The landscape of treatment for HR+HER2- advanced breast cancer has seen significant evolution with the emergence of CDK4/6 inhibitors like abemaciclib. With its approval for both advanced and high-risk early-stage breast cancer, abemaciclib has become a pivotal player in the therapeutic arsenal. According to the DelveInsight analysis, the total market size in the US for Metastatic HR+/HER2− breast cancer was approximately USD 7 billion in 2023, where Verzenio has already crossed USD 1 billion in revenue post its approval in the adjuvant setting in 2021,  which is expected to show strong growth during the forecast period (2024-2034). Even though IBRANCE dominated the market for metastatic HR+/HER2− breast cancer, VERZENIO is projected to surpass it in revenue generation by 2034.

Moreover, the recommendation by the NCCN for VERZENIO as a Category 1 treatment option in the adjuvant setting underscores its clinical significance. The postMONARCH trial, a landmark study, demonstrated compelling evidence of abemaciclib's efficacy when administered post-progression on prior CDK4/6 inhibitor therapy. The significant improvement in progression-free survival and objective response rate, alongside consistent benefits across various subgroups, including those with specific genetic mutations, underscores its potential to revolutionize treatment paradigms. 

During a recent oral presentation, Eli Lilly and Company shared significant findings from their postMONARCH studies of VERZENIO (abemaciclib), a CDK4/6 inhibitor, at the ASCO 2024 annual meeting. The study, involving 368 patients randomized to receive abemaciclib plus fulvestrant, demonstrated promising results. At the interim analysis, the study met predetermined criteria, indicating a substantial improvement in investigator-assessed progression-free survival (PFS) with abemaciclib plus fulvestrant compared to placebo plus fulvestrant. Notably, at the primary analysis, the PFS rates at 6 months were 50% and 37% for the abemaciclib and placebo arms, respectively. This positive outcome was consistently observed across various clinical and genomic subgroups, including patients with baseline ESR1 or PIK3CA mutations.

Moreover, abemaciclib treatment resulted in a notable enhancement in objective response rate (ORR) compared to  placebo, particularly evident in patients with measurable disease (17% versus 7%). Additionally, progression-free survival assessed by blinded independent central review (BICR) also exhibited improvement. Although overall survival data are still premature, the safety profile of abemaciclib remained consistent with previously established knowledge. This unveiling of data underscores the potential of abemaciclib in augmenting therapeutic outcomes for patients, promising advancements in cancer treatment.

KOL insights

“postMONARCH is the first randomized, placebo-controlled, Phase III study to demonstrate the benefit of continued CDK4/6 inhibition beyond progression on a CDK4/6 inhibitor.” –Expert Opinion.

“The approvals of targeted therapy after frontline CDK4/6 inhibition had been limited to biomarker-positive advanced disease, including those with PI3K pathway alterations and those with ESR1 mutations. Despite these advances, the median PFS with these approaches are under 6 months, and absolute improvement is generally limited to approximately one to two scan intervals.”–Expert Opinion.

Conclusion- 

CDK4/6 inhibitors combined with endocrine therapy stand as the standard first-line treatment for HR+, HER2-advanced breast cancer (ABC). Abemaciclib, an oral and potent CDK4/6i with heightened selectivity for CDK4, enabling continuous dosing with reduced myelosuppression, is approved in conjunction with an aromatase inhibitor (AI) or fulvestrant in ABC. It is the first and sole CDK4/6i sanctioned for monotherapy in ABC and combination with ET for high-risk early breast cancer. Presented at the 2024 ASCO Annual Meeting, trial results revealed meeting the primary endpoint of investigator-assessed PFS at the interim analysis juncture, encompassing 70% of the planned events. The combination exhibited a median PFS of 5.6 months compared to 3.9 months with fulvestrant alone, even though the control arm outperformed expectations. Abemaciclib notably enhanced PFS in patients with HR+, HER2- ABC who had experienced disease progression on prior CDK4/6i + ET, yielding a 27% risk reduction for PFS events. This benefit proved consistent across various prespecified and clinically relevant subgroups, including pivotal biomarker subsets. Safety remained in line with established abemaciclib profiles, with a low discontinuation rate observed.