Neutropenia management with palbociclib in Japanese patients with advanced breast cancer

Norikazu Masuda, Hirofumi Mukai, Kenichi Inoue, Yoshiaki Rai, Shinji Ohno, Yuko Mori, Satoshi Hashigaki, Yasuaki Muramatsu, Yoshiko Umeyama, Hiroji Iwata, Masakazu Toi, Norikazu Masuda, Hirofumi Mukai, Kenichi Inoue, Yoshiaki Rai, Shinji Ohno, Yuko Mori, Satoshi Hashigaki, Yasuaki Muramatsu, Yoshiko Umeyama, Hiroji Iwata, Masakazu Toi

Abstract

Background: The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib, in combination with endocrine therapy (ET), significantly prolonged progression-free survival in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) in PALOMA-2 and PALOMA-3. Neutropenia and palbociclib dose reductions/interruptions occurred more frequently in the Japanese versus overall populations. We evaluated neutropenia patterns, palbociclib dose management, and clinical responses after dose reduction in Japanese patients in PALOMA-2 and PALOMA-3 and a single-arm Japanese phase 2 study.

Methods: PALOMA-2 and the Japanese phase 2 study enrolled postmenopausal women with estrogen receptor-positive, HER2- ABC who had not received prior systemic therapy for advanced disease; PALOMA-3 enrolled women with HR+/HER2- ABC, regardless of menopausal status, whose disease had progressed after prior ET. Palbociclib (125 mg/day) was administered 3 weeks on/1 week off. Dose reduction/interruption, cycle delay, tumor response, and laboratory-assessed neutropenia were analyzed in Japanese patients who received palbociclib.

Results: A total of 101 Japanese patients received palbociclib + ET. Among Japanese patients in the 3 studies, the frequency of all-grade/grade 3/grade 4 neutropenia was 94%/53%/34%, 100%/69%/21%, and 100%/67%/26%, respectively. Twenty (63%), 28 (67%), and 15 (56%) patients required palbociclib dose reduction. Dose interruption or reduction did not affect palbociclib treatment duration, and durable tumor response was observed despite dose reduction.

Conclusion: Neutropenia was manageable with dose modifications, without affecting palbociclib treatment duration or efficacy.

Trial registration: Pfizer (NCT01740427, NCT01684215, NCT01942135).

Keywords: Advanced breast cancer; Cyclin-dependent kinase; Japanese patients; Neutropenia; Palbociclib.

Conflict of interest statement

N. Masuda has received honoraria from Chugai, AstraZeneca, Pfizer, and Takeda and has received research funding from Chugai, AstraZeneca, Kyowa-Kirin, MSD, Novartis, Pfizer, Eli Lilly, and Daiichi Sankyo. H. Iwata has received honoraria and research funding from Pfizer and AstraZeneca and fees for promotional materials from AstraZeneca. H. Mukai and Y. Rai have no conflicts of interest to report. K. Inoue has received research funding from Parexel, Puma Biotechnology, MSD, Novartis, GlaxoSmithKline, Pfizer, Chugai, and Daiichi Sankyo (institutional). S. Ohno has received honoraria from Chugai, AstraZeneca, Pfizer, Novartis, Taiho, Eisai, Kyowa-Hakko Kirin. M. Toi has received honoraria from Novartis, MSD, Takeda, AstraZeneca, Taiho, Chugai, Pfizer, Eisai, Eli Lilly, Kyowa-Hakko Kirin, and Genomic Health Institute; research funding from Novartis, AstraZeneca, Taiho, Chugai, Pfizer, and Eli Lilly; served as a consultant/independent contractor for Kyowa-Hakko Kirin and on an advisory board for Genomic Health Institute. S. Hashigaki and Y. Muramatsu are employees of Pfizer. Y. Mori and Y. Umeyama are employees of and stockholders in Pfizer.

Figures

Fig. 1
Fig. 1
Dosing schedules in Japanese patients. Dosing schedules in Japanese patients who completed the 3/1 schedule, patients with cycle delay, and patients with dose interruption with and without dose reduction during the first 2 cycles in a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib. aPatients with interrupted palbociclib dose and no dose reduction during the first 2 cycles and/or at the start of cycle 3. bPatients with interrupted palbociclib dose and dose reduction during the first 2 cycles and/or at the start of cycle 3. See Supplementary Figure 2 for detail regarding group categorization and dosing schedule examples
Fig. 1
Fig. 1
Dosing schedules in Japanese patients. Dosing schedules in Japanese patients who completed the 3/1 schedule, patients with cycle delay, and patients with dose interruption with and without dose reduction during the first 2 cycles in a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib. aPatients with interrupted palbociclib dose and no dose reduction during the first 2 cycles and/or at the start of cycle 3. bPatients with interrupted palbociclib dose and dose reduction during the first 2 cycles and/or at the start of cycle 3. See Supplementary Figure 2 for detail regarding group categorization and dosing schedule examples
Fig. 2
Fig. 2
Dose levels and treatment duration in Japanese patients with and without dose reduction within 180 days of treatment initiation. a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib
Fig. 2
Fig. 2
Dose levels and treatment duration in Japanese patients with and without dose reduction within 180 days of treatment initiation. a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib
Fig. 3
Fig. 3
Tumor shrinkage in Japanese patients. Changes in tumor size for individual patients without (left) and with (right) dose reduction within 180 days of treatment initiation in a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib
Fig. 4
Fig. 4
Time course of neutrophil count in Japanese patients. Neutrophil counts over time in patients who completed the 3/1 schedule, patients with cycle delay, and patients with dose interruption with and without dose reduction during the first 2 cycles in a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. Abs absolute, BL baseline, FUL fulvestrant, LET letrozole, PAL palbociclib. aPatients with interrupted palbociclib dose and no dose reduction during the first 2 cycles and/or at the start of cycle 3; bpatients with interrupted palbociclib dose and dose reduction during the first 2 cycles and/or at the start of cycle 3. See Supplementary Figure 2 for detail regarding group categorization and dosing schedule examples
Fig. 4
Fig. 4
Time course of neutrophil count in Japanese patients. Neutrophil counts over time in patients who completed the 3/1 schedule, patients with cycle delay, and patients with dose interruption with and without dose reduction during the first 2 cycles in a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. Abs absolute, BL baseline, FUL fulvestrant, LET letrozole, PAL palbociclib. aPatients with interrupted palbociclib dose and no dose reduction during the first 2 cycles and/or at the start of cycle 3; bpatients with interrupted palbociclib dose and dose reduction during the first 2 cycles and/or at the start of cycle 3. See Supplementary Figure 2 for detail regarding group categorization and dosing schedule examples
Fig. 5
Fig. 5
Correlation between baseline and cycle 1 day 15 neutrophil counts in Japanese patients. a PALOMA-2, b Japanese phase 2 study, and c PALOMA-3. FUL fulvestrant, LET letrozole, PAL palbociclib

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Source: PubMed

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