Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
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.
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; and Jacobs, Samuel A, "Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial." (2019). Articles, Abstracts, and Reports. 914.