Abstract 4607: Pharmacokinetic analysis of palbociclib and association with safety/efficacy in patients with HR-positive/HER2-negative advanced breast cancer: Result from PATHWAY trial

Abstract Background: We recently reported that the combination of palbociclib and tamoxifen significantly extended progression-free survival (PFS) in patients with HR+/HER2- advanced breast cancer, in both pre-, peri-, and post- menopausal Asian patients versus tamoxifen alone (PATHWAY trial, NCCH1607, NCT03423199). Here, we report on palbociclib pharmacokinetic (PK) analysis results and their relationship to adverse events and PFS. Methods: In the PATHWAY study, 184 patients were randomized to palbociclib plus tamoxifen group (91 patients) or placebo plus tamoxifen group (93 patients). Blood samples were collected to assess steady-state trough plasma concentrations of palbociclib (at C1D15 and C2D15). PK data from patients who had been administered 125 mg of palbociclib or placebo once daily for seven consecutive days before sample collection, and for whom samples were collected within 24 hours ± 10% of the dose administered the day prior to sample collection, were used in the analysis. All the PK analyses were performed using LC/MS/MS. The study has been conducted as a Clinical Research Collaboration with the National Cancer Center Hospital as the regulatory study sponsor and Pfizer providing drug and financial support. Results: A total of 171 patients were included in the analysis: 82 in the palbociclib group and 89 in the placebo group. In the palbociclib group, 82 patients had samples collected at C1D15, and 47 at C2D15, and the median palbociclib concentration (interquartile range) was 84.8 (62.45 - 104.75) ng/mL and 67.9 (51.75 - 80.05) ng/mL, respectively. In the quartile analysis of palbociclib C1D15 PK, the lowest quartile (Q1) group tended to have a higher rate of progressive disease than the other quartile groups (Q2-4) (Q1 vs Q2-4, 14.3% vs 1.6%). In terms of adverse events, the frequency of hematological toxicities such as neutropenia and thrombocytopenia increased in both cycle one and the entire treatment period, in correlation with the quartile of palbociclib C1D15 PK. On the other hand, the frequency of dose reductions also increased in correlation with the quartile. Finally, PFS in the Q1 group was comparable to placebo but significantly shorter than in the Q2-4 group (median PFS 95% confidence interval) Placebo; 11.1 (8.5 - 14.9) months, Q1; 9.5 (5.4 - NR) months, Q2-4; 29.5 (20 - 38.2) months, p=0.033). Conclusion: In combination therapy with palbociclib and tamoxifen for HR+/HER2- advanced breast cancer, the palbociclib PK at C1D15 correlated with the frequency of hematological toxicity. At the same time, patients with lower exposures of palbociclib may not benefit in terms of PFS. Further accumulation of real-world PK data may lead to optimization of palbociclib dosing, which in turn could potentially reduce adverse events and improve survival outcomes. Citation Format: Kazuki Sudo, shigehiro Yagishita, Emi Noguchi, Naohito Yamamoto, Takashi Yamanaka, Hirohumi Mukai, Chi-Feng Chung, Yen-Shen Lu, Joo Hyuk Sohn, Kyung Hun Lee, Soo Chin Lee, Tsutomu Iwasa, Hiroji Iwata, Kenichi Watanabe, Kyung Hae Jung, Yuko Tanabe, Seok Yun Kang, Hiroyuki Yasojima, Kenjirou Aogi, Eriko Tokunaga, Sung Hoon Sim, Yoon Sim Yap, Koji Matsumoto, Ling-Ming Tseng, Yuko Mori, Yoshiko Umeyama, Yuki Kojima, Tomomi Hata, Aya Kuchiba, Taro Shibata, Kenichi Nakamura, Yasuhiro Fujiwara, Akinobu Hamada, Kenji Tamura, Kan Yonemori. Pharmacokinetic analysis of palbociclib and association with safety/efficacy in patients with HR-positive/HER2-negative advanced breast cancer: Result from PATHWAY trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4607.