Combination of Abemaciclib and Trastuzumab Improves OS in HR+, HER2+ Advanced Breast Cancer

Abemaciclib (Verzenio) plus trastuzumab (Herceptin), with or without fulvestrant, improved overall survival (OS) in women with hormone receptor–positive, HER2-positive advanced breast cancer vs standard-of-care chemotherapy plus trastuzumab, according to data presented at the 2022 European Society for Medical Oncology Congress (ESMO).¹

Fabrice André, MD, PhD, director of research at Gustave Roussy in Villejuif, France, presented the data from a prespecified final analysis from the phase 2 monarcHER trial (NCT02675231) at the congress.

As of the data cutoff on March 31, 2022, median OS in arms A (experimental regimen plus fulvestrant), B (experimental regimen alone), and C (control therapy) were 31.1 months (arms A vs C: HR, 0.71; 95% CI, 0.48-1.05; 2-sided P value = .086), 29.2 months (arms B vs C: HR, 0.84; 95% CI, 0.57-1.23; 2-side P value = .365), and 20.7 months, respectively. In comparing arms A and C, the triplet regimen with the oral CDK4/6 inhibitor induced a statistically significant improvement in OS compared with trastuzumab plus chemotherapy.

Moreover, there was a consistent benefit observed with the pooled abemaciclib arms across all pre-specified subgroups.

An exploratory analysis of RNA sequencing of intrinsic subtypes showed that luminal subtypes of disease compared with non-luminal subtypes were associated with longer median progression-free survival (PFS; 8.6 months vs 5.4 months; HR, 0.54; 95% CI, 0.38-0.79) and OS (31.7 months vs 19.7 months; HR, 0.68; 95% CI, 0.46-1.00).

André said there were no new adverse events (AEs).

In the randomized, multicenter, open-label phase 2 trial, patients were randomized 1:1:1 to receive either abemaciclib plus fulvestrant and trastuzumab (arm A; n = 79), abemaciclib plus trastuzumab (arm B; n = 79), or trastuzumab plus standard-of-care chemotherapy (arm C; n = 79) at doses of:

• 150 mg abemaciclib twice daily on days 1 through 21 of a 21-day cycle;
• 8 mg/kg of intravenous trastuzumab on cycle 1, day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle
• 500 mg intramuscular fulvestrant on days 1, 15, and 29 and once every 4 weeks thereafter.

Investigator-assessed PFS in the intent-to-treat population (arm A vs C, then arm B vs C) served as the primary end point. Secondary end points included OS, overall response rate, patient-reported outcomes, and pharmacokinetics. Safety was also assessed in any patient who received at least 1 dose of study treatment.

Patients were eligible if they were 18 years or older; had hormone receptor–positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease; had an ECOG performance status of 0 or 1; had previously received at least 2 HER2-directed targeted therapies for advanced disease; and has prior ado-trastuzumab emtansine (T-DM1; Kadcyla) and taxane therapy.

In the previously reported data, after a median follow-up of 19.0 months (range, 14.7-25.1), treatment on arm A compared with arm C induced superior median PFS at 8.3 months (95% CI, 5.9-12.6) vs 5.7 months (95% CI, 5.4-7.0) with control therapy for a reduction in the risk for disease progression or death of 33% (HR, 0.67; 95% CI, 0.45-1·00; P = .051).²

The most common grade 3/4 treatment-emergent adverse event (TRAE) in arms A, B, and C, was neutropenia (27% vs 22% vs 26%, respectively). In arm A, the most common serious AEs included pyrexia (4%), diarrhea (3%), urinary tract infection (3%), and acute kidney injury (3%).

_References

_{1) Andre F, Nadal JC, Denys H, et al. Final overall survival (OS) for abemaciclib plus trastuzumab +/- fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER): A randomized, open-label, phase II trial. Ann Oncol. 2022;33(suppl 7):LBA18. doi:10.1016/j.annonc.2022.08.013}

_{2) Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(6):763-775. doi:10.1016/S1470-2045(20)30112-1}