Abstract GS3-02: PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib
Authors: Dowsett M , Jacobs S , Johnston S , Bliss J , Wheatley D , Holcombe C , Stein R , McIntosh S , Barry P , Dolling D , Snowdon C , Perry S , Batten L , Dodson A , Martins V , Modi A , Cornman C , Puhalla S , Wolmark N , Julian T , Pogue-Geile K , Robidoux A , Provencher L , Boileau JF , Shalaby I , Thirlwell M , Fisher K , Huang Bartlett C , Koehler M , Osborne K , Rimawi M 
Published: May 2019

Abstract
Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial collaboration between UK and NSABP investigators evaluating the biological and clinical effects of palbociclib with letrozole combination as neoadjuvant therapy.
Methods: Postmenopausal women with ER+ primary breast cancer and tumors &gt;2.0cm (ultrasound) were randomized to one of 4 treatment groups (3:2:2:2 ratio): Group A: letrozole (2.5mg/d) for 14 weeks; Group B: letrozole for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group C: palbociclib for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group D: letrozole + palbociclib for 14 weeks. Palbociclib was given 125mg/d PO on a 21 days on, 7 days off schedule. Post-14 week treatment was at the discretion of the treating clinician including letrozole until surgery. Core-cut biopsies were taken at baseline, 2 weeks and 14 weeks. Co-primary endpoints for letrozole alone vs palbociclib groups (Group A vs Groups B+C+D) were: (i) change in Ki67 (IHC) between baseline and 14 weeks (log-fold change, Mann-Whitney test); (ii) clinical response (ultrasound) after 14 weeks (4 group, ordinal, Mann-Whitney test). Complete cell-cycle arrest (CCCA) (Ki67≤2.7%) was analyzed using a logistic regression model adjusting for recruitment region. Pre-specified exploratory biomarkers included c-PARP (apoptosis).
Results: 307 patients were recruited between 27 Feb 2015 and 08 Mar 2018; 103 were randomized to letrozole alone and 204 to letrozole + palbociclib. 279 (90.9%) patients were evaluable for 14 week clinical response. Clinical response was not significantly different between letrozole vs letrozole + palbociclib groups [(p=0.20; CR+PR 49.5% (46/93) vs 54.3% (101/186) and PD 5.4% (5/93) vs 3.2% (6/186)] nor was the small proportion of patients with pathological CR (1/87, 1.1% vs 6/180, 3.3%; p=0.43). 190 (61.9%) patients were evaluable for 14 week change in Ki67. The median log-fold change in Ki67 was greater with letrozole + palbociclib vs letrozole alone (-4.1 vs -2.2; p&lt;0.001) corresponding to a geometric mean change of -97.4% vs -88.5%. Similarly, a greater proportion of patients who received letrozole + palbociclib achieved CCCA (90% vs 59%, p&lt;0.001). 146 (47.6%) patients were evaluable for c-PARP and the log-fold change (suppression) was greater with letrozole + palbociclib vs letrozole alone (-0.80 vs -0.42; p=0.003) corresponding to a geometric mean change of -56.8% vs -31.4%. Other biomarkers of response / resistance are being evaluated. A higher proportion of patients had a grade ≥3 toxicity on letrozole + palbociclib than letrozole alone (49.8% vs 17.0%; p&lt;0.001) mainly due to asymptomatic neutropenia.
Conclusion: Adding palbociclib to letrozole markedly enhanced the suppression of malignant cell proliferation as assessed by Ki67 but did not substantially increase the clinical response of primary ER+ breast cancer over a 14-week period. Concurrent reductions in cell death may have reduced the speed of tumor shrinkage.
Citation Format: Dowsett M, Jacobs S, Johnston S, Bliss J, Wheatley D, Holcombe C, Stein R, McIntosh S, Barry P, Dolling D, Snowdon C, Perry S, Batten L, Dodson A, Martins V, Modi A, Cornman C, Puhalla S, Wolmark N, Julian T, Pogue-Geile K, Robidoux A, Provencher L, Boileau JF, Shalaby I, Thirlwell M, Fisher K, Huang Bartlett C, Koehler M, Osborne K, Rimawi M. PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-02.