Capivasertib Shows Promise Against Refractory AKT-mutated Tumors
Key findings
- This nonrandomized, open-label study of capivasertib, an investigational oral pan-AKT inhibitor, enrolled 35 patients with an AKT1 E17K-mutated tumor, who received continuous 28-day cycles
- The overall response rate was 29% (one patient who had endometrial adenocarcinoma had a complete response; nine patients had a partial response), 16 had stable disease, two had progressive disease and seven were not evaluable for response
- Median progression-free survival was 5.5 months, the six-month progression-free survival rate was 50%, and the median overall survival was 14.5 months
- Grade 3 adverse events in ≥10% of patients were hyperglycemia and maculopapular rash, grade 4 hyperglycemia occurred in one patient and 11 discontinued treatment because of adverse events (five of them in cycle 1)
- Capivasertib is now being trialed in combination with hormonal therapy or chemotherapy
Preclinical studies suggest capivasertib, an investigational oral drug, inhibits AKT, a protein needed for cancer cell growth. Keith Flaherty, MD, director of clinical research at the Massachusetts General Hospital Cancer Center, and colleagues found that capivasertib has meaningful activity in patients with various refractory AKT1 E17K-mutated tumors, including triple-negative breast cancer and rare cancers. The findings appear in JAMA Oncology.
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Methods
The National Cancer Institute's MATCH trial, which opened in 2015, provides genomic testing to patients with refractory cancer and directs them to investigational targeted treatments.
A subprotocol of that trial was a nonrandomized, open-label study of capivasertib that enrolled 35 patients with an AKT1 E17K-mutated tumor, which are rare in humans. 86% had received two or more previous lines of therapy. Most had breast cancer (n=18) or gynecologic cancer (n=11).
Patients received oral capivasertib twice daily for four days on, three days off in continuous 28-day cycles. The trial enrolled from July 13, 2016, to August 10, 2017, and ended on November 8, 2019.
Efficacy
The primary endpoint, the overall response rate, was 29%: one patient with endometrial adenocarcinoma achieved complete response and nine patients had a partial response. Sixteen patients had stable disease, of whom seven had stability for ≥5.5 months. Two patients had progressive disease and seven weren't evaluable for response.
Key secondary endpoints were:
- Median progression-free survival—5.5 months
- Six-month progression-free survival (PFS) rate—50%
- Median overall survival—14.5 months
Safety
Grade 1/2 adverse events (AEs) that occurred in ≥20% of patients were diarrhea, fatigue, nausea, proteinuria, hyperglycemia and anorexia. Grade 3 AEs in ≥10% were hyperglycemia and maculopapular rash. There was one grade 4 event, hyperglycemia. The one death was not treatment-related.
15 patients required at least one AE-related dose modification. 11 patients discontinued treatment because of AEs, five during cycle 1. Three were discontinued because of hyperglycemia; only one had preexisting diabetes.
Current Status
Capivasertib, which remains investigational, is now being trialed in combination with hormonal therapy or chemotherapy.
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