A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB)

Abstract

Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine if addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Experimental Design: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. Results: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib vs. placebo arm was 43% vs. 45% and 63% vs. 61% in the PIK3CA-mutant and -wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT vs. placebo plus letrozole. Conclusions: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

“…neoadjuvant setting, a PIK3CA-mut has no predictive value for treatment with the pan-PI3Ki pictilisib (OPPORTUNE trial) or the a-selective PI3Ki alpelisib (NEO-ORB trial), but seems to predict benefit from the b-sparing PI3Ki taselisib (LORELEI trial) [5,6,12,18].…”

“…The OPPORTUNE trial suggested that patients with progesterone receptor-negative or luminal B tumours may benefit more from pictilisib due to the drug's antiproliferative effect [5,6], but this was not demonstrated in the NEO-ORB trial [18].…”

“…mutations in PTEN) have a low frequency, statistical challenges and the risk of overfitting exist. Only the more recent trials have prospectively assessed PIK3CA-mut status or PI3K pathway activation before patients inclusion [7,9,10,[16][17][18]22], but still the predictive value of PIK3CA-mut was only proven in the b-sparing and a-selective PI3Ki trials. This may partly be explained by the low tolerability of pan-PI3Ki when compared with isoform-selective PI3Ki: exposure to pan-PI3Ki was often reduced due to their toxicity, and this could have led to inadequate pathway inhibition.…”

Update Breast Cancer 2020 Part 3 – Early Breast Cancer

“…The use of endocrine-based therapy in the neoadjuvant situation represents an alternative to chemotherapy for a certain patient population and is currently being investigated intensively in studies 51 , 52 , 53 . In particular, a neoadjuvant study can investigate how certain resistance mechanisms are overcome by CDK4/6 inhibitors.…”

“…Der Einsatz endokrin basierter Therapie in der neoadjuvanten Situation stellt für eine gewisse Patientinnenpopulation eine Alternative zur Chemotherapie dar und wird derzeit in Studien intensiv untersucht 51 , 52 , 53 . Insbesondere kann in einer neoadjuvanten Studie untersucht werden, wie durch CDK4/6-Inhibitoren gewisse Resistenzmechanismen überwunden werden.…”