postMONARCH Meets Primary End Point of Improvement of PFS in HR+/HER2– Breast Cancer Post–CDK4/6i Progression

Kevin Kalinsky, MD, MS

The progression-free survival (PFS) benefit observed with abemaciclib (Verzenio) plus fulvestrant (Faslodex) vs placebo plus fulvestrant in patients with hormone receptor–positive, HER2-negative advanced breast cancer following disease progression on a CDK4/6 inhibitor and endocrine therapy highlighted to the potential for continuing a CDK4/6 inhibitor in this patient population, particularly in those who do not harbor ESR1 mutations or PI3K pathway alterations, according to Kevin Kalinsky, MD, MS.

At the 2024 ASCO Annual Meeting, Kalinsky and colleagues shared data from the phase 3 postMONARCH study (NCT05169567), which demonstrated that the primary end point of investigator-assessed PFS was met at the time of the primary analysis. Treatment with the investigative combination (n = 182) elicited a median PFS of 6.0 months (95% CI, 5.6-8.6) compared with 5.3 months (95% CI, 3.7-5.6) with fulvestrant plus placebo (n = 186; HR, 0.73; 95% CI, 0.57-0.95; P = .02).¹

“[Findings from postMONARCH] demonstrated that [continuing a a CDK4/6 inhibitor and switching endocrine therapy] is a strategy for patients [after frontline progression on a CDK4/6 inhibitor–based regimen]. Abemaciclib is widely available with a toxicity profile that we know and understand,” Kalinsky emphasized.

In an interview with OncLive^®, Kalinsky discussed the rationale for conducting this randomized phase 3 trial of fulvestrant plus placebo vs fulvestrant plus abemaciclib in patients with hormone receptor–positive, HER2-negative advanced breast cancer following disease progression on a CDK4/6 inhibitor and endocrine therapy; expanded on the results of the investigation; and highlighted outcomes in subgroups based on stratification factors and biomarker status.

Kalinsky is a professor and medical oncology division director of the Department of Hematology and Medical Oncology at Emory University School of Medicine; director of the Glenn Family Breast Center at Emory Winship Cancer Institute; and a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: What was the rationale behind the postMONARCH trial?

Kalinsky: We've had data from randomized phase 2 trials—[the MAINTAIN (NCT05207709), PALMIRA (NCT03809988), and PACE (NCT03147287) trials]—that have shown inconsistent findings in terms of whether there's a benefit for continuing a CDK4/6 inhibitor and switching the endocrine therapy after a patient has a tumor that has progressed on frontline hormonal therapy and an aromatase inhibitor. [postMONARCH] is the first randomized, phase 3 trial to address that question.

How was the trial designed, and what were some of the key efficacy findings presented at the 2024 ASCO Annual Meeting?

The trial design was for patients who had hormone receptor–positive, HER2-negative advanced disease. This was a true second-line study, where patients were patients were randomly assigned to fulvestrant plus placebo vs fulvestrant plus abemaciclib. This was a 1:1 [randomized] study that was looking at 368 patients were enrolled.

The assumption was that we would see an investigator-assessed PFS difference with an HR of 0.70. That is what we saw. Our HR was 0.73, translating into a benefit for patients when they continued abemaciclib and switching endocrine therapy to fulvestrant after progression on frontline therapy.

Were there safety findings from this analysis that are important to note?

Safety was consistent with what we know about abemaciclib. We saw that 4% [of patients in the abemaciclib arm] had grade 3 or higher diarrhea, 25% had [grade 3 or higher] neutropenia, and 30% of patients dose reduced with, two-thirds of those being from 150 mg twice a day to 100 mg twice a day. Six percent of patients discontinued due to adverse effects.

Were there any secondary end points or findings that are important to note?

We did spend some time talking about the investigator-assessed PFS by the stratification factors. Those [factors] were visceral metastasis and prior duration on CDK4/6 inhibition. The majority of patients—[129 in the abemaciclib arm and 144 in the placebo arm]—were on their prior CDK4/6 inhibitor for at least 12 months. [In this population], there was an HR for PFS of 0.70 [95% CI, 0.52-0.94], and it translated into about a 1.6-month PFS difference [7.0 months (95% CI, 5.6-9.0) in the abemaciclib arm vs 5.4 months (95% CI, 4.0-5.7) in the placebo arm].

When we look at those with or without visceral metastasis, in those without visceral metastasis, we had a HR for PFS of 0.53 [95% CI, 0.34-0.83], which translated into a 5.5-month median PFS benefit [11.1 months (95% CI, 6.3–not reached) in the abemaciclib arm vs 5.6 months (95% CI, 5.3-9.2) in the placebo arm]. In terms of visceral metastasis, the magnitude of benefit was a little bit lower [HR, 0.87; 95% CI, 0.64-1.17].

What are the implications of these findings?

Thirty percent of patients in this study were biomarker-negative, which means that they didn't have an ESR1 mutation or a PI3K pathway alteration. For those patients, this offers a targeted therapy option post–CDK4/6 inhibition.

Additionally, regardless of whether you had the presence or absence of an ESR1 mutation or PI3K pathway alteration, we saw benefit with fulvestrant and abemaciclib.

Reference

Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. J Clin Oncol. 2024;42(suppl 17):LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001