Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor–Positive Early Breast Cancer: PALLET Trial
Authors: Stephen Johnston, Shannon Puhalla, Duncan Wheatley, Alistair Ring, Peter Barry, Chris Holcombe, Jean Francois Boileau, Louise Provencher, André Robidoux, Mothaffar Rimawi, Stuart A. McIntosh, Ibrahim Shalaby, Robert C. Stein, Michael Thirlwell, David Dolling, James Morden, Claire Snowdon, Sophie Perry, Chester Cornman, Leona M. Batten, Lisa K. Jeffs, Andrew Dodson, Vera Martins, Arjun Modi, C. Kent Osborne, Katherine L. Pogue-Geile, Maggie Chon U Cheang, Norman Wolmark, Thomas B. Julian, Kate Fisher, Mairead MacKenzie, Maggie Wilcox, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith M. Bliss, Samuel A. Jacobs
Journal: Journal of Clinical Oncology (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 &lt; .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 &lt; .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 &lt; .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P &lt; .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.