NEW YORK – Metastatic breast cancer patients who received CDK4/6 inhibitors plus endocrine therapy as a first-line treatment experienced no survival or quality-of-life advantages over those who received the drugs as a second-line therapy, according to data presented at the American Society of Clinical Oncology's annual meeting this week.
However, in the Phase III SONIA trial, hormone receptor (HR)-positive, HER2-negative metastatic breast cancer patients who received first-line CDK4/6 inhibitor treatment combined with endocrine therapy did experience more toxicities and higher costs than those who received endocrine therapy first and CDK4/6 inhibitors upon progression.
Gabe Sonke, a lead investigator with the SONIA trial, estimated that giving CDK4/6 inhibitors at the outset increased costs by $200,000 per patient versus waiting until the second line. In presenting the data from this trial at the meeting, Sonke, who is an oncologist at the Netherlands Cancer Institute, called for more post-marketing academic trials like SONIA to optimize the use of newly approved treatments.
Data from a number of prospective, randomized-controlled trials including PALOMA-2, MONALEESA-2, MONARCH-3, and others have established combining CDK4/6 inhibitors with endocrine therapy as a first-line option for HR-positive/HER2-negative advanced breast cancer patients and shown disease-free survival benefits with three approved CDK4/6 inhibitors in this setting: Pfizer's Ibrance (palbociclib), Novartis' Kisqali (ribociclib), and Eli Lilly's Verzenio (abemaciclib).
The trials that led to the approval of these therapies didn't directly compare patients' outcomes on first- and second-line therapy. However, absolute improvements were greater in patients who received the CDK4/6 inhibitor as a first-line therapy, resulting in guidelines favoring first-line therapy as the preferred strategy.
"Many patients do very well on [first-line] endocrine therapy alone," Sonke pointed out during his presentation. "Combination treatment leads to a higher risk of the emergence of treatment resistance patterns such as ESR1 mutations. CDK4/6 inhibitors also come with added costs and toxicities."
Given the absence of head-to-head comparative data between first- and second-line therapy outcomes, Sonke and his team designed the SONIA trial to test the hypothesis that patients may do as well or better when they receive CDK4/6 inhibitors once they experience disease progression on first-line endocrine therapy, as opposed to receiving the CDK4/6-endocrine therapy regimen at the outset and then endocrine therapy upon progression. The trial was funded by the Dutch government and Dutch health insurance companies and 74 hospitals in the Netherlands participated.
In the trial, Sonke's team randomized 1,050 patients with HR-positive/HER2-negative advanced breast cancer to receive a nonsteroidal aromatase inhibitor plus a CDK4/6 inhibitor in the first line followed by fulvestrant at disease progression; or just a nonsteroidal aromatase inhibitor in the first line followed by fulvestrant and a CDK4/6 inhibitor at progression. Physicians could choose any of the approved CDK4/6 inhibitors, though they chose Ibrance most often.
Researchers were primarily interested in tracking patients' progression-free survival after two lines of treatment. They also tracked overall survival, quality of life, and safety, and analyzed biomarkers as secondary endpoints.
The median duration of treatment with a CDK4/6 inhibitor was 24.6 months in the first-line setting and 8.1 months in the second-line setting. Sonke pointed out the 16.5-month median difference as notable.
Progression-free survival for patients in the first-line CDK4/6 inhibitor treatment group was 24.7 months compared to 16.1 months for those who received such treatments in the second-line setting.
However, noting that the primary endpoint of the trial was progression-free survival after two lines of therapy, Sonke pointed out that first-line and second-line patients had comparable progression-free survival. At that point, the median progression-free survival advantage for the CDK4/6 inhibitor first-line group over the second-line group — 31.0 months and 26.8 months, respectively — did not reach statistical significance. There was also no statistically significant difference in overall survival, which was 45.9 months for CDK4/6 inhibitor first-line treatment and 53.7 months for second-line. Subgroup analysis, including groups receiving different CDK4/6 inhibitors, also showed no significant advantages.
Investigators measured quality of life using a set of validated questionnaires and found no differences between study arms. Patients on first-line CDK4/6 inhibitors had 42 percent more grade 3 or higher adverse events.
Sonke concluded that treatment with first-line CDK4/6 inhibitors did not improve progression-free survival, overall survival, or quality of life, while extending the time on the drugs by 16.5 months and increasing toxicity at a cost of $200,000 per patient. "SONIA shows that delaying CDK4/6 inhibitors until second-line treatment is as good as starting these drugs earlier while minimizing toxicity and costs. Second-line CDK4/6 inhibitor treatment should therefore be the standard for HR-positive HER2-negative advanced breast cancer patients, while biomarker studies try to identify the patients that benefit from a first-line strategy," Sonke said in an interview.
Recent trials such as NATALEE and monarchE have shown that CDK4/6 inhibitors plus endocrine therapy benefit early-stage breast cancer patients, raising further questions about the ideal timing for CDK4/6 therapy. "During the SONIA trial, patients were not given adjuvant treatment using CDK4/6 inhibitors because the monarchE and NATALEE studies had not reported results at the time we designed the trial," Sonke said. "If adjuvant treatment with CDK4/6 inhibitors becomes the new standard approach, the effectiveness of these inhibitors in the advanced setting for patients with recurrent disease is likely to be reduced, making first-line treatment even less appealing."
Sonke added that the SONIA trial results will remain important for patients with de novo metastatic disease, which accounts for about one-third of patients with HR-positive/HER2-negative disease. "Of note, it is uncertain whether adjuvant treatment will be adopted as the standard for all patients, as it requires treating around 30 patients to prevent or delay a single instance of disease recurrence," Sonke estimated.
Sonke hopes that the results from SONIA will encourage more academic researchers to undertake similar trials. "Post-marketing academic trials like SONIA can help to significantly reduce the toxicity of effective drugs and make them more accessible to those who would otherwise find them unaffordable," Sonke said.