Nicholas Turner, MD

NICHOLAS TURNER, MD, of The Royal Marsden and the Institute of Cancer Research in the UK, called the findings of MONARCH 3 “practice-changing.” The cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have answered the need for agents that target the biology of estrogen receptor–positive breast cancer, specifically targeting a factor that is critical to cell growth, he said. 

As the invited discussant of MONARCH 3, Dr. Turner noted median progression-free was not reached with abemaciclib/endocrine therapy but would probably improve progression-free survival by approximately 12 months. “This is a substantial improvement in progression-free survival for these patients, and importantly, this benefit was confirmed by independent blinded central review,” he commented. 

Comparing Landmark Studies 

TO DR. TURNER, THIS EFFICACY appears similar among the three available CDK4/6 inhibitors based on the similar hazard ratios demonstrated across the landmark trials: in the first-line setting, 0.54 in MONARCH 3 (abemaciclib), 0.58 in MONALEESA 2 (ribociclib [Kisqali]), and 0.58 in PALOMA 2 (palbociclib [Ibrance]). In endocrine-pretreated patients, in combination with fulvestrant, the hazard ratios were 0.55 in MONARCH 2 (abemaciclib) and 0.50 in PALOMA 3 (palbobiclib). 

“We have to be careful comparing among studies, but what is remarkable is the consistency of the hazard ratios across studies with different drugs and in slightly different indications,” observed Dr. Turner. “It’s clear that we have a class effect with CDK4/6 inhibitors in metastatic breast cancer.” 

The drugs do, however, have somewhat different tolerability profiles, with less neutropenia seen with abemaciclib compared with the other two but more diarrhea. Long-term follow-up is needed to determine side effects of long-term use, he added. 

Dr. Turner suggested the results of MONARCH 3 and the other CDK4/6 inhibitor trials will ultimately trigger a shift away from chemotherapy in the first-line treatment of metastatic estrogen receptor–positive/ HER2-negative breast cancer—a practice that is not recommended but that occurs “in the real world,” he added. 

“These studies emphasize that the combination of endocrine therapy plus CDK4/6 inhibition is potentially much better than chemotherapy,” he said. 

Clinical Subgroups 

ALTHOUGH DR. DI LEO IDENTIFIED subgroups of patients who appear to benefit more from the combination therapy, Dr. Turner fell short of making treatment recommendations based on these analyses. He noted that the hazard ratios were fairly similar across all clinical subgroups—an observation seen in the other trials as well. The analysis according to treatment-free interval in MONARCH 3 is exploratory, and not predefined, he reminded listeners. Dr. Di Leo agreed with Dr. Turner regarding the exploratory nature of the subgroup analyses. “It will be important to see whether the previously reported trials (PALOMA-2 and MONALEESA-2) will report similar results in terms of absolute benefits within the subgroups of patients as those investigated in MONARCH 3,” Dr. Di Leo noted. 

Meanwhile, Dr. Turner observed, “We have been unable to identify biomarkers for relative benefit. We have some rough clinical characteristics to identify who is more likely to do well on letrozole alone, but they don’t pick out this population that well.” ■

DISCLOSURE: Drs. Turner and Di Leo reported no conflicts of interest.