Early treatment-related neutropenia predicts response to palbociclib

Abstract

Background: Palbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib.

Methods: Blood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment.

Results: One hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11-0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38-0.85, p = 0.006) cohorts. Grade 3-4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38-0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51-1.47, p = 0.596). Multivariate analysis yielded similar results.

Conclusions: Treatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing.

Clinical trials registration information: Basket Trial: NCT01037790; Sarcoma Trial: NCT01209598.

Conflict of interest statement

N.P.M. received research funding from Novartis and Daiichi Sankyo; advisory board honorarium from Novartis, Daiichi Sankyo, and Genomic Health; consulting honorarium from Daiichi Sankyo and Novartis; travel accommodation from TRIO, Daiichi Sankyo, and Roche, as well as speaking honorarium from Novartis. M.A.D. has received research funding from Pfizer, Eli-Lilly, and AADi, along with providing consultation and advisory to Pfizer and Celgene. A.S.C. has received research funding from Novartis. D.V. received research funding from Merck, Astellas, and Genetech, along with providing consultation and sitting on the advisory board to Merck. M.H.O. received research support from Eli Lilly, BMS, and Celldex and received Honoraria from Astra Zeneca, along with providing consultation to Karyopharm and Exelixis. P.J.O. has received research funding from Amgen, Bayer, BBI Healthcare, Bristol-Myers Squibb, Celgene, Five Prime Therapeutics, Forty Seven, Genentech, GlaxoSmithKline, Merck, Mirati Therapeutics, Novartis, Pfizer, and Pharmacyclics, along with providing consultation and advising to Bristol-Myers Squibb, Five Prime Therapeutics, Forty Seven, and Genentech. A.D. has received research funding from Novartis, Pfizer, Genentech, Calithera, and Menarini, along with providing consultation to Contact Therapeutics, Pfizer, Novartis, and Calithera. All remaining authors have declared no conflict of interests.

Figures

Fig. 1. Nadir ANC in cycles 1–2 vs PFS weeks—Cox predicted relative hazard values.

Spearman’s rho = −0.4073 (p < 0.001). HR 1.22 (95% CI 1.13–1.32).

Fig. 2. Kaplan-Meier survival by cycle 1–2 maximum grade neutropenia.

a All patients. Grade 0: (reference); median PFS 6.0 weeks. Grade 1: HR 0.65 (0.40–1.07), p = 0.092; median PFS 8.1 weeks. Grade 2: HR 0.60 (0.40–0.90), p = 0.014; median PFS 15.6 weeks. Grade 3: HR 0.49 (0.33–0.74), p = 0.001; median PFS 19.4 weeks. Grade 4: HR 0.19 (0.06–0.62), p = 0.006; median PFS 60.0 weeks. Overall log-rank p = 0.002. b Breast patients. Grade 0: (reference); median PFS 5.0 weeks. Grade 1: HR 0.30 (0.05–1.56), p = 0.152; median PFS 13.9 weeks. Grade 2: HR 0.27 (0.10–0.75), p = 0.012; median PFS 16.3 weeks. Grade 3: HR 0.33 (0.12–0.87), p = 0.024; median PFS 19.4 weeks. Grade 4: HR 0.05 (0.01–0.52), p = 0.011; median PFS 25.4 weeks. Overall log-rank p = 0.028. c Non-breast patients. Grade 0: (reference); median PFS 6.0 weeks. Grade 1: HR 0.73 (0.43–1.23), p = 0.232; median PFS 8.0 weeks. Grade 2: HR 0.66 (0.41–1.06), p = 0.083; median PFS 15.6 weeks. Grade 3: HR 0.46 (0.28–0.75), p = 0.002; median PFS 18.0 weeks. Grade 4: HR 0.20 (0.02–1.17), p = 0.071; median PFS 60.0 weeks. Overall log-rank p = 0.013.

Fig. 3. Kaplan-Meier survival by cycle 1–2 any grade or grade 3–4 neutropenia (breast patients).

a Any grade neutropenia. Grade 0: (reference); median PFS 5.0 weeks. Grade 1–4: HR 0.29 (95% CI 0.11–0.74), p = 0.010; median PFS 17.3 weeks. b Grade 3–4 neutropenia. Grade 0–2: (reference); median PFS 12.7 weeks. Grade 3–4: HR 0.87 (95% CI 0.51–1.47), p = 0.596; median PFS 20.7 weeks.