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Medical Crossfire®: Expert Perspectives on the Emerging Role of CDK4/6 Inhibitors for the Management of Metastatic Breast Cancer PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap


Current Challenges in the Management of Metastatic Breast Cancer, CDK4/6 Inhibitor Mechanisms, and Key Findings From Clinical Trials

This first of 3 PER Pulse™ Recaps focuses on current challenges pertaining to the treatment of hormone receptor‒positive (HR+), metastatic breast cancer, the mechanistic rationale for the development of CDK4/6 inhibitors, and key findings from clinical trials assessing the role of CDK4/6 inhibitors in the treatment of breast cancer.

Although aromatase inhibitors have remained an essential component in the treatment of patients with breast cancer, resistance to AI therapy and other available options is common, and this resistance often necessitates the use of new sequences and combinations, as well as consideration of novel treatment options. There are multiple mechanisms of endocrine therapy resistance, including alteration of cell signaling in multiple pathways.1 Success has been seen with the combination of an mTOR antagonist and exemestane, as well as the addition of CKD 4/6 inhibitor therapy to letrozole.1-3

Cyclin-dependent kinases (CDKs) are a group of proteins that influence cell cycle progression. This activity depends on association with protein regulators called cyclins, which activate the catalytic activity of their CDK partners.4 CDK4 and CDK6 (CDK4/6) work in conjunction with cyclin D1 to regulate cell cycle progression.5 Both CDK4/6 overexpression and D1 amplification occur in patients with HR+ breast cancers, and play a role in the emergence of endocrine resistance.6,7 CDK4/6 inhibitors, which arrest cell cycle progression in the G1 phase, have been studied extensively in patients with metastatic breast cancer, with 2 therapies currently approved and a third in phase III development.

PALOMA-28 and PALOMA-39 were key randomized phase III studies that showed significant improvements in progression-free survival (PFS) when palbociclib was paired with endocrine therapy compared with placebo plus endocrine therapy. Improvements in response rates were also seen.8,9 The MONALEESA-2 trial10 evaluated ribociclib in combination with letrozole in the first-line setting, and also showed a significant improvement in PFS and overall response rate (ORR).

Abemaciclib has demonstrated single-agent activity in the MONARCH1 trial,11 with an ORR of 20% and a clinical benefit rate of 42% in patients with estrogen receptor‒positive, metastatic breast cancer. Ongoing phase III trials (MONARCH2 and MONARCH3) are investigating abemaciclib in combination with fulvestrant or a nonsteroidal aromatase inhibitor, respectively. Recently, it was announced that both of these trials met their primary endpoint of improved PFS in abemaciclib-treated patients.

Even with these developments, several key questions remain regarding optimizing treatment of patients with HR+ metastatic breast cancer. Future studies will help to provide insight into which settings and combinations can further optimize the use of CDK4/6 inhibitors, as well as clarification of testing modalities in assessing the evolution of estrogen receptor‒positive, metastatic breast cancer.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources.

References

  1. Johnston SR. Enhancing endocrine therapy for hormone receptor-positive advanced breast cancer: cotargeting signaling pathways. J Natl Cancer Inst. 2015;107(10). doi: 10.1093/jnci/djv212.
  2. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. doi: 10.1056/NEJMoa1109653.
  3. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as dirst-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. doi: 10.1016/S1470-2045(14)71159-3.
  4. 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.
  5. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 2016;45:129-138. doi: 10.1016/j.ctrv.2016.03.002.
  6. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi: 10.1038/nature11412.
  7. Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol. 2013;10(4):191-210. doi: 10.1038/nrclinonc.2013.29.
  8. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
  9. 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):425-439. doi: 10.1016/S1470-2045(15)00613-0.
  10. 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. doi: 10.1056/NEJMoa1609709.
  11. Dickler MN, Tolaney SM, Rugo HS, et al: MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Presented at: the 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 510. http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.510.


