Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor–Positive Early Breast Cancer: PALLET Trial
Authors: Johnston Stephen , Puhalla Shannon , Wheatley Duncan , Ring Alistair , Barry Peter , Holcombe Chris , Boileau Jean Francois , Provencher Louise , Robidoux André , Rimawi Mothaffar , McIntosh Stuart A. , Shalaby Ibrahim , Stein Robert C. , Thirlwell Michael , Dolling David , Morden James , Snowdon Claire , Perry Sophie , Cornman Chester , Batten Leona M. , Jeffs Lisa K. , Dodson Andrew , Martins Vera , Modi Arjun , Osborne C. Kent , Pogue-Geile Katherine L. , Cheang Maggie Chon U , Wolmark Norman , Julian Thomas B. , Fisher Kate , MacKenzie Mairead , Wilcox Maggie , Huang Bartlett Cynthia , Koehler Maria , Dowsett Mitch , Bliss Judith M. , Jacobs Samuel A. 
Published: December 2018

PURPOSE

CDK4/6 inhibitors are used to treat estrogen receptor (ER)–positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy.

PATIENTS AND METHODS

Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the  MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase.

RESULTS

Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% versus −88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (−0.80 v −0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia.

CONCLUSION

Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.