363P - Palbociclib exposure in relation to response and toxicity in patients with advanced breast cancer

Background

The addition of CDK4/6 inhibitors to endocrine therapy has nearly doubled progression free survival (PFS) of advanced hormone-receptor positive breast cancer in both 1^st and 2^nd line treatment. Up to now, data on exposure-response or exposure-toxicity relationships of CDK4/6 inhibitors are limited and inconclusive. Therefore, we aimed to investigate whether a relationship between palbociclib levels and PFS or toxicity exists.

Methods

All data was derived from patients in the randomized phase 3 SONIA-trial that compares the efficacy of CDK4/6 inhibitors added to 1^st line endocrine therapy (aromatase inhibitor) or 2^nd line (fulvestrant). Blood for pharmacokinetics (PK) was taken at day 15 of cycle 1 and 2. For every patient the average trough levels of palbociclib during cycle 1 and 2 were calculated. 1^st and 2^nd line were analysed separately. PFS was compared between palbociclib levels below and above median using a Cox proportional hazard model. For toxicity analyses, palbociclib levels were divided in quartiles. Chi-squared test for trend was used to test whether more adverse events (AEs) in the first 3 months or dose reductions (DR) during the total treatment period were seen with higher palbociclib exposure.

Results

PK data was available for 329 patients: 227 in 1^st and 102 in 2^nd line. In 1^st line, PFS did not differ between palbociclib levels above or below the median of 62 ng/mL (HR 1.00, 90% CI 0.76-1.35). Also, when palbociclib levels were divided in quartiles, no difference in PFS was seen between levels above or below the 1^st quartile limit of 48 ng/mL (HR 0.98, 90% CI 0.70-1.37). Similar results were found for patients treated in 2^nd line. There was no significant trend for more AEs (all toxicity ≥grade 3 and neutropenia ≥grade 3) with higher palbociclib levels. However, there was a trend (p=0.01) showing more DR with higher palbociclib levels.

Conclusions

No relationship between palbociclib levels and PFS was found. Although patients with higher palbociclib levels more frequently underwent DR, this was not reflected by a higher incidence of grade 3-4 AEs in the first 3 months. These results suggest that patients might be exposed to unnecessary high palbociclib levels, indicating opportunities for DR to reduce the burden of a targeted agent.

Clinical trial identification

NCT03425838 (8 February 2018).

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The Netherlands Organisation for Health Research and Development and Dutch Health Insurers.

Disclosure

C.L. Braal: Financial Interests, Personal, Full or part-time Employment: Eli Lily; Financial Interests, Personal, Advisory Role: Daiichi Sankyo. G.S. Sonke: Financial Interests, Institutional, Advisory Board, unrelated to this abstract: Agendia, AstraZeneca, Novartis, Roche, Seagen; Financial Interests, Institutional, Research Funding, unrelated to this abstract: Merck. I.R. Konings: Financial Interests, Institutional, Research Grant, unrelated to this abstract: Novartis, Gilead; Financial Interests, Institutional, Other, travel grant, outside this abstract: Daiichi Sankyo, AstraZeneca. A. Jager: Financial Interests, Institutional, Research Grant, unrelated to this abstract: Pfizer, Novartis. N. Steeghs: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Bristol-Myers Squibb, Ellipses Pharma; Financial Interests, Personal, Advisory Board: GSK, Incyte; Financial Interests, Institutional, Local PI: Abbvie, Actuate Therapeutics, Amgen, Anaveon, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, CellCentric, Cogent Biosciences, Crescendo Biologics, Deciphera, Exelixis, Genentech, GSK, IDRx, Immunocore, Incyte, Janssen, Kling Biotherapeutics, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Pfizer, Revolution Medicin, Roche, Sanofi, Sanofi, Seattle Genetics, Seattle Genetics, Taiho, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Blueprint Medicines, Deciphera, GSK, Lixte, Merck, Novartis, Pfizer, Roche, Zentalis. R.H. Mathijssen: Financial Interests, Institutional, Invited Speaker: Bayer, Novartis; Financial Interests, Institutional, Advisory Board: Servier, NaDeNo Nanoscience; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis, Nordic Pharma; Financial Interests, Institutional, Coordinating PI: Pamgene; Financial Interests, Institutional, Funding: Echo Pharmaceuticals, Deuter Oncology. All other authors have declared no conflicts of interest.