Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.
Date
2019-01-20Author
Johnston, S
Puhalla, S
Wheatley, D
Ring, A
Barry, P
Holcombe, C
Boileau, JF
Provencher, L
Robidoux, A
Rimawi, M
McIntosh, SA
Shalaby, I
Stein, RC
Thirlwell, M
Dolling, D
Morden, J
Snowdon, C
Perry, S
Cornman, C
Batten, LM
Jeffs, LK
Dodson, A
Martins, V
Modi, A
Osborne, CK
Pogue-Geile, KL
Cheang, MCU
Wolmark, N
Julian, TB
Fisher, K
MacKenzie, M
Wilcox, M
Huang Bartlett, C
Koehler, M
Dowsett, M
Bliss, JM
Jacobs, SA
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Humans
Breast Neoplasms
Piperazines
Pyridines
Receptor, erbB-2
Receptors, Estrogen
Antineoplastic Combined Chemotherapy Protocols
Aromatase Inhibitors
Protein Kinase Inhibitors
Chemotherapy, Adjuvant
Neoadjuvant Therapy
Drug Administration Schedule
Postmenopause
Aged
Middle Aged
Female
Letrozole
Research team
Endocrine Therapy Resistance
Clinical Trials & Statistics Unit
Genomic Analysis – Clinical Trials
Endocrinology
Language
eng
Date accepted
2018-11-01
License start date
2019-01
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 37 (3), pp. 178 - 189
Publisher
AMER SOC CLINICAL ONCOLOGY