Do All CDK4/6 Inhibitors Treat HR+/HER2- Metastatic Breast Cancer Patients Equally?

 

Another year, and 2017 ESMO annual congress held in Madrid, Spain kept its promise of being busy, exciting and promising with several reports on latest, ground-breaking data.

Resistance to hormonal therapies is a known phenomenon in advanced HR+ breast cancer, and CDK4/6 inhibitors may help overcome this resistance. At a Presidential Symposia on Sunday, September 10, Dr. Angelo Di Leo (Prato, Italy) presented the first Phase III interim analysis of abemaciclib from the MONARCH-3 study. This trial is evaluating abemaciclib as initial therapy for post-menopausal women with HR+/HER2- advanced breast cancer (which represents approximately 70% of advanced breast cancer cases). 493 women were randomized 2:1 to receive either abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). The primary end point (PFS) was met at the time of interim analysis, the PFS benefit with abemaciclib plus NSAI was confirmed by blinded independent central review with HR of 0.5038. After a median follow-up of 17.8 months, the median PFS was not yet reached. An ORR of 59.2% in all patients, and 43.8% in patients with measurable disease was also demonstrated. There is evidence for substantial activity of the drug in combination with an AI in first-line AI sensitive patients, with a safety profile compatible for longer term dosing.

The effect of treatment with abemaciclib was consistently observed across subgroups based on risk reductions. An exploratory analysis suggests that patients with indicators of poor prognosis achieved substantial benefit from the addition of abemaciclib, however, in patients with a long treatment-free interval or bone-only disease, endocrine monotherapy may be appropriate as first-line therapy. Abemaciclib dosed on a continuous schedule was generally well tolerated with 21.1% grade 3/4 neutropenia and 9.5% grade 3 diarrhea. As discussed by Dr. Nicholas Turner, there is likely to be 11-12 months’ improvement in median PFS with more mature data.

Interestingly, the HR value for PFS as a primary endpoint in registration trials (PALOMA-2 & 3, MONALEESA-2 &3) for all CDK4/6 inhibitors is in the range of 0.50 to 0.58. Experts don’t see much of a difference in activity between three key CDK4/6 inhibitors – Ibrance (palbociclib), Kisqali (ribociclib) and abemaciclib – except for abemaciclib having 14 times more potent activity against cyclin D1/CDK4 than cyclin D3/CDK6, although incidence of diarrhea is more than what is seen with other in-class agents, perhaps due to its continuous, daily administration. After such encouraging early data, it will be imperative to understand the long-term effects of abemaciclib, for how long do the patients need to continuously receive it and will price compare with other CDK4/6 brands to compete effectively in the market?

CDK4/6 inhibitors have demonstrated improved PFS in AI-resistant HR+/HER2- metastatic breast cancer exhibiting a “class effect” in this patient subgroup. The NCCN, ASCO and ESMO-ESO ABC3 guidelines now recommend CDK4/6 inhibitors in combination with an AI as the preferred first-line treatment option for post-menopausal, HR+/HER2- metastatic breast cancer patients bolstering it as a rational therapeutic approach. These agents are also being investigated in adjuvant breast cancer (Ibrance in PALLAS, PENELOPE-B; Kisqali in EarLEE-1 and EarLEE-2, abemaciclib in monarchE).

The presented data might have practice changing implications in first-line patients if supported with more collaborative data from meta-analysis. However, two key question themes remain:

  • What is the optimal sequence of treatment in the era of multiple CDK4/6 inhibitors? Which agent should be prescribed first, in which sequence, and should they be used first-line or only added after progression?
  • How can we optimize use of these agents using predictive biomarkers to guide appropriate patient selection?

This is an exciting time for this subgroup of advanced breast cancer when new or “revitalized” treatment options are emerging after more than a decade without any significant improvement. Below is a snapshot of recent drug approvals for management of HR+/HER2- metastatic breast cancer:

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References:

  1. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. 2017 ESMO Annual Meeting Abstract #236O_PR
  2. Turner NC, et al., Lancet 2017; 389-2403-14
  3. Finn RS, et al., N Engl J Med 2016; 375:1925-1936
  4. Hortobagyi GN, et al., N Engl J Med 2016; 375:1738-1748

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