therapies, and the remaining (n = 11; 44%) received more than 3 prior therapies. The most common tumor types among patients included gynecologic (n = 6), gastrointestinal (n = 6), and genitourinary (n = 4).

Of the 35 total patients, 30 were included in the toxicity analysis. The most common grade 1 or 2 treatment-related adverse events (TRAEs) included hyperglycemia (n = 11), fatigue (n =12), diarrhea (n = 11) and nausea (n = 10). Grade 3 TRAEs most commonly presented as hypertension (n = 9), hyperglycemia (n = 7), rash (n = 2), and muscle weakness (n = 2). One patient reported grade 4 hyperglycemia, and zero patients experienced any grade 5 TRAEs. Seventeen patients (68%) discontinued treatment because of PD. 

Because copanlisib reached the ORR primary end point, investigators suggested that this drug was a practical treatment choice for patients with tumors harboring the PIK3CA mutation. Further study is warranted.

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. J Clin Oncol. 2022;40(14):1552-1561. doi:10.1200/JCO.21.01648