2 of 3
PER Pulse™ Recap

Application of CDK4/6 Inhibitor Use in Contemporary Clinical Practice

This second of 3 PER Pulse™ Recaps focuses on clinical application of CDK4/6 inhibitors in the management of patients with hormone receptor‒positive (HR+), metastatic breast cancer. The faculty discuss the clinical application of data from key clinical trials, using a variety of patient scenarios to address the merits of different treatment approaches, including patients with de novo ER+ metastatic breast cancer as well as those who have had several years of aromatase inhibitor therapy. The panel of experts also addresses patients with minimal disease burden, as well as clinical considerations for effective management of potential toxicities associated with the use of CDK4/6 inhibitors.

A subgroup analysis of the MONALEESA-2 study1 of patients with de novo HR+/HER2-negative, advanced breast cancer showed that PFS improved significantly in the group treated with ribociclib plus letrozole compared with the group that received letrozole alone. The 12-month, progression-free survival (PFS) rate was 82% for the ribociclib-plus-letrozole group compared with 66% for the letrozole-alone group.1 In PALOMA-3, 21% of the patients in each of the comparison groups were pre- or perimenopausal, and the combination of palbociclib and fulvestrant showed significant improvement in PFS regardless of menopausal state.2

The toxicity profiles of palbociclib and ribociclib are characterized primarily by the common appearance of neutropenia due to their inhibition of CDK4/6.3 Grade 3/4 neutropenia has been reported in the majority of patients receiving palbociclib in key clinical trials, such as PALOMA-23 and PALOMA-3.3 Most neutropenic events are grade 3, and it is very unusual to see febrile neutropenia or infections.2-4 Palbociclib is administered on a schedule of 3 weeks of treatment, followed by 1 week off treatment. Patients may be unaware of being neutropenic, necessitating periodic complete blood count assessment.4 Patients may also experience anemia, thrombocytopenia, fatigue, sore mouth, hair thinning, and other side effects.5 Ribociclib, like palbociclib, is administered on a 3-weeks-on, 1-week-off routine.6 Ribociclib also has a potential toxicity profile that includes neutropenia, which needs to be monitored regularly; ribociclib has also been associated with QTc prolongation.6,7 Guidance pertaining to monitoring and dosage adjustments for these treatments is detailed in the prescribing information.5,6

While the toxicity profiles of palbociclib and ribociclib highlight concerns regarding neutropenia and fatigue, abemaciclib has been associated more commonly with fatigue and gastrointestinal toxicities, including diarrhea. In the MONARCH1 study,8 19.7% of patients experienced treatment-related grade 3 diarrhea. In the neoMONARCH study,9 patients were treated prophylactically with loperamide every 12 hours during the first 28 days of receiving abemaciclib. Although more than half of patients experienced problems with diarrhea, the majority of cases were grade 1 or grade 2.9

For additional commentary about these topics and others, visit www.gotoper.com to access more resources.

References

  1. O’Shaughnessy J, Petrakova K, Sonke GS, et al. First-line ribociclib letrozole in patients with de novo HR+, HER2– advanced breast cancer (ABC): a subgroup analysis of the MONALEESA-2 trial. Presented at: the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P4-22-05.
    doi: 10.1158/1538-7445.SABCS16-P4-22-05.
  2. 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):425-439. doi: 10.1016/S1470-2045(15)00613-0.
  3. Rugo HS, Vidula N, Ma C. Improving response to hormone therapy in breast cancer: new targets, new therapeutic options. Am Soc Clin Oncol Educ Book. 2016;35:e40-e54. doi: 10.14694/EDBK_159198.
  4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
  5. IBRANCE [prescribing information]. New York, NY: Pfizer Inc; April 2017.
  6. KISQALI) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2017.
  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. doi: 10.1056/NEJMoa1609709.
  8. Dickler MN, Tolaney SM, Rugo HS, et al: MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Presented at: the 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 510. http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.510.
  9. Hurvitz S, Martin M, Fernández Abad M, et al. Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with hormone receptor–positive, HER2-negative breast cancer. Presented at: the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S4-06. http://www.abstracts2view.com/sabcs/view.php?nu=SABCS16L_917&terms=.

