131P Efficacy of neoadjuvant letrozole and palbociclib in HER2-low vs HER2 zero luminal breast cancer: An analysis of the Unicancer Neopal phase II study

Conflicting results have been reported on the impact of HER2-low expression on the efficacy of CDK4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer. No data are yet available in the neoadjuvant setting. We investigated the efficacy of letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment according to HER2 expression in an exploratory analysis of the NeoPAL study (UCBG104, NCT02400567). NeoPAL was a randomised, parallel, non-comparative phase II study which assigned pts with HR+ HER2-, Prosigna®-defined luminal B or A and node-positive, stage II-III breast cancer to LETPAL or chemotherapy. Primary endpoint was residual cancer burden (RCB 0-I rate). Secondary endpoints included clinical response, proliferation-based markers, and safety. HER2 low status was centrally reviewed according to the ASCO/CAP guidelines. 40/53 patients treated in the LETPAL arm were evaluable for this substudy: HER2-low (n=20), HER2-0 (n=20). Luminal B molecular subtype was predominant in both groups (95% and 80% respectively) with a baseline high risk Prosigna® ROR score in 88.9% and 82.6% of patients, respectively. After 4 months of LETPAL, RCB 0-I was observed in one patient of each group and pathological complete response rates were 2.5% and 0% in the HER2-low and HER2-0 subgroups respectively. A 0-I PEPI score was observed in 4 patients in each group. Interestingly, the HER2 status switched (either way) in 7 out of 28 analysable matched samples (25%). LETPAL induced a decrease in the ROR score at surgery in a similar proportion in both groups: 68.4% and 60.0% of tumors switched from high or intermediate risk to low risk in the HER2-low and HER2-zero groups, respectively. All exploratory p values were >0.1. Strikingly similar results were observed in the chemotherapy arm. Neoadjuvant palbociclib activity in combination with letrozole does not seem to be influenced by the tumor’s HER2 status (low versus zero).