Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients – Data from the Real-World Registry PRAEGNANT

Abstract

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2− HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time.

Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2− HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated.

Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 – 2022), about 70 – 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics.

Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

Zusammenfassung

Hintergrund Umfangreiche Daten aus prospektiven klinischen Studien liefern einen hohen Evidenzgrad für den Einsatz von CDK4/6-Hemmern in Kombination mit einer endokrinen Therapie (CDK4/6i + ET) als Standard bei der First-Line-Behandlung von metastatischem HER2-negativen hormonrezeptorpositiven (HER2−/HR+) Brustkrebs. Reale Daten von Patientinnengruppen, die damit in der Praxis behandelt wurden, liefern Erkenntnisse über Veränderungen von Patientenmerkmalen und Prognosen im Laufe der Zeit.

Methoden Die Daten wurden dem prospektiven praxisbezogenen PRAEGNANT-Register (NCT02338167) entnommen. Die eingeschlossenen Patientinnen hatten fortgeschrittenen primären und metastasierten HER2−/HR+ Brustkrebs. Die gewählten Therapien, das progressionsfreie Überleben und das Gesamtüberleben der jeweiligen Therapie sowie die Zeitspanne, während der die Behandlung erfolgte, werden dargelegt.

Ergebnisse Nachdem CDK4/6-Hemmer erstmals im November 2016 eingesetzt wurden, stieg die Häufigkeit ihres Einsatzes schnell an. In den letzten Jahren (2018 – 2022) wurden ca. 70 – 80% aller Patientinnengruppen mit CDK4/6-Hemmern behandelt; eine endokrine Monotherapie wurde rund 10% und eine Chemotherapie ungefähr 15% aller Patientinnen verabreicht. Die schlechteste Prognose hatten Patientinnen, die eine Chemotherapie erhielten. Seit Kurzem erhalten hauptsächlich Patientinnen mit guter Prognose eine endokrine Monotherapie; Patientinnen, die eine Chemotherapie erhalten, haben eine ungünstigere Prognose. Das progressionsfreie Überleben und das Gesamtüberleben von mit CDK4/6i + ET behandelten Patientinnen blieb über einen längeren Zeitraum ähnlich, obwohl sich die Patientenmerkmale änderten.

Schlussfolgerung Die Behandlung mit CDK4/6i + ET entwickelte sich rasch zum First-Line-Therapiestandard für Patienten mit fortgeschrittenem Mammakarzinom. Seit der Einführung von CDK4/6i + ET wird die endokrine Monotherapie nur bei Patientinnen mit einer sehr günstigen Prognose eingesetzt, während Chemotherapie meist nur an Patientinnen verabreicht wird, die eine eher ungünstige Prognose haben. Veränderungen der Patientenmerkmale scheinen die Prognose von mit CDK4/6i + ET behandelten Patientinnen nicht zu beeinflussen.

Key words

advanced breast cancer - real world data - chemotherapy - CDK4/6 inhibitor - endocrine treatment

Schlüsselwörter

fortgeschrittenes Mammakarzinom - reale Daten - Chemotherapie - CDK4/6-Hemmer - endokrine Behandlung

