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CDK4/6 Inhibitors for MBC
How I Am Using CDK4/6 Inhibitors for My Patients With Hormone Receptor–Positive MBC

Released: September 21, 2016

Expiration: September 20, 2017

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Recently, I have been asked about the use of CDK4/6 inhibitors for patients with metastatic breast cancer (MBC). In this commentary, I will illustrate some key points regarding the use of this class of agents through a recent case from my practice. The patient was an 82-year-old white female diagnosed 4 years ago with an ER-positive/PgR-positive invasive ductal carcinoma located in the right upper outer quadrant. At that time, she underwent a right partial mastectomy. Pathology reported a 2.8-cm tumor, and she had a negative sentinel lymph node biopsy. She received postoperative radiation, was started on letrozole and denosumab because of osteopenia/osteoporosis, and was followed at 6-month intervals by her oncologist.

A few months ago, the patient developed shortness of breath. She had a chest x-ray, which showed a large right-side pleural effusion. Thoracentesis revealed the presence of malignant, ER-positive/PgR-positive cells, consistent with a breast cancer recurrence while receiving letrozole. Her oncologist recommended tamoxifen as a next line of therapy.

She came to me for a second opinion. No other disease sites outside of her pleural effusion were found during a staging workup with brain MRI and PET/CT. I told her that tamoxifen was an option, but I recommended that she receive fulvestrant and palbociclib, as we know that patients who add a CDK4/6 inhibitor benefit significantly more than those who receive either letrozole alone or fulvestrant alone. Because she had been receiving continuous letrozole, I thought it was better to switch her to a regimen that includes fulvestrant.

Palbociclib Combination Therapy for Hormone Receptor–Positive/HER2-Negative MBC
My recommendation of fulvestrant plus palbociclib for this patient was based on data from the prospective, multicenter, double-blind phase III PALOMA-3 study that randomized women with hormone receptor–positive/HER2-negative MBC after progression on endocrine therapy to receive fulvestrant with either palbociclib or placebo. Palbociclib was orally administered at 125 mg each day for 21 days followed by 7 days off. Fulvestrant was dosed at 500 mg intramuscularly on Days 1 and 15 of the first cycle and then every 4 weeks beginning on Day 29. The addition of palbociclib to fulvestrant significantly improved both median PFS (9.5 vs 4.6 months; P < .0001) and objective response rate (19% vs 9%; odds ratio: 2.47; P = .0019) vs fulvestrant alone.

If this patient had completed 5 years of letrozole and 2 more years had elapsed before the appearance of metastases, it would have been appropriate to start her on letrozole with palbociclib and give her denosumab or a bisphosphonate for the prevention of skeletal-related events. If she had had progression with bone-only metastases, which are typical for a relapse in patients strongly positive for hormone receptor this many years into treatment, with an area of metastatic bone involvement that was painful, adding a focused period of radiation would also be appropriate.

The strongest evidence supporting the choice of letrozole with palbociclib was obtained from the international, multicenter, double-blind phase III PALOMA-2 study that randomized postmenopausal women with ER-positive/HER2-negative advanced breast cancer to receive letrozole with either palbociclib or placebo. Adding palbociclib significantly improved median PFS (24.8 vs 14.7 months; P < .000001) and objective response rate (42% vs 35%; odds ratio: 1.4; P = .0310) vs letrozole alone.

At this time, for the majority of my patients presenting with hormone receptor–positive/HER2-negative MBC for first-line or second-line hormonal therapy, my standard of practice is to recommend a regimen containing palbociclib. Exceptions include patients who have already failed a CDK4/6 inhibitor, those who cannot tolerate palbociclib even after 2 dose reductions, those who have some other allergic reaction or intolerance to this agent, and perhaps the rare patient with multiple comorbidities and a poor performance status who might not tolerate a 2-drug combination.

Treatment-Related Neutropenia and Patient Monitoring
Toxicity data from the pivotal clinical trials tell us that more than one third of patients treated with palbociclib may require a dose reduction (40% in PALOMA-1; 36% in PALOMA-2; 34% in PALOMA-3) due to neutropenia. Consequently, a very common question that I am asked is: Why not start patients on a lower dose of palbociclib and escalate once they have tolerated it? This is a legitimate question. However, the incidence of febrile neutropenia in these trials was very low at approximately 1%. Because the neutropenia occurs without complication in the vast majority of patients, I think that we, as oncologists, should increase our tolerance for low white cell counts.

When I start patients on palbociclib, I check their absolute neutrophil count (ANC) on Day 15, approximately in the middle of the 28-day treatment cycle. If the ANC is > 1000 cells/mm3, the patient can complete the cycle. After 2 or 3 cycles monitored this way (ie, biweekly), ANC testing on Day 1 of every cycle is sufficient. However, for an ANC < 1000 cells/mm3, the dose should be held until neutrophils recover.

The patient described here tolerated palbociclib well, except that her ANC was 1200 cells/mm3 on Day 1 of the second cycle. If she had developed more severe neutropenia or fever, I would have waited for a full recovery and then restarted at the next lower dose. Instead of 125 mg, she would have received 100 mg. Patients with this complication can be dose-reduced twice, if needed: from 125 to 100 mg and then from 100 to 75 mg. If the patient does not tolerate the 75-mg dose, then it is appropriate to switch the patient to another treatment option.

Overall, the doubling of PFS with palbociclib is very impressive, and neutropenia, which seems to be the most common toxicity, is really a “paper” toxicity. No patient comes in complaining of neutropenia; we discover it on a blood count and inform the patient. Although mucositis occurs, it occurs at a much lower frequency than with everolimus or cytotoxic combination chemotherapy. This is, perhaps, the reason that febrile neutropenia incidence is only approximately 1% vs 15% with docetaxel. The relative lack of mucositis provides no portal for bacteria to enter circulation to cause bacteremia concomitant with a nadir of neutrophils. Patients receiving chemotherapy who simultaneously develop mucositis and neutropenia are at a much higher risk of febrile neutropenia than patients receiving palbociclib.

CDK4/6 Inhibitors on the Horizon: Abemaciclib and Ribociclib
Additional CDK4/6 inhibitors, such as abemaciclib and ribociclib, are being developed. Both abemaciclib and ribociclib have a breakthrough therapy designation from the FDA. In the phase II MONARCH 1 study, single-agent abemaciclib (200 mg every 12 hours) demonstrated activity in previously treated patients with hormone receptor–positive/HER2-negative MBC. In contrast to palbociclib, the predominant adverse event associated with abemaciclib was diarrhea. Two phase III studies of abemaciclib combined with endocrine therapy are ongoing. The combination of letrozole plus ribociclib is being evaluated in the phase III MONALEESA-2 trial, which randomized 668 postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer to letrozole with or without ribociclib. A recent press release indicated this trial was stopped early when it met its primary endpoint of improved PFS with the combination. We await the reporting of more detailed safety and efficacy data from this study.

Final Thoughts
Therapeutic options for hormone receptor–positive/HER2-negative MBC are evolving quickly. Because randomized trials are ongoing and maturing, the field will continue to evolve as drug combinations change and improve. Stay tuned for developments in this setting in the coming year.

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In your current practice, what do you recommend for your patients who are similar to the case described in this commentary?
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