As reported in JAMA Oncology by Kevin Kalinsky, MD, MS, and colleagues, the NCI-MATCH trial’s phase II subprotocol EAY131-Y has shown activity of the pan-AKT inhibitor capivasertib in a range of metastatic tumors with an AKT1 E17K mutation.

The NCI-MATCH trial, which opened in 2015, is an initiative that uses genomic testing to evaluate investigational molecularly targeted treatments in patients with disease refractory to standard treatments. The trial includes subprotocols representing nearly 40 single-group phase II trials.

Kevin Kalinsky, MD, MS

Study Details

The phase II trial enrolled 35 evaluable adult patients with an AKT1 E17K–mutated metastatic tumor between July 2016 and August 2017 whose disease had progressed on standard treatment. Patients received oral capivasertib at 480 mg twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxicity. Among patients with metastatic breast cancer receiving hormone therapy, the dose was 400 mg twice daily. The primary endpoint was objective response rate.

The most common cancers included in the trial were breast cancer (n = 18, 51%)—including 15 patients with hormone receptor (HR)-positive/HER2-negative disease and 3 with triple-negative disease—and gynecologic cancers (n = 11, 31%).

Responses

An objective response was achieved in 10 patients (28.6%, 95% confidence interval = 15%–46%, P < .001 vs the null rate of 5%). A confirmed complete response was observed in one patient with endometrioid endometrial adenocarcinoma, who remained on therapy for 35.6 months at last follow-up. Among the nine patients with a confirmed partial response, seven had HR-positive/HER2-negative breast cancer, one had uterine leiomyosarcoma, and one had oncocytic carcinoma of the parotid gland; the latter patient had remained on treatment for 28.8 months at last follow-up. The median duration of response was 4.4 months (range = 3.1 to ≥ 31.7 months).

Four patients were categorized as having stable disease on the basis of missing follow-up scans confirming partial response. An additional 16 patients (46%) had stable disease.

At median follow-up of 28.4 months, median progression-free survival was 5.5 months (range = 0–35 months), with a 6-month rate of 50%. Median overall survival was 14.5 months.

Adverse Events

The most common grade 1 or 2 adverse events were diarrhea (49%), fatigue (43%), nausea (37%), proteinuria (29%), hyperglycemia (23%), and anorexia (20%). The most common grade 3 or 4 adverse events (all grade 3, except for one case of grade 4 hyperglycemia) were hyperglycemia (26%), maculopapular rash (11%), diarrhea (9%), and decreased lymphocytes (9%). Capivasertib was discontinued due to adverse events in 11 patients (31%), including discontinuation due to hyperglycemia in 3.  

The investigators concluded, “This nonrandomized trial found that, in patients with an AKT1 E17K–mutated tumor treated with capivasertib, a clinically significant objective response rate was achieved, including one complete response. Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers.”

Dr. Kalinsky, of Winship Cancer Institute at Emory University, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.