Ribociclib plus Endocrine Therapy in Early Breast Cancer

Author(s): Dennis Slamon, M.D., Ph.D., Oleg Lipatov, M.D., Zbigniew Nowecki, M.D., Nicholas McAndrew, M.D., Bozena Kukielka-Budny, M.D., Daniil Stroyakovskiy, M.D., Ph.D., Denise A. Yardley, M.D., Chiun-Sheng Huang, M.D., Ph.D., Peter A. Fasching, M.D., John Crown, M.D., Aditya Bardia, M.D., Stephen Chia, M.D., Seock-Ah Im, M.D., Ph.D., Manuel Ruiz-Borrego, M.D., Sherene Loi, M.D., Ph.D., Binghe Xu, M.D., Ph.D., Sara Hurvitz, M.D., Carlos Barrios, M.D., Michael Untch, M.D., Ph.D., Rebecca Moroose, M.D., Frances Visco, J.D., Karen Afenjar, M.S., Rodrigo Fresco, M.D., Irene Severin, B.Sc., Yan Ji, Ph.D., Farhat Ghaznawi, M.D., Zheng Li, Ph.D., Juan P. Zarate, M.D., Arunava Chakravartty, Ph.D., Tetiana Taran, M.D., and Gabriel Hortobagyi, M.D.

Source: N Engl J Med 2024;390:1080-1091

Dr. Anjan Patel's Thoughts

For your stage II – III HR+, HER2-neg breast cancer patients. Adjuvant Ribociclib + AI showed a ~3% invasive DFS benefit vs. an AI alone (90 vs 87%). This is a 3-year treatment protocol as opposed to 5 years of an AI, which some patients may appreciate.

BACKGROUND

Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.

METHODS

In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease–free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease–free survival was evaluated with the use of the Kaplan–Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.

RESULTS

As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease–free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease–free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P=0.003). Secondary end points — distant disease–free survival and recurrence-free survival — also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.

CONCLUSIONS

Ribociclib plus an NSAI significantly improved invasive disease–free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.)

Author Affiliations

From the David Geffen School of Medicine at the University of California, Los Angeles (D. Slamon, N.M.); Republican Clinical Oncology Dispensary, Ufa (O.L.), and Moscow City Oncology Hospital No. 62, Moscow (D. Stroyakovskiy) — both in Russia; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw (Z.N.), and Centrum Onkologii Ziemi Lubelskiej im. św. Jana z Dukli, Lublin (B.K.-B.) — both in Poland; the Sarah Cannon Research Institute at Tennessee Oncology, Nashville (D.A.Y.); the National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei City (C.-S.H.); University Hospital Erlangen, the Comprehensive Cancer Center Erlangen–European Metropolitan Region of Nuremberg, Friedrich-Alexander University Erlangen–Nuremberg, Erlangen (P.A.F.), and the Interdisciplinary Breast Cancer Center, Helios Klinikum Berlin–Buch, Berlin (M.U.) — both in Germany; St. Vincent’s Hospital, Dublin (J.C.); Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston (A.B.); the British Columbia Cancer Agency, Vancouver (S.C.), and Translational Research in Oncology (TRIO), Edmonton, AB (I.S.) — both in Canada; the Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Hospital Virgen del Rocío, Seville, and Grupo Español de Investigación en Cáncer de Mama, Spanish Breast Cancer Group, Madrid — both in Spain (M.R.-B.); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S.L.); the Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (B.X.); the Fred Hutchinson Cancer Center, University of Washington, Seattle (S.H.); the Latin American Cooperative Oncology Group, Porto Alegre, Brazil (C.B.); the Orlando Health Cancer Institute, Orlando, FL (R.M.); the National Breast Cancer Coalition, Washington, DC (F.V.); TRIO, Paris (K.A.); TRIO, Montevideo, Uruguay (R.F.); Novartis Pharmaceuticals, East Hanover, NJ (Y.J., F.G., Z.L., J.P.Z., A.C.); Novartis Pharma, Basel, Switzerland (T.T.); and the Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston (G.H.).

PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer

Findings from the PACE study show that the addition of Palbociclib to Fulvestrant was not better than Fulvestrant alone, and the addition of Avelumab to Fulvestrant improved and nearly doubled the PFS. This is compelling and should be studied further for our patients with HR+ HER2- MBC.

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

This is a study showing tumor agnostic activity of trastuzumab deruxtecan (T-DXd) with an all-comer overall response rate (ORR) of 37.1%, duration of response (DOR) of 11.3 months and an overall survival (OS) of 13.4 months in an otherwise heavily pre-treated group. Those with IHC-3+ derived larger benefit than 2+. Patients with ERBB2 mutations who had no expression of HER2 were excluded from the trial.

Randomized Trial of Exercise and Nutrition on Chemotherapy Completion and Pathologic Complete Response in Women With Breast Cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis Study

There have been studies showing decreased recurrence in women who underwent curative breast surgeries (walking and yoga). This study assesses if it will affect the intensity of chemotherapy delivered. Although it did not affect it, women who underwent the program had better pathologic complete response (pCR), we need more studies to assess role of nutrition and exercise in treating cancer as we develop a wholesome approach to treat our patients, something we may be able to do in our practice.

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial

This is a 10-year follow-up of the ShortHER study using nine weeks vs. 12 months of adjuvant trastuzumab in HR+ non-metastatic breast cancer. With long-term follow-up, non-inferiority could not be claimed statistically. Still, the DFS/OS results are identical in those patients with N0-N3 disease, while those with N4 disease seemed to have a significant difference favoring 12 months of therapy, suggesting that volume/burden of disease drives the margin of benefit in adjuvant trastuzumab therapy.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial

This is another option for HR positive patients after failing hormonal therapy, with an acceptable toxicity profile. Patients were HER-2 negative. (The study does not indicate if patients were HER-2 low.) It will be interesting to see how this will fair in this population now that there is another option with Enhrtu. Interesting though, patients without visceral metastases did better with chemotherapy.