image: Prof. Gabriel N. Hortobagyi, Professor of Medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, US view more
Credit: ESMO
Lugano, Switzerland, 19 September 2021 – Adding a CDK 4/6 inhibitor to first-line hormonal treatment prolongs survival by one year for postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer, according to late breaking results of the MONALEESA-2 trial presented at the ESMO Congress 2021. (1)
This is the first report of a statistically significant and clinically meaningful overall survival benefit in this patient population.
Study author Prof. Gabriel N. Hortobagyi, Professor of Medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, US said: “Previous studies have shown that CDK 4/6 inhibitors in combination with standard hormonal treatment prolong the duration of disease control, also called progression-free survival (PFS), by approximately one year. These drugs were subsequently approved by the regulatory agencies and have been available for patients with HR positive, HER2 negative advanced breast cancer. Today’s results add to this by showing that the CDK 4/6 inhibitor ribociclib extends survival by one year.”
The trial randomly allocated 668 patients to ribociclib plus the aromatase inhibitor letrozole or placebo plus letrozole. Patients were excluded if they had previously received a CDK 4/6 inhibitor, chemotherapy or endocrine therapy in the advanced setting. As already reported, the median PFS was 25.3 months for ribociclib plus letrozole and 16.0 months for placebo plus letrozole. (2) Overall survival was evaluated after 400 deaths and showed a median duration of 63.9 months for ribociclib plus letrozole compared with 51.4 months for placebo plus letrozole.
Hortobagyi commented: “To put these results into perspective, in my 45 years as an oncologist there have been tens of thousands of clinical trials for breast cancer and while a PFS benefit has been shown many, many times, we have rarely observed an improvement in overall survival. It is difficult to show a statistically significant extension in survival for first-line therapy in this type of breast cancer because due to the development of resistance, patients receive four to 15 different types of treatment over the course of their disease and these dilute the effect of the first therapy.”
Commenting on the findings, Prof. Giuseppe Curigliano, Clinical Director, Division of Early Drug Development for Innovative Therapy, European Institute of Oncology, Milan, Italy pointed out: “It is important to note that these data are related to endocrine-sensitive patients who had not previously received endocrine therapy for metastatic disease. The clinical implication is that now we have a clear demonstration that the combination of endocrine therapy plus the CDK 4/6 inhibitor ribociclib prolongs both progression-free survival and overall survival.”
“My advice would be to compare the exceptional responders and long-term survivors with the exceptional progressors and short-term survivors,” Curigliano said, hinting at the need for further research: “This could identify biological features that may predict which patients benefit the most from this therapy. If a mechanism of resistance is found, then research could be conducted to develop new therapies for the non-responders.”
Hortobagyi noted that research is ongoing to examine whether there are any subgroups in the study that benefitted more or less from treatment. “We are also looking for biomarkers, meaning proteins or other substances that could be tested to tell the physician which patients are likely to respond to therapy and which patients are unlikely to respond,” he said. “Those are very important decisions because these drugs are enormously expensive and while they are well tolerated, they do produce some side-effects and toxicities.”
He added that the findings can be generalised to patients with this type of cancer around the world: “This trial included patients from 29 countries in Western Europe, the Americas and East Asia and the results can be extrapolated to HR positive, HER2 negative metastatic breast cancer regardless of their ethnicity.”
Hortobagyi concluded: “While this is the only CDK 4/6 inhibitor to demonstrate an overall survival benefit in this patient population so far, we are still waiting for results of the palbociclib and abemaciclib trials. And of course there are other emerging treatments such as other kinase inhibitors so there is more research to come in this field.”
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Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO Congress 2021
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References
1 LBA17_PR ‘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)‘ will be presented by Gabriel N. Hortobagyi during the Proffered Paper session - Breast cancer, metastatic on Sunday, 19 September, 13:30 to 14:55 (CEST) on Channel 1. Annals of Oncology, Volume 32, 2021 Supplement 5
2 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.