3 of 3
PER Pulse™ Recap

Unanswered Clinical Questions and Ongoing Clinical Investigations of CDK4/6 Inhibitor Applications

This third of 3 PER Pulse™ Recaps focuses on clinical questions that may soon be answered by ongoing clinical investigations evaluating CDK4/6 inhibitors. The faculty discuss a wide range of studies, such as the neoMONARCH study of abemaciclib in the neoadjuvant treatment of postmenopausal patients with hormone receptor‒positive (HR+), HER2- breast cancer.1 In this study, abemaciclib +/- anastrozole significantly lowered Ki67 expression compared with anastrozole alone.1

Dosing schedules of CDK4/6 inhibitor therapy are currently undergoing investigation, such as a study assessing the combination of ribociclib and fulvestrant in the treatment of patients with HR+, HER2- advanced breast cancer.2 There are several ongoing trials that are also addressing the challenge of breast cancer cell resistance to CDK4/6 inhibitors, as multiple mechanisms for this phenomenon may exist.3 New combinations and sequences may help to overcome these challenges.4,5 Studies looking at the use of CDK4/6 inhibitors in the neoadjuvant setting6-9 and in patients who are HER2+10-12 are also underway.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources.

References

  1. Hurvitz S, Martin M, Fernández Abad M, et al. Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with hormone receptor–positive, HER2-negative breast cancer. Presented at: the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S4-06. http://www.abstracts2view.com/sabcs/view.php?nu=SABCS16L_917&terms=.
  2. Tolaney SM, Forero-Torres A, Boni V, et al. Ribociclib plus fulvestrant in postmenopausal women with HR+, HER2- advanced breast cancer. Presented at the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P4-22-12. doi: 10.1016/j.breast.2016.06.008.
  3. Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer [erratum appears in Cancer Res.2016; 6(19):5907]. Cancer Res. 2016;76(8):2301-2313. doi: 10.1158/0008-5472.CAN-15-0728. 
  4. Mundi PS, Codruta C, Accordino MK, et al. A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer. Presented at the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract OT2-01-19. http://abstracts.asco.org/199/AbstView_199_186255.html.
  5. Bardia A, Hurvitz S, Yardley DA, et al. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2- advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor. Presented at the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract OT2-01-05. doi: 10.1158/1538-7445.SABCS16-OT2-01-05.
  6. Neoadjuvant response-guided treatment of luminal B-type tumors and luminal A-type tumors with node metastases (PREDIX LumB). clinicaltrials.gov/ct2/show/NCT02603679. Updated September 6, 2016. Accessed June 12, 2017.
  7. Neoadjuvant response-guided treatment of slowly proliferating hormone receptor positive tumors (PREDIX LumA). clinicaltrials.gov/ct2/show/NCT02592083. Updated September 7, 2016. Accessed June 12, 2017.
  8. A phase II randomized study evaluating the biological and clinical effects of the combination of palbociclib with letrozole as neoadjuvant therapy in post-menopausal women with estrogen-receptor positive primary breast cancer (PALLET). clinicaltrials.gov/ct2/show/NCT02296801. Updated March 27, 2017. Accessed June 12, 2017.
  9. Letrozole plus ribociclib or placebo as neo-adjuvant therapy in ER-positive, HER2-negative early breast cancer (FELINE). clinicaltrials.gov/ct2/show/NCT02712723. Updated February 17, 2017. Accessed June 12, 2017.
  10. A study of abemaciclib (LY2835219) in women With HR+, HER2+ locally advanced or metastatic breast cancer (monarcHER). clinicaltrials.gov/ct2/show/NCT02675231. Updated June 2, 2017. Accessed June 12, 2017.
  11. Neoadjuvant study of palbociclib in combination with letrozole and trastuzumab in stage II-III ER+ HER2+ breast cancer (PALTAN).  clinicaltrials.gov/ct2/show/NCT02907918. Updated June 6, 2017. Accessed June 12, 2017.12. "Neo-adjuvant treatment with palbociclib: effect on Ki67 and apoptosis before, during and after treatment " (NA-PHER2). clinicaltrials.gov/ct2/show/NCT02530424. Updated April 7, 2016.






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