Abstract PD5-04: Ki67 changes and PEPI score in the LORELEI trial: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative early-stage breast cancer
Authors: de Azambuja E , Saura C , Nuciforo P , Frantal S , Oliveira M , Zardavas D , Jallitsch-Halper A , de la Pena L , Dubsky P , Lombard JM , Vuylsteke P , Castaneda Altamirano C , Sanchez C , Ballestrero A , Colleoni M , Santos Borges G , Ciruelos E , Bardia A , Fornier M , Boer K , Wilson TR , Stout TJ , Hsu JY , Shi Y , Piccart M , Baselga J , Gnant M 
Published: February 2018

Abstract
Background: Taselisib is an oral, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms with enhanced activity against PIK3CA mutant cancer cells. LORELEI trial demonstrated a significant improvement in ORR (objective response rate) centrally assessed by MRI with neoadjuvant taselisib plus letrozole compared to letrozole plus placebo in all randomized patients as well as in the PIK3CA mutant cohort (Saura et al, ESMO 2017).
Methods: 334 postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable breast cancer and evaluable tumor tissue for PIK3CA genotyping were randomized (1:1) to receive daily letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Tumor tissue collection was performed at baseline, week 3 (W3) and at surgery. Secondary objectives included, but were not restricted to, ORR assessed by MRI in patients with PIK3CA wild type (WT) tumors, ORR using alternative methods of tumor assessment (ultrasound, mammogram and clinical breast exam) in all patients and patients with PIK3CA mutant and WT tumors, central assessment of Ki67 at different timepoints (baseline, W3 and surgery), and the centrally derived PEPI score. Central Ki67 was assessed by two independent readers blinded to treatment arms and PIK3CA status (Vall D'Hebron Institute of Oncology, Barcelona).
Results: ORR by centrally assessed MRI was similar in the two treatment arms in patients with PIK3CA WT tumors (45.7 vs 40.4% for taselisib and placebo, respectively). ORR assessed by breast US was also significantly higher with taselisib compared to placebo in all randomized patients and in the PIK3CA mutant cohort. The highest concordance rate between MRI and other imaging modalities was found with breast ultrasound (53.7%). Centrally assessed Ki67 changes are reported in Table 1. Ki67 values decreased from baseline to W3 and from baseline to surgery in both treatment arms. No significant differences in the decrease of Ki67 values between treatment arms were detected. Unplanned analysis of Complete Cell Cycle Arrest (CCCA) at W3 was numerically higher with taselisib than with placebo in all randomized patients (49.6% vs 38.5%) and in the PIK3CA mutant cohort (60.9% vs 47.5%). Due to the variability in timing between the last dose of taselisib (median time 11 days; interquartile range 6-16 days) and tissue collection at surgery, considering the half-life of taselisib of approximately 40 hours, centrally derived PEPI score is not interpretable.
Ki67 proportional changes, %Taselisib + letrozolePlacebo + letrozoleBaseline to W3All patients-83.8-80.4PIK3CA mutant-84.5-79.1PIK3CA WT-82.8-81.1Baseline to surgeryAll patients-75.6-80.5PIK3CA mutant-71.9-79.9PIK3CA WT-78.2-81.2
Conclusion: Among the investigated alternative methods for assessing ORR, breast ultrasound performed similar to MRI. Decrease in the Ki67 values from baseline to W3 and to surgery were observed in both treatment arms. The time interval between taselisib cessation and tissue collection at surgery are being further investigated.
Clinical trial information: NCT02273973
Citation Format: de Azambuja E, Saura C, Nuciforo P, Frantal S, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Pena L, Dubsky P, Lombard JM, Vuylsteke P, Castaneda Altamirano C, Sanchez C, Ballestrero A, Colleoni M, Santos Borges G, Ciruelos E, Bardia A, Fornier M, Boer K, Wilson TR, Stout TJ, Hsu JY, Shi Y, Piccart M, Baselga J, Gnant M. Ki67 changes and PEPI score in the LORELEI trial: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative early-stage breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-04.