Yuan Yuan, MD, PhD

Yuan Yuan, MD, PhD, a medical oncologist at City of Hope, Duarte, California, commented on the IPATunity130 trial. “Targeting the PIK3CA/AKT/mTOR cancer driver pathway is the holy grail for breast cancer in general. About 30% to 40% of breast cancers carry an alteration. Activation of this pathway leads to cell proliferation and metastasis,” she explained.

“We know from studies a decade ago that targeting mTOR with everolimus leads to modest improvements in progression-free survival in estrogen receptor–positive metastatic breast cancer. However, its efficacy in triple-negative breast cancer is limited,” explained Dr. Yuan. “The phase II LOTUS trial showed a promising improvement in progression-free survival when ipatasertib was combined with paclitaxel compared with paclitaxel alone for triple-negative breast cancer, especially in tumors that carried PIK3CA/AKT1/PTEN alterations. The LOTUS trial suggested we had a new target. Then, the PAKT trial showed a similar modest progression-free benefit of about 3 months with capivasertib in triple-negative breast cancer,” she continued.

“These studies ignited a lot of interest in developing these drugs for triple-negative breast cancer in phase III clinical trials,” Dr. Yuan noted.

Different Results in Phase II and III Trials

“At ESMO 2020, we saw overlapping curves of progression-free survival for estrogen receptor–positive metastatic disease in the IPATunity130 trial, and at this meeting, we saw the same thing in triple-negative breast cancer. This is not the first time we have seen positive phase II trials and negative phase III trials. We saw this with the first PARP inhibitor, iniparib, tested in breast cancer,” she continued.

Dr. Yuan noted that the reasons for the difference between the LOTUS and IPATunity130 trials are unknown. They could be related to patient selection, tumor heterogeneity, and bypassing signal pathways. “Perhaps, the benefits seen in the LOTUS trial with just 124 patients disappear in a broader population, such as in IPATunity130. Further biomarker correlatives hopefully may help to elucidate the underlying etiology of a lack of response,” she suggested.

To Come: Phase III CAPItello-290 Trial

So far, Dr. Yuan still has hope for more positive outcomes from the phase III CAPItello-290 trial of capivasertib in metastatic triple-negative breast cancer.¹ “If CAPItello-290 is negative, it may be a death sentence for AKT inhibition in triple-negative breast cancer,” she predicted.

“However, we are not done with this approach. I am aware that ipatasertib and capivasertib are now being studied in combination with endocrine therapy for hormone receptor–positive, HER2-negative breast cancer [TAKTIC, CAPItello-291]. It may be that chemotherapy is not the best partner in hormone receptor–positive breast cancer,” Dr. Yuan commented.

“The drug is being developed in the adjuvant setting for hormone receptor–positive breast cancer using circulating tumor DNA to detect residual disease. We hope to see further biomarker analysis from the IPATunity130 trial. At first glance, it is negative,” she stated. 

DISCLOSURE: Dr. Yuan has served as a consultant or advisor to Eisai, Genentech, Immunomedics, Novartis, and Pfizer; has participated in a speakers bureau for Eisai and Genentech; has received research funding from Eisai, Genentech, Merck, Novartis, Pfizer, and Puma Biotechnology; and has provided expert testimony on behalf of Novartis.

REFERENCE

1. Schmid P, Cortes J, Robson M, et al: Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290). 2019 San Antonio Breast Cancer Symposium. Abstract OT2-08-02.