Interim overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor in patients with HR+, HER2- advanced breast cancer from the MONARCH 3 study

It is estimated that 90% of all breast cancers are detected at an early stage. Although the prognosis for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) early breast cancer (EBC) is generally positive, 20% of patients will experience recurrence potentially to incurable metastatic disease. The risk of recurrence is greatest within the initial two to three years post-diagnosis, particularly in patients with node-positive, high-risk EBC. 

The emergence of several novel CDK4/6 inhibitors in ER+/HER2- breast cancer space has demonstrated a widespread potential for this patient population in combination and as monotherapy. Verzenio (abemaciclib), a targeted treatment known as a CDK4/6 inhibitor, is one such example. Verzenio works inside the cell to block CDK4/6 activity and help stop the growth of cancer cells, so they may eventually die. On February 26, 2018, the US FDA approved Verzenio in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced or metastatic breast cancer. The approval was based on the MONARCH 3 trial. Robust PFS benefit in MONARCH-3 trial led to the regulatory approval but at that time OS data was immature with 29.5% events observed across both arms. In the final PFS data with a median follow-up of 26.7 months, PFS was prolonged by a median of 13.4 months in patients receiving Abemaciclib. 

Abemaciclib showed prolonged overall survival when added to a NSAI in HR-positive, HER2-negative breast cancer, according to updated findings from the MONARCH 3 trial presented at 2022 ESMO, both in the intention-to-treat (ITT) population and in the subgroup of patients with visceral disease (sVD).  Recent findings showed that the addition of abemaciclib to a non-steroidal aromatase inhibitor (NSAI) resulted in a 12.6-month increase in median OS in patients with HR-positive, HER2-negative advanced breast cancer. OS was a key secondary endpoint in the study and a prespecified Interim Analysis-2 (IA2) was performed after ~252 events had occurred in the intent-to-treat (ITT) population, representing 80% of planned events for the final OS analysis. Follow-up for the patients enrolled in MONARCH 3 is ongoing and a final OS analysis is planned once at least 315 and 189 OS events have occurred in the ITT and sVD populations, respectively.  

Patients with HR-positive, HER2-negative recurrent breast cancer that was not amenable to surgical resection or radiotherapy with curative intent, or with metastatic disease were randomized 2:1 to receive an NSAI plus abemaciclib (n=328) or an NSAI plus placebo (n=165). At the time of IA2, the median follow-up was 5.8 years.

In the ITT population, the median OS was 67.1 months for abemaciclib plus NSAI compared with 54.5 months for placebo plus NSAI. At the time of IA-2, p-value did not reach the threshold for statistical significance, but the data is maturing in a favorable trend. The observed difference in the median OS was 12.6 months. According to the findings, consistent trends are seen across the pre-specified sub-groups. 

Similar findings were observed in the subgroup of patients with the visceral disease (sVD, n=263) with a median OS of 65.1 months for abemaciclib plus NSAI compared with 48.8 months for placebo plus NSAI. At the time of IA-2, p-value did not reach the threshold for statistical significance, but the data is maturing in a favorable trend. The observed difference in the median OS was 16.3 months. According to the findings, consistent trends are seen across the pre-specified sub-groups. 

Safety data were consistent with the known safety profile of abemaciclib.In conclusion, even though in both the ITT and sVD populations, the threshold for statistical significance was not met in the IA2 according to the predefined alpha spend procedure, the data is maturing in favorably.  At 5 years, nearly 27% of patients in the Abemaciclib + NSAI arm remained progression free vs. 9.6% in the placebo + NSAI arm, demonstrating the likelihood of obtaining a meaningful OS improvement. The final OS analysis is scheduled for 2023.

In terms of this drug versus the others, there have been other comparable reports from the MONALEESA series of trials and the PALOMA series of trials using ribociclib and palbociclib respectively. Palbociclib achieved a median OS of 53.9 months in the palbociclib plus letrozole (PAL+LET) arm and 51.2 months in the PBO + LET arm. Median OS was more than 12 months longer with ribociclib than with placebo in the MONALEESA-2 study.

Among the approved therapies, CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have attracted the most attention. Approximately 29 and 14% of patients with HR+/HER2− BC were found to have amplification of cyclin D1 and CDK4, respectively. Importantly, even when hormonal resistance develops, the tumors still depend on CDK4/6-cyclin D1 for proliferation. Therefore, more pronounced G1-S cell cycle arrest was observed in HR+/HER2− BC after treatment with a combination of hormonal therapy and CDK4/6 inhibitor. Apart from CDK4/6 inhibitors, the upcoming SERDS could also muscle its way into this treatment space for this patient pool. The other class of therapies includes AKT inhibitors, mTOR inhibitors, SERMS, PI3K inhibitors, PARP inhibitors, and TROP-2 targeting antibody-drug conjugate.

These long-term OS follow-up studies of CDK 4/6 inhibitors are very important because it has allowed each of the CDK 4/6 inhibitors abemaciclib, ribociclib, and palbociclib to demonstrate a survival benefit, not just progression-free survival, but an overall survival benefit as well. 

Get more detailed insights, at: HR+/HER2- Breast Cancer Market Outlook / Triple Negative Breast Cancer Market