Expert Point of View: Richard S. Finn, MD and Ingrid A. Mayer, MD

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Richard S. Finn, MD, of the David Geffen School of Medicine at UCLA, Los Angeles, commented on MONARCH 2 and the field of cyclin-dependent kinase 4/6 (CDK4/6) inhibition in general in an interview with The ASCO Post.

“MONARCH 2 is confirmatory for the role of CDK4/6 inhibition in estrogen receptor–positive breast cancer. This study met its endpoints, as the studies of the other molecules have,” he said. “We see a consistent benefit of adding a CDK4/6 inhibitor to an endocrine agent.” 

Ingrid A. Mayer, MD

Ingrid A. Mayer, MD

Ingrid A. Mayer, MD, Co-leader and Clinical Director of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer, Nashville, the invited discussant of MONARCH 2, added that while all CDK4/6 inhibitors may not be “created equal,” they are all “similar.” 

She noted the differences between the progression-free survival of MONARCH 2 and -PALOMA-3, which evaluated palbociclib (Ibrance) plus fulvestrant (Faslodex) in the second-line setting as well. While the two studies had similar hazard ratios (0.55 and 0.46, respectively), median progression-free survival differed in both the experimental and control arms: 16.4 vs 9.3 months in MONARCH 2 and 9.5 vs 4.6 months in -PALOMA-3. The shorter median progression-free survival with palbociclib/fulvestrant was likely due to the fact that MONARCH 2 patients received less treatment prior to the study.

Patient Population Differences

Dr. Finn agreed that baseline patient characteristics are largely responsible for such differences in outcomes among the trials. While “absolute numbers” are important, he said, the differences in patient populations render it impossible to establish the relative benefit of one CDK4/6 inhibitor over another, based on current trial data. 

We see a consistent benefit of adding a CDK4/6 inhibitor to an endocrine agent.
— Richard S. Finn, MD

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It is more informative, he suggested, to focus on the hazard ratios. These are largely similar among the trials, ranging from 0.49 to 0.56 in first-line studies and from 0.46 to 0.55 in second-line studies of the different agents. “The key point is that we see a similar magnitude of benefit,” Dr. Finn emphasized. 

Dr. Mayer said her treatment strategy “relies on biology.” Patients with a long disease-free interval and presumably acquired endocrine resistance may do well on an aromatase inhibitor alone, with the CDK4/6 inhibitor postponed for the second line. Patients with primary endocrine resistance, on the other hand, may benefit more from the combination upfront. In each situation, everolimus (Afinitor) plus an aromatase inhibitor would follow in the third-line setting. Each of these strategies should yield a progression-free survival approaching 40 months, Dr. Mayer said. 

Next up for this class of agents are adjuvant trials. “There’s only marginal benefit to chemotherapy in high-risk patients,” Dr. Finn said. “Can we prove a CDK4/6 inhibitor plus endocrine therapy negates the need for chemotherapy in early-stage breast cancer?” 

“We should absolutely incorporate CDK4/6 inhibitors and endocrine therapy at some point in the treatment of estrogen receptor–positive metastatic breast cancer,” Dr. Mayer concluded. “The good quality of life, long duration of clinical benefit, and delay in chemotherapy initiation are clear reasons to do so.” ■

DISCLOSURE: Dr. Finn reported no conflicts of interest. Dr. Mayer is a consultant for Novartis and Astra-Zeneca and has received research funding from Pfizer.

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