There are still too many unknowns, given the lack of overall survival benefit observed so far, and too much risk of harm, given the reported side effects and high cost of treatment, Bishal Gyawali, MD, PhD, a medical oncologist at Queen's University in Kingston, Ontario, Canada, and colleagues explain in ecancermedicalscience.
Considering the "dubious or even non-existent benefit in a small percentage of patients, we believe it is premature to recommend adjuvant abemaciclib to patients with early breast cancer without waiting for mature data," Gyawali and co-authors Amol Akhade, MD, and Simon Van Wambeke, MD, write.
For now, "it's safe to say that CDK 4/6 inhibitors can be reserved for later lines" of therapy, Gyawali told Medscape Medical News.
Last October, the US Food and Drug Administration approved the use of abemaciclib with endocrine therapy in the adjuvant setting for women with early HR-positive, HER2-negative breast cancer who are at high risk for relapse and who have a Ki-67 score of 20% or higher.
At the time, drugmaker Eli Lilly noted in a press release that the approval made abemaciclib the first add-on that was approved for adjuvant endocrine therapy in nearly 20 years.
A researcher on the company's approval study called the new indication "practice-changing" and said this combination could "become a new standard of care."
A month later, the American Society of Clinical Oncology updated its guidelines to give a strong recommendation for the use of abemaciclib with adjuvant endocrine therapy for patients who meet the indication requirements.
As for uptake by the oncology community, Eli Lilly reported earning $384.3 million for abemaciclib in the US in the second quarter of 2022 — up 83% from the second quarter of 2021.
But Gyawali and colleagues give reasons to be wary.
For one, the approval was based on a significant improvement in invasive disease-free survival at 36 months — 79% with endocrine therapy alone, vs 86% with the addition of abemaciclib; however, invasive disease-free survival has not been validated as a surrogate for overall survival. And in the trial, an overall survival benefit had not emerged at 27 months.
In addition, abemaciclib's side effects are notable. Almost 50% of patients experienced grade 3 or higher adverse events with abemaciclib, vs 16% with placebo.
And with a price tag of more than $300,000 over 2 years, the authors worry about "substantial financial toxicity" for a drug with "uncertain benefit" and "known toxicities."
Another potential downside: Giving the drug too early might generate treatment-resistant clones, potentially wiping out a benefit from abemaciclib in the advanced/metastatic setting.
In fact, "the possibility of a worse [overall survival] also exists, if early CDK 4/6 exposure leads to the development of an aggressive, treatment resistant clone," Gyawali and co-authors write.
The team also probed why another CDK 4/6 inhibitor, palbociclib, which has a similar mechanism of action to abemaciclib and is similar in efficacy for the treatment of metastatic disease, struck out twice in trials for early hormone- positive breast cancer — wondering, for instance, whether there is a "genuine difference" between the two that can explain the outcomes in the adjuvant setting.
Overall, the editorialists "urge caution" before accepting abemaciclib as standard of care in early breast cancer.
"We do not understand the haste in approving an agent in [the] adjuvant setting and including it in guidelines based on premature data," they write.
Gyawali has received consulting fees from Vivio Health, and another author has received speaker fees from Janssen and IPSEN.
Ecancermedicalscience. Published online August 30, 2022. Full text
M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: email@example.com.
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Cite this: 'Dubious' Benefit of Abemaciclib in Early Breast Cancer - Medscape - Sep 22, 2022.