OS Trending Positive for Abemaciclib

Abemaciclib (Verzenio; Eli Lilly) was approved in 2018 for patients newly diagnosed with hormone receptor–positive (HR⁺), HER2-negative (HER2⁻) breast cancer based on progression-free survival (PFS) data from the MONARCH 3 trial. But whether the drug increases overall survival (OS) in these patients has been unclear. The latest interim analysis of trial data shows a nonsignificant trend toward improved OS, with final results to come.

Abemaciclib is the third CDK4/6 inhibitor to be approved as an initial treatment, in combination with endocrine therapy, for patients with metastatic HR⁺/HER2⁻ breast cancer. Ribociclib (Kisqali; Novartis) stands out for increasing PFS and OS in the MONALEESA-2 trial. The median OS in the ribociclib group was 63.9 months versus 51.4 months in the control group. The third approved CDK4/6 inhibitor, palbociclib (Ibrance; Pfizer), extended PFS but did not lengthen OS in the PALOMA-2 trial.

Matthew Goetz, MD, of the Mayo Clinic in Rochester, MN, and colleagues presented the latest OS results for MONARCH 3, which reflect 5.6 years of follow-up, at the ESMO 2022 Congress in Paris, France. Patients who received abemaciclib and endocrine therapy with one of two aromatase inhibitors—letrozole or anastrozole—survived a median of 67.1 months versus 54.5 months for those who received a placebo and either aromatase inhibitor. Yet so far, this difference is not statistically significant. Still, says Goetz, “we are seeing a large numerical difference in overall survival.” 

The analysis also revealed other positive trends. For example, for patients with visceral disease, OS was 65.1 months in the abemaciclib group and 48.8 months in the placebo group. But again, the difference didn’t reach statistical significance.

The interim results confirmed earlier safety findings for abemaciclib. Diarrhea was the most common side effect, occurring in 83.2% of patients who received abemaciclib and 33.5% of patients who received the placebo. Neutropenia was second most common, detected in 46.8% and 1.9% of patients, respectively.

Oncologists decide which of the three approved CDK4/6 inhibitors to prescribe “on a case-by-case basis,” says Jessica Tao, MD, of Johns Hopkins Medicine in Baltimore, MD, who isn’t connected to the MONARCH 3 trial. “Ribociclib’s positive OS findings carry a lot of weight and are acknowledged in our decision-making.” However, she notes, the drug can cause cardiac side effects and isn’t suitable for some patients.

The final results for MONARCH 3 will be available after the data cutoff in 2023. Oncologists will have to see these numbers before deciding whether to incorporate abemaciclib into treatment, says Cesar Santa-Maria, MD, also of Johns Hopkins Medicine. “There is a trend, but I don’t think trends are necessarily sufficient to change clinical practice.” Even if the results are negative, he says, that won’t mean that abemaciclib is inferior to ribociclib because no trials have compared the drugs head-to-head. However, he thinks that if the final OS is not significant, physicians may prefer ribociclib because of its proven survival benefit.

The lack of statistical significance in the interim analysis is not worrying, says Nicholas McAndrew, MD, of the UCLA David Geffen School of Medicine in Los Angeles, CA. The results “are not trending in an unsurprising way.” Still, he says, the final outcome probably won’t change his prescribing decisions. Either way, he will have to balance the potential benefits and risks of each CDK4/6 inhibitor, including the fact that “abemaciclib is definitely a tougher drug” for patients to tolerate. –Mitch Leslie