Phase 3 SONIA Trial Challenges the Routine Practice of Using a 1st Line CDK4/6 Inhibitor
Those with HR+, HER2- MBC may find this interesting!
The Phase 3 SONIA study of 1,050 patients with HR+, HER2- MBC evaluated progression free survival (PFS) and overall survival (OS) from the initiation of first line treatment through failure of second line treatment. It compared two groups of patients. One group took the current first line standard-of care-treatment consisting of a combination of a CDK4/6 inhibitor with an aromatase inhibitor (followed by Faslodex as second-line treatment after progression). The second group started with an aromatase inhibitor alone, followed by a combination of a CDK4/6 inhibitor with Faslodex after progression on initial treatment.
As disclosed at ASCO 2023, the study determined that there was no statistically significant difference in time to progression and OS through second-line therapy between the two groups. Median OS through second line treatment reached 45.9 months when a CDK4/6 inhibitor was used in the first line, and 53.7 months when a CDK4/6 inhibitor was used in the second line (P = .83). (Anne's note: nearly 8 months' difference in OS sounds pretty significant to me!)
Patients who received a CDK4/6 inhibitor up-front remained on it for a median of 24.6 months until moving to second line treatment, whereas patients who received a CDK4/6 inhibitor in the second line took it for a median of 8.1 months until treatment failure - a 16.5 month difference. Because patients taking the CDK4/6 inhibitor as first line therapy remained on it much longer than patients taking it in the second line setting, they experienced a 42% increase in the incidence of grade 3/4 toxicity and an increase in drug expenditure of approximately $200,000 per patient.
According to Gabe Sonke, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, the SONIA results warrant rethinking of the current "CDK4/6 inhibitor in the first line setting for all" paradigm. And Daniel Stover, MD, of the Ohio State University Comprehensive Cancer Center, agreed that the SONIA trial asks the important question of whether all patients need to start with a CDK4/6 inhibitor as first-line therapy because identifying the ‘right size’ therapy for patients with HR+, HER2- MBC is highly important.
The SONIA study has some limitations. It reflects state-of-the-art treatment when the trial was initiated in 2017 but now may be considered somewhat dated. For example, more than 90% of patients in the study received Ibrance as the CDK4/6 inhibitor, which is currently considered the least attractive CDK4/6 inhibitor to use in the first line because of its relative lack of OS benefit. Moreover, in the second line setting, other treatment options are now available such as Piqray plus Faslodex and Elacestrant, along with other emerging agents and combinations.
In conclusion, as Dr. Sonke further commented, by conducting randomized clinical trials such as SONIA that evaluate shorter treatment courses, lower doses, or less frequent administration, researchers can determine the optimal treatment that minimizes harmful side effects while maintaining the therapeutic benefits. This approach can significantly reduce the toxicity of medications while making effective drugs more accessible to patients who would otherwise find them unaffordable. Furthermore, the costs of these trials can be covered by the savings achieved through the less-expensive treatments used in the study - the SONIA study saved approximately 25 million Euros on drug expenditure during the trial which may entice insurance companies and governments that are paying for patient care to fund these trials since they become self-funding.