Updated monarchE results show improved treatment effects of abemaciclib for breast cancer

In the preplanned overall survival (OS) interim analysis of the monarchE study, the combination of abemaciclib and endocrine therapy (ET) continued to provide benefit for individuals with HR+, HER2–, node-positive, high-risk early breast cancer even after completion of therapy.

“At a median follow-up of 42 months, all patients were off abemaciclib … [Our current findings show that] the benefit of adjuvant abemaciclib has deepened in magnitude with an increase in absolute IDFS* and DRFS** benefit at 4 years compared with the 2- and 3-year estimates,” said Dr Stephen Johnston from the Royal Marsden NHS Foundation Trust, London, UK, at SABCS 2022.

The IDFS benefit persisted beyond completion of abemaciclib treatment (hazard ratio [HR], 0.66; p_nominal<0.0001), translating to a 34-percent reduction in the risk of developing an IDFS event with abemaciclib-ET vs ET alone. [SABCS 2022, abstract GS1-09]

“The KM*** curves continued to separate beyond completion of the treatment period, suggesting a potential carryover effect,” said Johnston. At 4 years, the absolute difference in IDFS rates between the abemaciclib-ET vs ET alone arms was 6.4 percent, exceeding the 2- and 3-year differences of 2.8 percent and 4.8 percent, respectively.

Albeit lacking any statistical interaction, there was consistent IDFS benefit in favour of abemaciclib-ET in all prespecified subgroups (HRs ranging from 0.48 to 0.91). “With more events, [there is] an even more precise estimate of the individual treatment effect in each of the prespecified subgroups,” noted Johnston.

As for DRFS, the KM curves again separated and continued to do so after the treatment period, with a 34-percent reduction in the risk of developing a distant event or death with abemaciclib-ET vs ET alone (HR, 0.66; p_nominal<0.0001) and an absolute between-group difference of 5.9 percent at 4 years. Again, this difference was higher than the 2- and 3-year differences in DRFS rates (2.5 percent and 4.1 percent, respectively).

These findings were further reinforced by the post hoc results evaluating yearly treatment effect size (piecewise HRs, 0.72, 0.69, 0.65, and 0.58 for 0–1, 1–2, 2–3, and 3+ years, respectively). “The magnitude of abemaciclib benefit increases year upon year beyond completion of the study treatment period, again suggesting a potential carryover effect,” said Johnston.

The intent-to-treat population (n=5,637) consisted of two groups: Cohort 1 (91 percent of participants) had high-risk^# clinical pathologic features; cohort 2 consisted of those with intermediate risk^## factors. Participants were randomized 1:1 to receive ET^### for up to 10 years ± abemaciclib 150 mg BID for 2 years (on-study treatment period).

Is Ki-67 prognostic?

Ki-67 was evaluated in cohort 1 patients. In the abemaciclib-ET arm, those with high Ki-67 had a worse prognosis than those with low Ki-67, with 16 percent of patients with high Ki-67 having relapsed by 4 years as opposed to 11 percent of those with low Ki-67.

Looking at the HRs, these were similar in both the high (0.618 [IDFS] and 0.612 [DRFS]) and low Ki-67 groups (0.624 and 0.613, respectively), suggesting that abemaciclib’s treatment effect is seen regardless of Ki-67 score. Although not predictive of abemaciclib benefit, Johnston stressed that Ki-67 is clearly an important prognostic factor in this trial.

Benefit beyond treatment completion

OS data remain immature, but there were fewer deaths with abemaciclib-ET vs ET alone (n=157 vs 173; HR, 0.93; p_log-rank=0.50). “[This] suggests that a survival signal in favour of abemaciclib is emerging,” said Johnston. Continued follow-up is ongoing until final evaluation of OS.

The current safety findings align with those seen previously, with no new safety signals reported. “[Most] adverse events occurred early in patients on study and are managed by appropriate dose holds and reductions which were common in the study to allow patients to stay on study for the 2-year treatment period,” said Johnston. “The safety profile of abemaciclib is considered manageable and acceptable for these high-risk patients.”

“The clinically meaningful benefit of adjuvant abemaciclib added to ET … persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 years,” said Johnston. “[The current] data further support the addition of adjuvant abemaciclib to ET [in this patient setting].”