Manageable Safety Profiles

CDK4/6 inhibitors differ in their side effect profiles. Neutropenia is the most common adverse event for palbociclib and ribociclib.12 CDK4/6 inhibitor-associated neutropenia is more rapidly reversible than is the case with cytotoxic drugs.12 Palbociclib is also associated with leukopenia, nausea, and fatigue, whereas cardiac toxicity (QT prolongation) and liver toxicity are seen in patients who receive ribociclib.12

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“Patients on such therapies need to have their complete blood counts monitored every 4 weeks before commencing a new cycle of treatment,” Dr Murphy said. “They should be aware of the risk of febrile neutropenia — although thankfully this is rare — and be prepared to present for urgent evaluation if they become febrile or unwell.”

Abemaciclib has not yet been approved by the FDA but has notably lower rates of neutropenia but higher rates of diarrhea, noted Dr Murphy.

“Patients receiving abemaciclib as a single agent would be more heavily pretreated and have fewer treatment options, and may be more accepting of diarrhea as a side effect,” he said. “In the first- or second-line setting however, treatment would be expected to continue for months or even years, and patients may be less accepting of diarrhea unless there is a clear efficacy advantage to abemaciclib over its competitors.”

Also, thinning hair is more common than what is seen in patients taking letrozole alone, and this can be a source of distress for patients, Dr Murphy added.

“There are also potential drug̶drug interactions that must be taken into account,” he emphasized. “In my practice, I consider the addition of CDK4/6 inhibition to endocrine therapy for the majority of patients with advanced HR-positive breast cancer, but there are certain patients where concerns regarding ability to comply with complex instructions and/or travel for frequent assessments preclude this.”

Acquired Resistance

Not surprisingly, acquired drug resistance is an emerging problem.

“It is unfortunately true that resistance is virtually guaranteed to emerge with any therapies targeting intracellular signalling pathways,” Dr Murphy said.

“This is an area of active research and, like with other agents, there likely is not only 1 mechanism,” Dr Finn said. “Laboratory and small clinical experiences suggest loss of RB, gains in CDK6, cyclin E expression have been implicated.”

A potential strategy for preventing resistance is to combine inhibitors that target multiple nodes in a signalling pathway, thereby preventing feedback inhibition, Dr Murphy said. There is evidence that adding CDK4/6 inhibitors to the combination of endocrine therapy and PI3K inhibitors might overcome intrinsic and acquired resistance to the PI3K inhibitors, he noted.

CDK12 inhibition can reverse intrinsic and acquired PARP inhibitor resistance in xenograft models of triple-negative breast cancer, Dr Shapiro and colleagues have found.15

The Road Ahead

“The bar has been raised significantly for the development of new combinations in ER-positive breast cancer,” noted Dr Finn. “While novel combinations are being pursued, there will need to be very significant gains to show improvements above the 24 or 25 months PFS of AI and CDK4/6 inhibitors. Our preclinical data from 2009 suggested a role in HER2-positive disease and that is now an area of active research.”

Dr Finn also anticipates important insights from studies of CDK4/6 inhibitors in the treatment of early breast cancer.   

“Can we cure more women over endocrine therapy alone and can we remove the need for chemotherapy in the adjuvant treatment of ER+ breast cancer?”, he posited. “That would be great.”

References

  1. Shah AN, Cristofanilli M. The growing role of CDK4/6 inhibitors in treating hormone receptor-positive advanced breast cancer. Curr Treat Options Oncol. 2017;18(1):6. doi: 10.1007/s11864-017-0443-7
  2. Murphy CG, Dickler MN. The role of CDK4/6 inhibition in breast cancer. Oncologist. 2015;20(5):483-490.
  3. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17. doi: 10.1186/s13058-015-0661-5
  4. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417-430. doi: 10.1038/nrclinonc.2016.26
  5. Xu H, Yu S, Liu Q, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10:97. doi: 10.1186/s13045-017-0467-2
  6. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC). J Clin Oncol. 2017;35(15_suppl):1038.
  7. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748.
  8. Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017 June 26. doi: 10.1634/theoncologist.2017-0072
  9. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.
  10. Sledge GW, Masakazu T, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585
  11. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell cancer, and other solid tumors. Cancer Discov. 2016;6(7):740-753.
  12. Spring LM, Zangardi ML, Moy B, Bardia A. Clinical management of potential toxicities and drug interactions related to cyclin-dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations. Oncologist. 2017 Jul 13. [Epub ahead of print]. doi: 10.1634/theoncologist.2017-0142
  13. Lilly’s MONARCH-3 and RANGE phase III readouts for advanced breast and urothelial cancers. European Society for Medical Oncology website. http://www.esmo.org/Conferences/ESMO-2017-Congress/Press-Media/Press-Releases/Abemaciclib-Initial-Therapy-Improves-Outcome-in-Endocrine-sensitive-Advanced-Breast-Cancer. Published September 10, 2017. Accessed September 10, 2017.
  14. Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548:471-475. doi: 10.1038/nature23465
  15. Johnson SF, Cruz C, Greifenberg AK, et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 2016;17(9):2367-2381.

Topics:

Breast Cancer