CDK4/6 Inhibitors in Breast Cancer Treatment: Recent Research, Safety Profiles, Acquired Resistance, Next Steps

Abemaciclib is more selective for CDK4 than palbociclib or ribociclib.^11,12 Results from MONARCH-2 showed improved PFS when added to fulvestrant (PFS 16.4 months vs 9.3 months for fulvestrant alone) among women with HR-positive, HER2-negative advanced breast cancer whose disease had progressed during endocrine therapy.¹⁰ Unlike palbociclib and ribociclib, abemaciclib can be administered at continuous twice daily dosing instead of once-daily (3 weeks on, 1 week off). It also exhibits single-agency efficacy.¹⁰

MONARCH-3 (ClinicalTrials.gov Identifier: NCT02246621) findings were presented at the 2017 European Society of Medical Oncology (ESMO) Congress in Madrid Spain, Dr Murphy noted.

Those “showed a very similar PFS benefit in first-line to palbociclib and ribociclib (HR 0.54; P=0.00002) but a noticeable rate of grade 3 diarrhea” (9.5% ), he noted. Among the postmenopausal, HR-positive, HER2-negative patients, all-grade diarrhea and neutropenia affected 81.3% and 29.8% of patients receiving abemaciclib, compared to 41.3% and 1.9% for those receiving endocrine therapy alone.¹³

An abemaciclib response rate of approximately 20% in heavily pretreated patients in the MONARCH-1 study resulted in an application to the FDA for approval for single-agent therapy in this setting as well as for combination therapy in earlier lines of therapy, Dr Murphy noted.

Down the line, patients who have exhausted hormonal treatments may be candidates for abemaciclib monotherapy.

“You wouldn’t do that up front,” Dr Shapiro said.

Additional settings for approved agents are under investigation, as are new, investigational CDK4/6 inhibitors.

“We are currently accruing patients to the PENELOPE-B study [ClinicalTrials.gov Identifier: NCT01864746], which [randomly assigns] patients with a suboptimal response after neoadjuvant chemotherapy to standard endocrine therapy alone or with palbociclib in the post-operative setting,” Dr Murphy reported.

Another question is whether or not CDK4/6 inhibitors can improve outcomes for a subset of patients with triple-negative patients, Dr Shapiro noted.

“Many are RB [mutation]-negative and those wouldn’t be responsive. But some triple-negative tumors retain wild-type RB.”

The CDK4/6 inhibitor trilaciclib (G1T28) is an investigational CDK4/6 inhibitor being developed to reduce chemotherapy toxicities, Dr Shapiro noted. It is under study in combination with gemcitabine and carboplatin among patients with metastatic triple-negative breast cancer (TNBC; ClinicalTrials.gov Identifier: NCT02978716). That study should demonstrate whether or not trilaciclib can help preserve patients’ bone marrow and immune response.

The phase 2 PACE study (ClinicalTrials.gov Identifier: NCT03147287) at Dana-Farber Cancer Institute is currently recruiting patients to assess palbociclib after treatment with fulvestrant plus palbociclib alone or with avelumab, Dr Shapiro said.

Another intriguing avenue for investigation is combining CDK4/6 inhibition with immune checkpoint blockade. A recent study of animal breast cancer models published in Nature suggests that in addition to arresting tumor cell cycle, selective CDK4/6 inhibitors also promote antitumor immunity.¹⁴

“These data provide a rationale for an exciting new potential combination therapy approach in breast cancer, combining cdk4/6 inhibitors with immunotherapy,” Dr Murphy said.

Early-phase clinical studies of such combinations are already under way, Dr Shapiro noted, such as a phase 1b trial of abemaciclib plus pembrolizumab in patients with HR-positive, HER2-negative breast cancer and non-small cell lung cancer (ClinicalTrials.gov Identifier: NCT02779751).