CDK4/CDK6 Inhibitors Show Promise in Advanced Postmenopausal Breast Cancer

TON - July 2017, Vol 10, No 4 - Breast Cancer
Alice Goodman

Denver, CO—CDK4/CDK6 inhibitors are a promising addition to the armamentarium for the treatment of patients with breast cancer. At the 42nd annual meeting of the Oncology Nursing Society, 2 experts discussed the role of these new drugs, and how to factor them into treatment decisions.

“When cancer disrupts the CDK4/6 pathway, cellular proliferation occurs. Inhibiting CDK4/6 gets the cancer cell cycle back under control, providing a rationale for use of these agents,” explained Linda M. Sutton, MD, Medical Director, Duke Oncology Consortium, Duke Cancer Network, and Associate Professor of Medicine, Duke University School of Medicine, Durham, NC.

“Inhibition of CDK4/6 is cytostatic. You stop the growth of cancer cells, but you don’t kill them. Chemotherapy is cytotoxic and kills cells, so there may be a role for combinations with chemotherapy,” Dr Sutton noted.

Palbociclib was the first CDK4/CDK6 inhibitor to be approved by the FDA, and is indicated for the initial treatment of postmenopausal patients with hormone receptor (HR)-positive/HER2-negative (HR+/HER2−) advanced breast cancer, in combination with an aromatase inhibitor or fulvestrant. Ribociclib is approved as first-line therapy for postmenopausal patients with HR+/HER2− advanced breast cancer, in combination with an aromatase inhibitor. Abemaciclib has been granted fast-track status by the FDA for the treatment of patients with HR+/HER2− breast cancer.

“CDK4/CDK6 inhibitors are an active area of research in studies of advanced HR+/HER2− breast cancer, and a number of ongoing trials are looking at these agents as neoadjuvant therapy, part of combination therapy, and in early breast cancer,” Dr Sutton added.

There are some differences among these 3 CDK4/CDK6 inhibitors; ribociclib and palbociclib are given 3 weeks on and 1 week off, whereas abemaciclib is given continuously. Early data suggest that abemaciclib will be beneficial for control of brain metastasis. Almost all patients treated with palbociclib and abemaciclib have significant myelotoxicity, and ribociclib is associated with less severe myelosuppression. Abemaciclib increases serum creatinine, but this does not lead to nephrotoxicity.

Studies of the 3 drugs as monotherapies show that fatigue is the dose-limiting effect of abemaciclib, whereas neutropenia is the dose-limiting effect of palbociclib and ribociclib. The 3 most common grade 3/4 adverse events are neutropenia, leukopenia, and diarrhea for abemaciclib, and neutropenia, leukopenia, and lymphopenia for the other 2 CDK4/CDK6 inhibitors.

“Adverse events should be managed proactively,” Dr Sutton stated.

Clinical Trial Results

Dr Sutton reviewed promising data from clinical trials evaluating these drugs.

In the phase 2 PALOMA-1 clinical trial, the combination of palbociclib plus letrozole as first-line therapy for HR+/HER2− advanced postmenopausal breast cancer significantly improved progression-free survival (PFS) compared with letrozole alone, reducing the risk for recurrence by 51% (P = .004). The phase 3 PALOMA-2 trial showed a 42% reduction in risk for progression for palbociclib plus letrozole versus letrozole (P <.000001). The phase 3 PALOMA-3 trial included postmenopausal women with HR+/HER2− recurrent breast cancer that had progressed with hormonal therapy; palbociclib plus fulvestrant prolonged PFS to 9.2 months versus 3.8 months for fulvestrant alone (P <.000001) in this trial. The treatment effect was similar across all subgroups.

In the phase 3 MONALEESA-2 clinical trial of first-line therapy for postmenopausal patients with HR+/HER2− advanced breast cancer, the combination of ribociclib plus letrozole significantly improved PFS versus letrozole alone. Median PFS was not reached in the combination therapy arm versus 14.7 months in the letrozole alone arm. The combination was equally effective in patients with bone metastasis and visceral metastasis.

Preliminary results of the phase 3 MONARCH 2 trial are encouraging for use of abemaciclib plus fulvestrant in postmenopausal women with HR+/HER2− advanced breast cancer that progressed with endocrine therapy. The phase 3 MONARCH 3 trial is studying abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy.

Patient Communication Is Key

“These are promising therapies. We need to communicate with patients [in whom these therapies are indicated] that this is the right thing to do. Time spent in shared decision-making will expedite further steps,” explained Susan Kane, BSN, RN, CBCN, Duke Cancer Center, Durham, NC.

“You need to simplify language and make sure the patient understands the risks versus benefits of therapeutic options. The conversation about uncertainty associated with some treatment options may be difficult, but shared decision-making will become more important because patient preference is increasingly emphasized,” Ms Kane explained.

If there is only 1 treatment option, the conversation is more straightforward, she acknowledged.

“Eliciting patient preferences and values helps the clinician understand the patient. These preferences may not correlate with socioeconomic status, so there can be surprises. Make sure your language is tailored to the patient’s cultural background. Agree on a plan for the next steps in decision-making,” Ms Kane suggested.

Patients’ expectations of cancer treatment are often out of line with physicians’ expectations. A recent survey of >2000 women with advanced breast cancer showed that patients had much higher expectations compared with physicians (Lux MP, et al. Breast Cancer Res. 2013;139:429-440).

“This disparity highlights the need to incorporate shared decision-making,” Ms Kane emphasized.

“Don’t overload your patients with information. Split information between appointments, and be sure to restate what the physician has told them. Provide written material that they can review at home. Be attuned to patients’ responses, and make sure that they are comfortable asking questions and asking for help,” she advised.

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Last modified: August 7, 2017