Publication History

Received: 31 May 2022

Accepted after revision: 15 June 2022

Article published online:
12 July 2022

• References

• 1 Thill M, Friedrich M, Kolberg-Liedtke C. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2021. Breast Care (Basel) 2021; 16: 228-235
• 2 Ditsch N, Stickeler E, Behrens A. et al. Update Breast Cancer 2021 Part 2 – Advanced Stages, Long-Term Consequences and Biomarkers. Geburtshilfe Frauenheilkd 2021; 81: 539-548
• 3 Tesch H, Müller V, Wöckel A. et al. Update Breast Cancer 2020 Part 4 – Advanced Breast Cancer. Geburtshilfe Frauenheilkd 2020; 80: 1115-1122
• 4 Hortobagyi GN, Stemmer SM, Burris HA III. et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol 2021; 32: S1290-S1291
• 5 Hortobagyi GN, Stemmer SM, Burris HA. et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375: 1738-1748
• 6 Hortobagyi GN, Stemmer SM, Burris HA. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018; 29: 1541-1547
• 7 Slamon DJ, Neven P, Chia S. et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Ann Oncol 2019; 30: v856-v857
• 8 Slamon DJ, Neven P, Chia S. et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382: 514-524
• 9 Slamon DJ, Neven P, Chia S. et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 2018; 36: 2465-2472
• 10 Im SA, Lu YS, Bardia A. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381: 307-316
• 11 Tripathy D, Im SA, Colleoni M. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018; 19: 904-915
• 12 Sledge jr. GW, Toi M, Neven P. et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2020; 6: 116-124
• 13 Sledge jr. GW, Toi M, Neven P. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 2017; 35: 2875-2884
• 14 Goetz MP, Toi M, Campone M. et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35: 3638-3646
• 15 Finn RS, Crown JP, Lang I. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16: 25-35
• 16 Finn RS, Martin M, Rugo HS. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375: 1925-1936
• 17 Cristofanilli M, Turner NC, Bondarenko I. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17: 425-439
• 18 Turner NC, Ro J, André F. et al. PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015; 373: 209-219
• 19 Turner NC, Slamon DJ, Ro J. et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379: 1926-1936
• 20 Lobbezoo DJ, van Kampen RJ, Voogd AC. et al. In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium. Ann Oncol 2016; 27: 256-262
• 21 Schneeweiss A, Ettl J, Lüftner D. et al. Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer – Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany. Breast 2020; 54: 88-95
• 22 DeMichele A, Cristofanilli M, Brufsky A. et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. Breast Cancer Res 2021; 23: 37
• 23 Goldschmidt D, Dalal AA, Romdhani H. et al. Current Treatment Patterns Among Postmenopausal Women with HR+/HER2- Metastatic Breast Cancer in US Community Oncology Practices: An Observational Study. Adv Ther 2018; 35: 482-493
• 24 Edman Kessler L, Wiklander O, Hamberg E. et al. Efficacy and safety of cyclin dependent kinases 4/6 inhibitors in the treatment of metastatic breast cancer: a real-world experience. Acta Oncol 2020; 59: 1382-1387
• 25 Fountzilas E, Koliou GA, Vozikis A. et al. Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group. ESMO Open 2020; 5: e000774
• 26 Manso L, Hernando C, Galán M. et al. Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP). Breast 2020; 54: 286-292
• 27 Harbeck N, Bartlett M, Spurden D. et al. CDK4/6 inhibitors in HR+/HER2- advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies. Future Oncol 2021; 17: 2107-2122
• 28 Collins JM, Nordstrom BL, McLaurin KK. et al. A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status. Oncol Ther 2021; 9: 575-589
• 29 Olazagasti C, Lee CS, Liu A. et al. A deep dive into CDK4/6 inhibitors: Evaluating real world toxicities and treatment paradigms in the elderly population. J Oncol Pharm Pract 2021;
• 30 Lakdawalla DN, Shafrin J, Hou N. et al. Predicting Real-World Effectiveness of Cancer Therapies Using Overall Survival and Progression-Free Survival from Clinical Trials: Empirical Evidence for the ASCO Value Framework. Value Health 2017; 20: 866-875
• 31 Fasching PA, Brucker SY, Fehm TN. et al. Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. Geburtshilfe Frauenheilkd 2015; 75: 41-50
• 32 Hartkopf AD, Huober J, Volz B. et al. Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors – Data from the German PRAEGNANT breast cancer registry. Breast 2018; 37: 42-51
• 33 Müller V, Nabieva N, Häberle L. et al. Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. Breast 2018; 37: 154-160
• 34 Hein A, Gass P, Walter CB. et al. Computerized patient identification for the EMBRACA clinical trial using real-time data from the PRAEGNANT network for metastatic breast cancer patients. Breast Cancer Res Treat 2016; 158: 59-65
• 35 Laakmann E, Emons J, Taran FA. et al. Treatment Landscape and Prognosis After Treatment with Trastuzumab Emtansine. Geburtshilfe Frauenheilkd 2020; 80: 1134-1142
• 36 Wolff AC, Hammond MEH, Allison KH. et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018; 36: 2105-2122
• 37 Allison KH, Hammond MEH, Dowsett M. et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update. Arch Pathol Lab Med 2020; 144: 545-563
• 38 Brookmeyer R, Crowley J. A Confidence-Interval for the Median Survival-Time. Biometrics 1982; 38: 29-41
• 39 Salmen J, Neugebauer J, Fasching PA. et al. Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies. Breast Cancer Res Treat 2014; 148: 143-151
• 40 André F, Neven P, Marinsek N. et al. Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Curr Med Res Opin 2014; 30: 1007-1016
• 41 Swallow E, Zhang J, Thomason D. et al. Real-world patterns of endocrine therapy for metastatic hormone-receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer patients in the United States: 2002–2012. Curr Med Res Opin 2014; 30: 1537-1545
• 42 Martin M, Zielinski C, Ruiz-Borrego M. et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol 2021; 32: 488-499
• 43 ClinicalTrials.gov. Abemaciclib in Combination With Endocrine Therapy as First Line Therapy in Metastatic Breast Cancer Patients With Symp-tomatic Visceral Metastases or High Tumor Burden (Abemacare). 2022. Accessed May 25, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04681768
• 44 Bianchini G, Malorni L, Arpino G. et al. Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial. Cancer Res 2022; 82 (4_Supplement): GS3-07
• 45 Fasching PA. CAPTOR-BC: Gemeinsam Forschen für eine individualisierte Ribociclib-Therapie. 2022. Accessed May 25, 2022 at: https://www.senologiekongress.de/xconfig/upload/files/Programme/Seno2022_Programm.pdf
• 46 Clinicaltrials.gov. Combination of Abemaciclib and Endocrine Therapy in Hormone Receptor Positive HER2 Negative Locally Advanced or Metastatic Breast Cancer With Focus on Digital Side Effect Management (MINERVA). 2022. Accessed May 25, 2022 at: https://clinicaltrials.gov/ct2/show/NCT05362760
• 47 Bidard F-C, Hardy-Bessard A-C, Bachelot T. et al. Fulvestrant-palbociclib vs. continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Cancer Res 2022; 82 (4_Supplement): GS3-05
• 48 clinicaltrials.gov. Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1 m Before Progression (SERENA-6) (SERENA-6). 2021. Accessed October 24, 2021 at: https://clinicaltrials.gov/ct2/show/NCT04964934
• 49 European Society of Medical Oncology. ESMO Real World Data and Digital Health Working Group. 2022. Accessed May 25, 2022 at: https://www.esmo.org/about-esmo/organisational-structure/educational-committee/real-world-data-and-digital-health-working-group