Advertisement

Targeted Oncology

, Volume 12, Issue 3, pp 373–383 | Cite as

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer

  • Esther S. Kim
  • Lesley J. Scott
Adis Drug Evaluation

Abstract

Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

Keywords

Endocrine Therapy Metastatic Breast Cancer Letrozole Anastrozole National Comprehensive Cancer Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

During the peer review process, the manufacturer of palbociclib was offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflicts of Interest

Esther Kim and Lesley Scott are salaried employees of Adis/Springer, are responsible for the article content and declare no relevant conflicts of interest.

References

  1. 1.
    International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. 2016. http://globocan.iarc.fr. Accessed 26 Apr 2017.
  2. 2.
    American Cancer Society. Breast cancer. 2016. http://www.cancer.org. Accessed 7 Nov 2016.
  3. 3.
    Breastcancer.org. What is hormonal therapy? 2016. http://www.breastcancer.org. Accessed 26 Apr 2017.
  4. 4.
    Garrido-Castro AC, Metzger-Filho O. Novel strategies in hormone receptor-positive advanced breast cancer: overcoming endocrine resistance. Curr Breast Cancer Rep. 2016;8(4):193–205.CrossRefGoogle Scholar
  5. 5.
    Koehler M, VanArsdale TL, Shields D, et al. Mechanism of action for combined CDK4/6 and ER inhibition in ER positive breast cancer [abstract no. 60P]. Ann Oncol. 2014;25(Suppl 1):i21–2.CrossRefGoogle Scholar
  6. 6.
    Pfizer Laboratories. IBRANCE® (palbociclib) capsules for oral use: US prescribing information. 2017. https://www.fda.gov. Accessed 26 Apr 2017.
  7. 7.
    European Medicines Agency. Ibrance hard capsules: summary of product characteristics. 2017. http://ema.europa.eu. Accessed 26 Apr 2017.
  8. 8.
    Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–38.PubMedGoogle Scholar
  9. 9.
    Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Alves CL, Elias D, Lyng M, et al. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(22):5514–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Hu W, Sung T, Jessen BA, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res. 2016;22(8):2000–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Zheng J, Amantea M, Wang D. Effect of palbociclib concentration on heart rate-corrected QT interval in patients with cancer [abstract no. P5–19-16]. Cancer Res. 2015;75(9 Suppl).Google Scholar
  13. 13.
    Ruiz-Garcia A, Gauthier E, Durairaj C, et al. Evaluation of the effects of palbociclib (PAL) + letrozole (LET) on QTc [abstract no. P4–22-10 plus poster]. Cancer Res. 2017;77(4 Suppl).Google Scholar
  14. 14.
    Iwata H, Im S-H, Masuda N, et al. PALOMA-3: phase III trial of fulvestrant with or without palbociclib in premenopausal and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer that progressed on prior endocrine therapy—safety and efficacy in Asian patients. J Glob Oncol. 2017; doi: 10.1200/JGO.2016.008318.Google Scholar
  15. 15.
    Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.CrossRefPubMedGoogle Scholar
  16. 16.
    Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925–36.CrossRefPubMedGoogle Scholar
  17. 17.
    Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209–19.CrossRefPubMedGoogle Scholar
  18. 18.
    Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425–39.CrossRefPubMedGoogle Scholar
  19. 19.
    Pfizer Inc. Pfizer's novel CDK 4/6 inhibitor palbociclib plus letrozole significantly prolonged progression-free survival in patients with advanced breast cancer [media release]. 6 Apr 2014. http://www.pfizer.com.
  20. 20.
    Finn R, Jiang Y, Rugo H, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER+/HER2- advanced breast cancer (ABC) [abstract no. LBA15 plus poster]. In: 41st Congress of the European Society for Medical Oncology 2016.Google Scholar
  21. 21.
    Rugo H, Dieras V, Gelmon K, et al. Impact of palbociclib plus letrozole on health-related quality of life compared with letrozole alone in treatment-naive postmenopausal patients with ER+ HER2− advanced/metastatic breast cancer: results from PALOMA-2 [poster no. 2627]. In: 41st Congress of the European Society for Medical Oncology 2016.Google Scholar
  22. 22.
    Finn RS, Crown JP, Ettl J, et al. Treatment patterns of post-disease progression in the PALOMA-1/TRIO-18 trial [abstract no. P4–13-02]. Cancer Res. 2016;76(4 Suppl).Google Scholar
  23. 23.
    Rugo HS, Turner NC, Finn RS, et al. Palbociclib in combination with endocrine therapy in treatment-naive and previously treated elderly women with HR+, HER2- advanced breast cancer: a pooled analysis from randomized phase 2 and 3 studies [abstract no. P4–22-03 plus poster]. Cancer Res. 2017;77(4 Suppl).Google Scholar
  24. 24.
    Turner NC, André F, Cristofanilli M, et al. Treatment postprogression in women with endocrine-resistant HR+/HER2- advanced breast cancer who received palbociclib plus fulvestrant in PALOMA-3 [abstract no. P4–22-06 plus poster]. Cancer Res. 2017;77(4 Suppl).Google Scholar
  25. 25.
    Loibl S, Turner NC, Ro J, et al. Palbociclib (PAL) in combination with fulvestrant (F) in pre−/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy - results from Paloma-3 [abstract no. 524 plus poster]. J Clin Oncol. 2016;34(15 Suppl).Google Scholar
  26. 26.
