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MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor
A Jo Chien1, Debasish Tripathy2, Kathy S Albain3
1University of California, San Francisco, San Francisco, CA.
Purpose:
The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.
Patients And Methods:
I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.
Results:
MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).
Conclusion:
The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
Insights
The pan-Akt inhibitor MK-2206 combined with standard therapy showed improved pathologic complete response (pCR) rates in high-risk early-stage breast cancer, particularly in HR-negative and HER2-positive subtypes.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is crucial in breast cancer survival and therapeutic resistance.
- Targeting this pathway offers a potential strategy for overcoming treatment challenges in breast cancer.
Purpose of the Study:
- To evaluate the efficacy and safety of the pan-Akt inhibitor MK-2206 in combination with standard neoadjuvant therapy for high-risk early-stage breast cancer.
- To identify predictive biomarker signatures associated with treatment response.
Main Methods:
- A multicenter, phase II, adaptively randomized neoadjuvant platform trial (I-SPY 2) was conducted.
- Patients were stratified by hormone receptor (HR), human epidermal growth factor receptor 2 (HER2), and MammaPrint statuses.
- Patients received standard neoadjuvant therapy with or without MK-2206, with pathologic complete response (pCR) as the primary endpoint.
Main Results:
- MK-2206 demonstrated higher estimated pCR rates in specific patient subgroups: HR-negative/HER2-positive (0.48 vs. 0.29), HR-negative (0.62 vs. 0.36), and HER2-positive (0.46 vs. 0.26).
- Exploratory analyses suggested a numerical improvement in event-free survival for MK-2206 in its graduating signatures.
- The most frequent grade 3-4 toxicities were rash, including maculopapular and acneiform types.
Conclusions:
- The combination of MK-2206 with standard neoadjuvant therapy increased pCR rates in HR-negative and HER2-positive early-stage breast cancer.
- While MK-2206 is not currently under further development, Akt inhibitors remain a class of agents of significant clinical interest for breast cancer treatment.
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