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MIAMI BEACH -- Emerging data have helped optimize the use of CDK4/6 inhibitors in metastatic hormone receptor (HR)-positive breast cancer, and the focus has turned to overcoming resistance, a breast cancer specialist said here.

Phase III trials of the three approved have shown a fairly consistent absolute improvement in progression-free survival (PFS) of about 10-15 months versus control, translating into reductions in hazard ratios of 44-46%. With the exception of the PALOMA-2 trial of first-line palbociclib (Ibrance) plus letrozole, the studies also yielded a significant improvement in median overall survival (OS). Three trials of ribociclib (Kisqali) plus endocrine therapy and one with abemaciclib (Verzenio) showed double-digit absolute improvement in OS versus control.

The lack of OS benefit in PALOMA-2 might be explained by differences in patient populations, prior and post-progression therapy, drug chemistry, or lack of statistical power, said Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, during the Miami Breast Cancer Conference.

"There are additional factors that influence our treatment choices today: toxicity profile, comorbidities, patient and schedule preferences," said Sharma. "Within the landscape of treatment for early-stage, hormone receptor-positive [breast cancer], the appropriate therapy for patients who will develop disease recurrence while on adjuvant CDK4/6 inhibitors remains to be determined."

(ASCO) clinical guidelines recommend a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor (AI) as initial treatment for postmenopausal HR-positive metastatic breast cancer and for premenopausal patients with the addition of ovarian function suppression. ASCO recommends fulvestrant (Faslodex) plus a CDK4/6 inhibitor for patients with progression during treatment with an AI or within 1 year of adjuvant AI therapy. Treatment with a CDK4/6 inhibitor should be limited to patients with no prior exposure to CDK4/6 inhibition in the metastatic setting.

The guidelines recommend a CDK4/6 inhibitor plus an AI as a first-line option for metastatic HR-positive breast cancer, but point out that the choice of CDK4/6 inhibitor remains controversial in the absence of head-to-head comparative trials. Nonetheless, the guidelines note that "in phase III randomized controlled trials, ribociclib + endocrine therapy has shown OS benefit in the first-line setting."

Informing Specific Situations

Sharma reviewed evidence for CDK4/6 inhibitor use in selected clinical situations. A phase II trial compared ribociclib plus endocrine therapy versus physician's choice of combination chemotherapy for pre-/perimenopausal patients with visceral metastasis or visceral crisis. The ribociclib regimen doubled median PFS (24.0 vs 12.3 months, P=0.0007).

Several trials have shown that endocrine therapy performs poorly in the post-CDK4/6 inhibitor setting, said Sharma. The randomized phase II MAINTAIN trial investigated the potential value of continuing CDK4/6 inhibition beyond progression. Patients received ribociclib or placebo plus endocrine therapy. Median PFS improved from 2.76 months with placebo to 5.29 months with ribociclib (HR 0.57, 95% CI 0.39-0.95, P=0.006).

On the other hand, the phase II PACE trial with palbociclib showed that continuing CDK4/6 inhibition beyond progression did not significantly improve PFS. Adding avelumab (Bavencio) to palbociclib and endocrine therapy did improve median PFS (8.1 vs 4.6-4.8 months), an intriguing but non-significant difference, said Sharma.

"There is no role for palbociclib beyond progression at this time," she said. "Switching to ribociclib after palbociclib may be a reasonable strategy for select patients (those without RB or PIK3CA mutation). It's unclear whether there is a need to switch both the endocrine therapy and the CDK4/6 inhibitor. We need a better understanding of genomic predictors of benefit and resistance, and we are awaiting data from several phase III switch/continuation trials."

Several ongoing trials are evaluating sequential use of CDK4/6 inhibitors, she added.

Understanding Mechanisms of Resistance

Understanding how resistance to CDK4/6 inhibition occurs remains an area of high unmet need. Multiple mechanisms , and resistance may involve more than one mechanism. Proposed mechanisms include aberrations in cell-cycle machinery and growth factor signaling as well as epigenetic changes (loss of basal subtype or HR expression), and changes in the tumor microenvironment. Future trials will likely address multiple therapeutic approaches to overcome resistance, including strategies that involve selective estrogen receptor degraders and CDK4/6 inhibitor continuation or switch, said Sharma.

"Endocrine therapy plus a CDK4/6 inhibitor is standard of care in first-line therapy for all patients with HR-positive metastatic breast cancer," she said in summary. "An AI plus CDK4/6 inhibitor is the choice for treatment-naive or AI-sensitive settings, fulvestrant plus a CDK4/6 inhibitor in the AI-resistant setting. Premenopausal women should receive ovarian function suppression in addition, and men should receive [gonadotropin-releasing hormone antagonist] GNRH analogs. Endocrine therapy alone may need to be considered in rare situations, such as poor performance status related to comorbidities."

For patients with symptomatic visceral disease, endocrine therapy plus a CDK4/6 inhibitor is an appropriate first-line option for most patients. The one notable exception is patients with elevated liver function tests or liver failure due to high disease burden, Sharma continued. In the post-progression setting of CDK4/6 inhibition, switching to ribociclib can be considered in select situations. The appropriate first-line endocrine therapy for recurrence during adjuvant CDK4/6 inhibition remains to be determined.

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