First- vs. second-line CDK4/6 inhibitor use fails to benefit breast cancer subgroup
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Key takeaways:
- CDK4/6 inhibitors in the earlier setting did not lead to statistically significant PFS or OS improvement.
- The results challenge the need for first-line use of CDK4/6 inhibitors.
CHICAGO — First-line use of cyclin-dependent kinase 4/6 inhibitors did not confer significant benefit vs. second-line use when added to endocrine therapy for women with hormone receptor-positive, HER2-negative, advanced breast cancer.
The findings, presented at ASCO Annual Meeting, suggested second-line cyclin-dependent kinase (CDK)4/6 inhibitors may be the preferred treatment option for most patients.
Rationale and methods
“CDK4/6 inhibitors have been shown to improve outcomes for women with estrogen receptor-positive HER2-advanced breast cancer. However, comparative data are lacking to help clinicians decide if CDK4/6 inhibitors should be added to first- or second-line endocrine therapy,” Gabe S. Sonke, MD, PhD, researcher at Netherlands Cancer Institute, told Healio. “While absolute improvement in first-line studies was larger than in second-line studies, only a minority of patients in the control arm of first-line studies crossed over to receive CDK4/6 inhibitors in the second-line setting. Moreover, these agents come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone.”
The phase-3, randomized, investigator-initiated, nationwide SONIA trial included 1,050 premenopausal and postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer receiving treatment across 74 Dutch hospitals.
Researchers randomly assigned patients to either first-line treatment with a nonsteroidal aromatase inhibitor plus a CDK4/6 inhibitor of physician’s choice, followed upon progression by fulvestrant, or first-line treatment with a nonsteroidal aromatase inhibitor, followed upon progression by fulvestrant plus a CDK4/6 inhibitor.
Ninety-one percent of patients in each group received palbociclib (Ibrance, Pfizer) as the CDK4/6 inhibitor.
Time from randomization to second objective disease progression, as assessed by local investigator, or death served as the primary endpoint. Secondary endpoints included OS, safety, quality of life and cost-effectiveness.
Median follow-up was 37.3 months.
Findings
Results showed the addition of CDK4/6 inhibitors in the first-line vs. second-line setting did not lead to a statistically significant nor clinically relevant PFS benefit (HR = 0.87; 95% CI, 0.74-1.03), OS benefit (HR = 0.98; 95% CI, 0.8-1.2) or quality-of-life improvement, according to Sonke.
In addition, first-line treatment with the CDK4/6 inhibitor combination extended time on treatment by 16.6 months, increased incidence of grade 3 to grade 4 adverse events by 42% and increased drug expenditures by approximately $200,000 per patient.
“While the treatment landscape has changed since the start of SONIA, it is important to note that patients in both arms were able to receive alpelisib [Piqray, Novartis] in case of a PIK3CA mutation after second progression,” Sonke said. “In addition, most patients used palbociclib, while ribociclib [Kisqali, Novartis] and abemaciclib [Verzenio, Eli Lilly & Co.] have become the preferred drug for many patients more recently. Since PFS with all three agents was remarkably similar in the pivotal trials, it is unlikely that the choice for one of the three CDK4/6 inhibitors impacted the read-out of the primary endpoint on PFS. Indeed, a preplanned subgroup analysis did not indicate a differential effect between palbociclib and ribociclib, and the numbers for abemaciclib are too small for comparison.”
Implications
The SONIA results challenge the need for first-line use of CDK4/6 inhibitors, Sonke told Healio.
“The general trend of treating earlier — first-line as opposed to second-line, but also moving treatments from the advanced to the adjuvant setting — may result in clinical benefit for a small number of patients, but the numbers needed to treat are often very high and drug expenditures rise steeply as a result of these strategies,” Sonke said. “Obviously, biomarkers are needed to identify subgroups of patients who benefit from one strategy or another, but unfortunately in the CDK4/6 inhibitor space, the search for biomarkers has not yet been successful.”
Meanwhile, endocrine monotherapy remains an excellent option for patients, particularly in the first-line metastatic setting as mechanisms of resistance occur in later lines with the use of targeted agents, he continued.
“Pivotal trials that lead to registration of a new drug provide data on efficacy and safety of the drug in an experimental setting designed to maximize the probability of a positive study result,” Sonke said. “These trials, however, often leave patients and physicians with unanswered questions on how to best use the new drug in clinical practice. By conducting randomized clinical trials like SONIA that evaluate lower doses, less frequent administration or shorter treatment courses, researchers can determine the optimal treatment-schedule that minimizes harmful side effects while maintaining therapeutic benefits.”
Perspective
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Aditya Bardia, MD, MPH
Are the results of the SONIA trial practice changing?
First, the authors are to be congratulated on conducting this important study. The results are certainly intriguing and potentially challenge the current paradigm.
We will have to look at additional details in terms of genomics and what the patients received later on. There was some concern that fulvestrant was used in the second line, whereas we are increasingly using combinations in second line such as fulvestrant plus alpelisib for PIK3CA-mutant or elacestrant for ESR1-mutant breast cancer. So, the standard of care might not be standard of care at this time.
Nevertheless, in our clinic, we all have patients who do very well on endocrine monotherapy. Before CDK4/6 inhibitors were approved, there was a subset of patients who would do very well on endocrine monotherapy. The question is, can we identify that subgroup by biomarkers? The SONIA trial provides us a strong impetus to identify biomarkers so that we can identify the subgroup of patients who can do well on endocrine-based monotherapy.
At this time, I would still consider endocrine therapy plus CDK4/6 inhibitors as first-line treatment until we get the biomarkers and additional clarification on the points raised above.
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Sonke GS, et al. Abstract LBA1000. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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