Ribociclib as first-line therapy for HR-positive, advanced breast cancer

G. N. Hortobagyi, S. M. Stemmer, H. A. Burris, Y. S. Yap, G. S. Sonke, S. Paluch-Shimon, M. Campone, K. L. Blackwell, F. Andre, E. P. Winer, W. Janni, S. Verma, P. Conte, C. L. Arteaga, D. A. Cameron, K. Petrakova, L. L. Hart, C. Villanueva, A. Chan, E. JakobsenA. Nusch, O. Burdaeva, E. M. Grischke, E. Alba, E. Wist, N. Marschner, A. M. Favret, D. Yardley, T. Bachelot, L. M. Tseng, S. Blau, F. Xuan, F. Souami, M. Miller, C. Germa, S. Hirawat, J. O'Shaughnessy

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Abstract

BACKGROUND The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.

Original languageEnglish (US)
Pages (from-to)1738-1748
Number of pages11
JournalNew England Journal of Medicine
Volume375
Issue number18
DOIs
StatePublished - Nov 3 2016

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letrozole
Hormones
Breast Neoplasms
Placebos
Disease-Free Survival
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Confidence Intervals
Therapeutics
Safety
Leukopenia
ribociclib
Neutropenia
Disease Progression
Appointments and Schedules
Survival Rate
Research Personnel

ASJC Scopus subject areas

  • Medicine(all)

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Hortobagyi, G. N., Stemmer, S. M., Burris, H. A., Yap, Y. S., Sonke, G. S., Paluch-Shimon, S., ... O'Shaughnessy, J. (2016). Ribociclib as first-line therapy for HR-positive, advanced breast cancer. New England Journal of Medicine, 375(18), 1738-1748. https://doi.org/10.1056/NEJMoa1609709

Ribociclib as first-line therapy for HR-positive, advanced breast cancer. / Hortobagyi, G. N.; Stemmer, S. M.; Burris, H. A.; Yap, Y. S.; Sonke, G. S.; Paluch-Shimon, S.; Campone, M.; Blackwell, K. L.; Andre, F.; Winer, E. P.; Janni, W.; Verma, S.; Conte, P.; Arteaga, C. L.; Cameron, D. A.; Petrakova, K.; Hart, L. L.; Villanueva, C.; Chan, A.; Jakobsen, E.; Nusch, A.; Burdaeva, O.; Grischke, E. M.; Alba, E.; Wist, E.; Marschner, N.; Favret, A. M.; Yardley, D.; Bachelot, T.; Tseng, L. M.; Blau, S.; Xuan, F.; Souami, F.; Miller, M.; Germa, C.; Hirawat, S.; O'Shaughnessy, J.

In: New England Journal of Medicine, Vol. 375, No. 18, 03.11.2016, p. 1738-1748.

Research output: Contribution to journalArticle

Hortobagyi, GN, Stemmer, SM, Burris, HA, Yap, YS, Sonke, GS, Paluch-Shimon, S, Campone, M, Blackwell, KL, Andre, F, Winer, EP, Janni, W, Verma, S, Conte, P, Arteaga, CL, Cameron, DA, Petrakova, K, Hart, LL, Villanueva, C, Chan, A, Jakobsen, E, Nusch, A, Burdaeva, O, Grischke, EM, Alba, E, Wist, E, Marschner, N, Favret, AM, Yardley, D, Bachelot, T, Tseng, LM, Blau, S, Xuan, F, Souami, F, Miller, M, Germa, C, Hirawat, S & O'Shaughnessy, J 2016, 'Ribociclib as first-line therapy for HR-positive, advanced breast cancer', New England Journal of Medicine, vol. 375, no. 18, pp. 1738-1748. https://doi.org/10.1056/NEJMoa1609709
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. New England Journal of Medicine. 2016 Nov 3;375(18):1738-1748. https://doi.org/10.1056/NEJMoa1609709
Hortobagyi, G. N. ; Stemmer, S. M. ; Burris, H. A. ; Yap, Y. S. ; Sonke, G. S. ; Paluch-Shimon, S. ; Campone, M. ; Blackwell, K. L. ; Andre, F. ; Winer, E. P. ; Janni, W. ; Verma, S. ; Conte, P. ; Arteaga, C. L. ; Cameron, D. A. ; Petrakova, K. ; Hart, L. L. ; Villanueva, C. ; Chan, A. ; Jakobsen, E. ; Nusch, A. ; Burdaeva, O. ; Grischke, E. M. ; Alba, E. ; Wist, E. ; Marschner, N. ; Favret, A. M. ; Yardley, D. ; Bachelot, T. ; Tseng, L. M. ; Blau, S. ; Xuan, F. ; Souami, F. ; Miller, M. ; Germa, C. ; Hirawat, S. ; O'Shaughnessy, J. / Ribociclib as first-line therapy for HR-positive, advanced breast cancer. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 18. pp. 1738-1748.
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title = "Ribociclib as first-line therapy for HR-positive, advanced breast cancer",
abstract = "BACKGROUND The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95{\%} CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0{\%} (95{\%} confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2{\%} (95{\%} CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7{\%} and 37.1{\%}, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10{\%} of the patients in either group were neutropenia (59.3{\%} in the ribociclib group vs. 0.9{\%} in the placebo group) and leukopenia (21.0{\%} vs. 0.6{\%}); the rates of discontinuation because of adverse events were 7.5{\%} and 2.1{\%}, respectively. CONCLUSIONS Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.",
author = "Hortobagyi, {G. N.} and Stemmer, {S. M.} and Burris, {H. A.} and Yap, {Y. S.} and Sonke, {G. S.} and S. Paluch-Shimon and M. Campone and Blackwell, {K. L.} and F. Andre and Winer, {E. P.} and W. Janni and S. Verma and P. Conte and Arteaga, {C. L.} and Cameron, {D. A.} and K. Petrakova and Hart, {L. L.} and C. Villanueva and A. Chan and E. Jakobsen and A. Nusch and O. Burdaeva and Grischke, {E. M.} and E. Alba and E. Wist and N. Marschner and Favret, {A. M.} and D. Yardley and T. Bachelot and Tseng, {L. M.} and S. Blau and F. Xuan and F. Souami and M. Miller and C. Germa and S. Hirawat and J. O'Shaughnessy",
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TY - JOUR

T1 - Ribociclib as first-line therapy for HR-positive, advanced breast cancer

AU - Hortobagyi, G. N.

AU - Stemmer, S. M.

AU - Burris, H. A.

AU - Yap, Y. S.

AU - Sonke, G. S.

AU - Paluch-Shimon, S.

AU - Campone, M.

AU - Blackwell, K. L.

AU - Andre, F.

AU - Winer, E. P.

AU - Janni, W.

AU - Verma, S.

AU - Conte, P.

AU - Arteaga, C. L.

AU - Cameron, D. A.

AU - Petrakova, K.

AU - Hart, L. L.

AU - Villanueva, C.

AU - Chan, A.

AU - Jakobsen, E.

AU - Nusch, A.

AU - Burdaeva, O.

AU - Grischke, E. M.

AU - Alba, E.

AU - Wist, E.

AU - Marschner, N.

AU - Favret, A. M.

AU - Yardley, D.

AU - Bachelot, T.

AU - Tseng, L. M.

AU - Blau, S.

AU - Xuan, F.

AU - Souami, F.

AU - Miller, M.

AU - Germa, C.

AU - Hirawat, S.

AU - O'Shaughnessy, J.

PY - 2016/11/3

Y1 - 2016/11/3

N2 - BACKGROUND The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.

AB - BACKGROUND The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5. RESULTS The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.

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