Abemaciclib plus fulvestrant extends OS in endocrine therapy-refractory advanced breast cancer
BARCELONA, Spain — The addition of abemaciclib to fulvestrant significantly prolonged OS among women with hormone receptor-positive, HER2-negative advanced breast cancer whose disease progressed following endocrine therapy, according to results of the randomized phase 3 MONARCH 2 trial presented at European Society for Medical Oncology Congress.
Researchers observed the benefit among both premenopausal and postmenopausal women, as well as among traditionally difficult-to-treat patient groups such as those with visceral metastases and those who had primary endocrine resistance.
The findings support the conclusion that cyclin-dependent kinase (CDK) 4/6 inhibitors such as abemaciclib (Verzenio, Eli Lilly) should be considered a standard-of-care option for patients with metastatic breast cancer, according to researcher George W. Sledge Jr., MD, professor of medicine at Stanford University Medical Center.
“I was pleasantly surprised by the magnitude of benefit,” Sledge told HemOnc Today. “We haven’t cured metastatic breast cancer, nor have we rendered our patients immortal. Having said that, it is absolutely clear that we have a real clinical benefit.”
The global, double-blind MONARCH 2 trial included 669 pre-, peri- or postmenopausal women with advanced endocrine therapy-resistant, hormone receptor-positive, HER2-negative advanced breast cancer.
Researchers randomly assigned the women 2:1 to fulvestrant plus either 150 mg abemaciclib every 12 hours or placebo.
Investigator-assessed PFS served as the primary objective, and OS served as a gated secondary endpoint.
Previously released results showed patients assigned the abemaciclib-fulvestrant combination achieved significantly longer median PFS (16.4 months vs. 9.3 months; HR = 0.55). The regimen also exhibited a generally tolerable safety profile.
At ESMO, Sledge and colleagues presented OS results from a prespecified interim analysis, which occurred after 338 deaths in the intent-to-treat population. This equated to 77% of the planned 441 deaths.
Results showed significantly longer median OS in the abemaciclib-fulvestrant group (46.7 months vs. 37.3 months; HR = 0.75; 95% CI, 0.6-0.94). This result met the prespecified boundary for significance (P for OS = 0.0137; prespecified boundary, P = .0208) and is considered definitive, Sledge and colleagues wrote.
“As a cynical old oncologist, I always expect the OS improvement to be less than the PFS improvement,” Sledge told said in an interview. “We saw the opposite here. This was a very impressive improvement in OS.”
The OS benefit appeared consistent across all stratification factors, with more pronounced effects observed among women with visceral disease (HR = 0.67) and those with primary resistance to previous endocrine therapy (HR = 0.68).
Researchers also observed a benefit with abemaciclib-fulvestrant with regard to PFS2 (HR = 0.67; 95% CI, 0.55-0.81) — defined as time to progression on next-line therapy or death — and time to chemotherapy (median, 50.2 months vs. 22.1 months; HR = 0.62; 95% CI, 0.49-0.77).
“I don’t know of any endocrine therapy that is more toxic than any chemotherapy for the average patient,” Sledge told HemOnc Today. “My patients certainly dread chemotherapy and want to delay the time to which they get it. The fact we were able to do so would certainly be a real selling point when discussing these agents with patients.”
Investigators observed no new safety signals with abemaciclib.
Abemaciclib is the third CDK 4/6 inhibitor to demonstrate an OS benefit for patients with advanced hormone receptor-positive, HER2-negative breast cancer, with the others being palbociclib (Ibrance, Pfizer) and ribociclib (Kisqali, Novartis).
“We not quite there in terms of knowing all of the OS data in the metastatic setting,” Sledge said. “Most of those data should emerge in the next year or so, and that will allow us to do a better job in terms of cross-trial and cross-drug comparisons than we’re currently able to do.
“I’m always very uncomfortable about cross-trial comparisons because of the differences between patients who go onto the trials, but across all of these drugs we are seeing impressive consistency of benefit,” he added. “They do have differences in terms of toxicities, and those differences play out in the clinic based on which patient is sitting in front of you. But, in general, these are well-tolerated agents and they provide huge benefits for our patients.” – by Mark Leiser
Reference: Sledge GW, et al. Abstract LBA6_PR. Presented at European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: Eli Lilly funded this study. Sledge reports clinical trial support, research grants, and travel accommodations from Eli Lilly. He also reports research grants from Pfizer; consultant roles with Symphogen, Syndax and Verseau Therapeutics; and a board of directors role with Tessa Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.