By Dr. Arya Miriam Roy & Dr. Shipra Gandhi
of Roswell Park Comprehensive Cancer Center
The CDK 4/6 inhibitors with endocrine therapy are the current standard of care for first-line treatment in advanced estrogen receptor-positive (ER+) HER2-negative breast cancer. The results of PALOMA -2 trial[1], MONALESSA-2[2], and MONARCH-3 [3]trials established the use of palbociclib, ribociclib, and abemaciclib respectively, for use in metastatic ER+ HER2-negative breast cancer. However, first-line use of the CDK 4/6 inhibitors is associated with prolonged side effects and higher costs. Despite the lack of adequate evidence, most guidelines recommend using CDK4/6 inhibitors as the first-line treatment. There is an ongoing question about delaying the use of CDK 4/6 inhibitors in metastatic ER+ HER2-negative breast cancer.
Dr. Sonke et al. presented the randomized phase III SONIA trial results at the 2023 ASCO annual meeting. The trial compared the use of CDK4/6 inhibitors as first vs. second-line treatment in patients with advanced ER+/HER2- breast cancer. The trial enrolled pre and post-menopausal women with ER+ HER2-negative breast cancer from Nov 2017 to September 2021 who had not received prior treatments for advanced breast cancer. Patients were randomized 1:1 to receive non-steroidal aromatase inhibitors (AI) and CDK4/6 inhibitors followed by fulvestrant alone upon progression vs. non-steroidal AI alone in the first line followed by fulvestrant + CDK 4/6 inhibitors as the second line. The primary endpoint was progression-free survival (PFS) after two lines of treatment (PFS2). The secondary endpoints were quality of life, overall survival (OS), and cost-effectiveness. Of the 1050 patients, 524 received CDK 4/6 inhibitors as first-line, and 526 received CDK 4/6 inhibitors as second line. The baseline characteristics were similar in both groups. The median follow-up was 37.3 months. The median duration of treatment of CDK 4/6 inhibitor in the first line was 24.6 months compared to 8.1 months in the second line. The primary endpoint PFS2 in the first line CDK 4/6 inhibitor was 31 months, and in the second line, it was 26.8 months, which was not statistically significant (Hazard ratio (HR) 0.87 (0.74-1.03), p-value 0.10). The OS was 45.9 months in the first line vs. 53.7 months in the second line setting, which was also not statistically significant (HR 0.98 (0.80-1.20), p-value 0.83. The effects were similar in the subgroup analysis (stratified based on the prior (neo)adjuvant chemotherapy, prior (neo) adjuvant hormonal therapy, visceral disease, type of CDK 4/6 inhibitors, visceral disease, bone-only disease). 42% more grade >= 3 adverse events were observed when CDK 4/6 inhibitors were used in the first line.
Based on the results of the SONIA trial, the use of CDK 4/6 inhibitors in the first line compared to the second line does not improve progression-free survival or overall survival or quality of life of patients. The use of CDK 4/6 inhibitors was associated with an increased drug expenditure of $200,000 per patient, which would be a huge burden to the healthcare system. Based on the given data, it would be critical to reconsider the recommendation of CDK 4/6 inhibitors as first-line for all advanced ER+ HER2-negative breast cancer patients. We need biomarkers to identify the patients who would benefit from the combination of endocrine and CDK 4/6 inhibitors in the first-line setting.
1. Finn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.A.; Gelmon, K.; Harbeck, N.; Lipatov, O.N.; Walshe, J.M.; Moulder, S.; et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016, 375, 1925-1936, doi:10.1056/NEJMoa1607303.
2. Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Hart, L.; Campone, M.; Petrakova, K.; Winer, E.P.; Janni, W.; et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022, 386, 942-950, doi:10.1056/NEJMoa2114663.
3. Goetz, M.P.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.H.; Tredan, O.; Chen, S.C.; Manso, L.; et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017, 35, 3638-3646, doi:10.1200/JCO.2017.75.6155.
