Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Breast Cancer: More Breakthroughs and an Embarrassment of Riches

Two oral cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors have thus far been approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal patients with advanced or metastatic, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. For such patients, either palbociclib or ribociclib can be used in combination with an aromatase inhibitor (AI) as initial therapy, or palbociclib can be used in combination with fulvestrant after prior endocrine therapy.1-3 The data suggest a drug-class effect, with similar improvements in the hazard ratio for progression-free survival of approximately 0.57 when palbociclib (PALOMA-2 [Palbociclib: Ongoing Trials in the Management of Breast Cancer 2]) or ribociclib (MONALEESA-2, ie, Mammary Oncology Assessment of LEE011's [Ribociclib's] Efficacy and Safety) are added to an AI in the first-line setting. Patients in the control arms of both studies (treated with an AI alone) initially did well, with an observed response rate of 70%. Both drugs cause mild toxicity that resembles chemotherapy effects, including a small risk of QT interval prolongation with ribociclib and similar rates of neutropenia due to quiescence of hematologic progenitors that is easily reversible with protocol-specified dose reductions.1-3 Subgroup analyses have demonstrated benefit across all patient and disease characteristics. Markers predictive of response/resistance have yet to be identified, and controlled studies testing the role of continuing a CDK4/6 inhibitor on progression are needed.

In the article that accompanies this editorial, Sledge et al4 report the results of MONARCH 2, a randomized trial of another CDK4/6 inhibitor, abemaciclib, which received FDA-designated breakthrough therapy designation in combination with fulvestrant in a design similar to PALOMA-3.2 Study participants were permitted to have experienced progression on endocrine therapy or to have relapsed within 12 months of completing adjuvant endocrine therapy. Initially dosed at 200 mg twice daily, abemaciclib was reduced to 150 mg twice daily after 27.4% of patients enrolled. In the intention-to-treat analysis, progression-free survival was 16.4 months in the abemaciclib/fulvestrant-treated group of MONARCH 2 compared with 9.3 months in the fulvestrant alone group (hazard ratio, 0.55; 95% CI, 0.45 to 0.68), and the overall response rate was 48%. The most common adverse effect was diarrhea, leading to a dose reduction in 30% of participants, and fatigue was more common than reported in the studies of palbociclib and ribociclib. Although less common than with the other two agents, grade 3 neutropenia still occurred in 24% of participants.4

The overall response rate achieved with abemaciclib plus fulvestrant in MONARCH 2 is reported as the highest observed in a phase III study of patients who had disease progression on prior endocrine therapy. This may be partly explained by more restrictive eligibility criteria; prior chemotherapy for metastatic disease had been administered to one third of patients treated with palbociclib and fulvestrant in PALOMA-3 whereas none was allowed in MONARCH 2.

Going forward, how will clinicians incorporate the results of MONARCH 2 into their clinical decision making? Do we need three drugs in the same class for the treatment of the same disease? Can these agents be used interchangeably? Given that the response to the CDK4/6 inhibitors thus far seems to be a class-specific effect, one would imagine that once a patient experiences progression on one CDK4/6 inhibitor, there would be no benefit to changing to another, although this has not been formally tested. At the same time, the minor differences in their toxicity profiles may lead to a switch from one drug in the class to another, much as is done with the AIs. An advantage of abemaciclib is that continuous dosing may be simpler for patients, which may balance the inconvenience of twice-daily dosing (an inconvenience already offset by the fact that most patients with advanced disease are likely to be on other twice- or thrice-daily medications before beginning treatment with a CDK4/6 inhibitor). In addition, abemaciclib is suggested to have CNS penetration in preclinical and clinical samples,5 which may be an advantage in the treatment of patients with brain metastases. Conversely, CNS penetration may eventually be found to cause greater toxicity.

The speed of development of all three CDK4/6 inhibitors is a testimony to efforts by the US FDA and its breakthrough therapy designation mechanism established by the FDA Safety and Innovation Act of 2012. This designation results in more intensive guidance and greater organizational commitment by the agency earlier in the development of drugs for the treatment of life-threatening diseases. It may also result in a priority review of the drug and allow smaller clinical trials, alternative drug designs, and use of surrogate end points.6 However, the breakthrough therapy designation and access to fast track do not minimize the fact that approved drugs still commonly enter clinical practice with minimal accumulated experience among prescribing clinicians.

At this time, individual clinicians have limited experience prescribing the CDK4/6 inhibitors in real-world settings. Little is known regarding the potential for drug-drug interactions, other than with strong CYP3A inhibitors and inducers. The observed QT interval prolongation caused by ribociclib, albeit infrequent, may pose a challenge for its use in routine practice and possibly later on in the adjuvant setting.3 Also, toxicities thus far observed in the controlled setting of clinical trials may become more consequential as use of the CDK4/6 inhibitors extends into more routine clinical practice, especially in patients who have received multiple lines of therapy or who would not have been eligible for the clinical trials by virtue of poorer performance status. Therefore, postmarketing surveillance must be encouraged and streamlined to build a shared knowledge base beyond the boundaries of the three individual pharmaceutical companies. If rigorous privacy protections are in place, rapid-learning health systems (...)

Journal of Clinical Oncology , éditorial en libre accès, 2016

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