Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment.

When treating patients with advanced ER-positive, HER2-negative breast cancer, CDK4/6 inhibitors should be incorporated at some point alongside standard endocrine therapy. Such was the take-home message from a series of presentations at the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL, during which data from three trials—MONARCH2, PALOMA-1, and TREnd—were highlighted.

The phase III MONARCH2 study enrolled 669 patients whose disease had progressed on endocrine therapy. They were randomized 2:1 to receive the investigational CDK4/6 inhibitor abemaciclib (Eli Lilly) or placebo, plus fulvestrant (Faslodex; AstraZeneca). George Sledge, MD, chief of oncology at Stanford University Medical Center in Palo Alto, CA, reported that abemaciclib significantly extended the median progression-free survival (PFS)—16.4 months versus 9.3 months for those given placebo. Among patients with measurable disease, the objective response rates (ORR) were 48.1% and 21.3%, respectively.

“To our knowledge, this ORR [with abemaciclib] is the highest recorded in an endocrine therapy–resistant population,” Sledge said. The median duration of response was not reached among patients who received abemaciclib, he added, compared with 25.6 months in the placebo arm.

Richard Finn, MD, of the Geffen School of Medicine at the University of California, Los Angeles, reported final overall survival (OS) results from PALOMA-1. The phase II study randomly assigned 165 patients to receive a different CDK4/6 inhibitor, palbociclib (Ibrance; Pfizer), with letrozole, or letrozole alone, as first-line therapy. Although previous analyses showed that this combination improved the median PFS by 10 months, the difference in median OS—37.5 months versus 34.5 months—was not statistically significant, Finn said. However, patients were able to put off second-line chemotherapy for 9 months longer than those given just letrozole.

Ingrid Mayer, MD, of Vanderbilt-Ingram Cancer Center in Nashville, TN, pointed out that due to its small sample size, PALOMA-1 was likely underpowered to detect a significant OS difference between study arms. Final analyses from two larger phase III trials, PALOMA-2 and MONALEESA-2—the latter evaluating ribociclib (Kisqali; Novartis) instead of palbociclib—are pending, and “we eagerly await the data to tell us if first-line use of CDK4/6 inhibitors plus letrozole will indeed prolong overall survival,” Mayer said.

In the TREnd trial, 115 patients with disease progression on endocrine therapy randomly received palbociclib as a single agent or alongside their prior hormone treatment. Luca Malorni, MD, PhD, of Istituto Toscano Tumori in Prato, Italy, noted that the clinical benefit rate (ORR plus stable disease) was similar: 60% and 54%, respectively. However, the median PFS was 4.3 months longer for patients in the combination arm, he added; according to subgroup analyses, this improvement was “mostly confined” to those with acquired, not intrinsic, resistance to endocrine therapy.

“It suggests that such acquired resistance could be reversed with palbociclib,” Malorni said. “Translational studies are ongoing to dissect the potential mechanisms involved.”

Whether resistance to endocrine therapy is intrinsic or acquired may determine when CDK4/6 inhibitors should be included—as part of first- or second-line treatment—Mayer noted. Regardless, “the overall good quality of life, long duration of benefit, and delay in chemotherapy initiation are absolutely clear reasons” to use these targeted agents in patients. –Alissa Poh