    Loibl S, De Michele AM, Turner NC, et al. Impact of palbociclib plus fulvestrant on patient-reported general health status compared with fulvestrant alone in HR+/HER2– metastatic breast cancer [poster no. 2199]. In: 41st Congress of the European Society for Medical Oncology 2016.Google Scholar
  27. 27.
    Finn RS, Crown JP, Ettl J, et al. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res. 2016; doi: 10.1186/s13058-016-0721-5.Google Scholar
  28. 28.
    Bell T, Crown JP, Lang I, et al. Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment. Curr Med Res Opin. 2016;32(5):959–65.CrossRefPubMedGoogle Scholar
  29. 29.
    Im S-A, Mukai H, Park I-H, et al. Palbociclib (PAL) plus letrozole (L) as first-line (1L) therapy (tx) in postmenopausal Asian women with estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2-) metastatic breast cancer (mBC) [abstract no. 1160]. Ann Oncol. 2016;27(Suppl 9).Google Scholar
  30. 30.
    Fribbens C, O'Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34(25):2961–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Harbeck N, Iyer S, Turner N, et al. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016;27(6):1047–54.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Verma S, Bartlett CH, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist. 2016;21(10):1165–75.CrossRefPubMedGoogle Scholar
  33. 33.
    Patt DA, Mitra D, Harrell RK, et al. Early treatment utilization of palbociclib for metastatic breast cancer (MBC) in a U.S. community oncology network [abstract no. e18112]. J Clin Oncol. 2016;34(15 Suppl)Google Scholar
  34. 34.
    Stearns V, Smith JW II, Patel R, et al. Safety results of the US expanded access program (EAP) of palbociclib in combination with letrozole as treatment of post-menopausal women with hormone-receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) for whom letrozole therapy is deemed appropriate [abstract no. P4–13-05 plus poster]. Cancer Res. 2016;(4 Suppl):76.Google Scholar
  35. 35.
    Diéras V, Rugo HS, Gelmon K, et al. Long-term safety of palbociclib in combination with endocrine therapy in treatment-naive and previously treated women with HR+ HER2- advanced breast cancer: a pooled analysis from randomized phase 2 and 3 studies [abstract no. P4–22-07 plus poster]. Cancer Res. 2017;77(4 Suppl)Google Scholar
  36. 36.
    Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34(25):3069–103.CrossRefPubMedGoogle Scholar
  37. 37.
    Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(29):3307–29.CrossRefPubMedGoogle Scholar
  38. 38.
    Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol. 2017;28(1):16–33.Google Scholar
  39. 39.
    Pfizer Inc. Pfizer receives U. S. FDA accelerated approval of IBRANCE® (palbociclib) [media release]. 3 Feb 2015. http://www.pfizer.com.
  40. 40.
    Pfizer. IBRANCE® (palbociclib) receives approval in European Union for the treatment of women with HR+/HER2- metastatic breast cancer [media release]. 10 Nov 2016. http://www.pfizer.com.
  41. 41.
    National Comprehensive Cancer Network. Breast cancer (version 2.2017). 2017. https://www.nccn.org. Accessed 26 Apr 2017.
  42. 42.
    Chirila C, Mitra D, Colosia A, et al. Efficacy of palbociclib combinations versus endocrine therapies in advanced/ metastatic breast cancer: network meta-analysis [abstract no. PCN13 plus poster]. Value Health. 2016;19(7):A710.CrossRefGoogle Scholar
  43. 43.
    Wilson FR, Varu A, Mitra D, et al. Network meta-analysis comparing palbociclib with chemotherapies for treatment of postmenopausal women with HR+/ HER2- advanced/ metastatic breast cancer [abstract no. PCN36 plus poster]. Value Health. 2016;19(7):A714.CrossRefGoogle Scholar
  44. 44.
    Lee NV, Eisele KJ, Chionis J, et al. Mechanisms of resistance to CDK4/6 inhibition in ER+ breast cancer [abstract no. P3–06-01 plus poster]. Cancer Res. 2016;76(4 Suppl)Google Scholar
  45. 45.
    Lenihan C, Bouchekioua-Bouzaghou K, Shia A, et al. Characterization of resistance to the selective CDK4/6 inhibitor palbociclib in ER positive breast cancer [abstract no. P3–06-02]. Cancer Res. 2016;76(4 Suppl)Google Scholar
  46. 46.
    Matter-Walstra K, Schwenkglenks M, Brauchli P, et al. A cost-effectiveness analysis of palbociclib plus letrozole as first-line treatment for estrogen receptor-positive, HER2-negative metastatic breast cancer [abstract no. 567]. J Clin Oncol. 2016;34(15 Suppl)Google Scholar
  47. 47.
    Bhattacharya K, Yang Y. A cost-effectiveness analysis of palbociclib and other aromatase inhibitors for treatment of advanced breast cancer [abstract no. PCN90 plus poster]. Value Health. 2016;19(3):A150.Google Scholar
  48. 48.
    Matter-Walstra K, Ruhstaller T, Klingbiel D, et al. Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK). Breast Cancer Res Treat. 2016;158(1):51–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Matter-Walstra K, Schwenkglenks M, Dedes KJ. Cost-effectiveness of palbociclib plus letrozole versus letrozole alone as a first-line treatment in women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. Breast Cancer Res Treat: Revised results for the Swiss health care setting; 2017. doi: 10.1007/s10549-017-4209-5.Google Scholar
  50. 50.
    Finn RS, Martin M, Rugo HS, et al. Paloma-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- advanced breast cancer (ABC) [abstract no. 507]. J Clin Oncol. 2016;34(15 Suppl)Google Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

Personalised recommendations