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LBA17_PR - 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)
G.N. Hortobagyi1, S.M. Stemmer2, H.A. Burris III3, Y.S. Yap4, G.S. Sonke5, L. Hart6, M. Campone7, K. Petrakova8, E.P. Winer9, W. Janni10, P.F. Conte11, D. Cameron12, F. André13, C. Arteaga14, J.P. Zarate15, A. Chakravartty15, T. Taran16, F. Le Gac16, P. Serra16, J. O'Shaughnessy17
1Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America, 2Department Of Oncology, Rabin Medical Center Davidoff Cancer Centre, Beilinson Campus, Tel Aviv, Israel, 3Oncology, Sarah Cannon Research Institute, Nashville, United States of America, 4Medical Oncology, NCCS - National Cancer Centre Singapore, Singapore, 5Medical Oncology, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 6Oncology, Florida Cancer Specialists, Sarah Cannon Research Institute, Ft. Myers, United States of America, 7Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France, 8Masarykův Onkologický Ustav, Brno, Czech Republic, 9Medicine, Dana Farber Cancer Institute, Boston, United States of America, 10Frauenklinik, Ulm Medical University, Ulm, Germany, 11Surgery, Oncology And Gastroenterology, University of Padova, Padova, Italy, 12Oncology, Edinburgh Cancer Centre Western General Hospital, Edinburgh, United Kingdom, 13Medical Oncology, Gustave Roussy, Villejuif, France, 14Hematology/oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, United States of America, 15Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States of America, 16Oncology Global Development Unit, Novartis Pharma AG, Basel, Switzerland, 17Medical Oncology, Texas Oncology - Baylor Sammons Cancer Center, Dallas, United States of America
Background: ML-2 (NCT01958021) is a randomized phase III clinical trial investigating first-line (1L) RIB, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), + letrozole (LET) vs placebo (PBO) + LET in postmenopausal pts with HR+/HER2− ABC. ML-2 previously reported a statistically significant improvement in progression-free survival (PFS; primary endpoint) with RIB + LET vs PBO + LET (HR, 0.56; 95% CI, 0.43-0.72). We report the protocol-specified final analysis of OS (key secondary endpoint).
Methods: Postmenopausal pts with HR+/HER2− ABC were randomized 1:1 to receive RIB + LET or PBO + LET. Pts were excluded if they received a prior CDK4/6i, chemotherapy (CT), or ET in the advanced setting. OS was evaluated with a stratified log-rank test and summarized using Kaplan–Meier methods. This protocol-specified analysis was planned after 400 deaths.
Results: The intention-to-treat population included 668 pts (RIB: 334; PBO: 334). At data cutoff (10 June 2021), 47 pts were still on treatment (RIB: 30 [9.0%]; PBO: 17 [5.1%]) and the median follow-up was 79.7 mo (min, 74.6 mo). Final OS was evaluated after 400 deaths (RIB: 181 [54.2%]; PBO: 219 [65.6%]). RIB + LET showed a significant OS benefit vs PBO + LET (median, 63.9 vs 51.4 mo; HR, 0.76; 95% CI, 0.63-0.93; P=.004) and met the boundary of statistical significance. Estimated 6-year OS rate was 44.2% for RIB vs 32.0% for PBO. Time to first CT (median, 50.6 vs 38.9 mo; HR, 0.74; 95% CI, 0.61-0.91) and CT-free survival (median, 39.9 vs 30.1 mo; HR, 0.74; 95% CI, 0.62-0.89) showed a consistent benefit for RIB vs PBO. Among pts who discontinued study treatment, 87.8% vs 90.2% received a subsequent antineoplastic therapy for RIB vs PBO, respectively, and 21.7% and 34.4% received a subsequent CDK4/6i. No new safety signals were observed.
Conclusions: To date, this is the first report of a statistically significant and clinically meaningful OS benefit with a 1L CDK4/6i in postmenopausal pts with HR+/HER2– ABC. After a median follow-up of >6.5 y, median OS improvement was >12 mo for 1L RIB + LET vs PBO + LET.
Clinical trial identification: NCT01958021 (CLEE011A2301)
Editorial acknowledgement: This abstract was developed with editorial assistance provided by Casey Nielsen, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study: Novartis Pharmaceuticals Corporation
Funding: Pharmaceutical, biotech, or other commercial company - Novartis Pharmaceuticals Corporation
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Disclosure: |
G.N. Hortobagyi: Financial Interests, Personal, Research Grant, Grant support to institution to conduct trial. Personal fees member/chair Steering Committee: Novartis. S.M. Stemmer: Financial Interests, Institutional, Research Grant: Rabin Medical Center. H.A. Burris III: Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Novartis; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Astra Zeneca; Financial Interests, Institutional, Other, Payment to institution for consulting services performed by Dr. Burris: Astra Zeneca; Financial Interests, Institutional, Other, Payment to institution for consulting services performed by Dr. Burris: FORMA Therapeutics ; Financial Interests, Institutional, Other, Payment to institution for consulting services performed by Dr. Burris: Celgene; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Incyte; Financial Interests, Institutional, Other, ayment to institution for consulting services performed by Dr. Burris: Incyte; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Roche; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : MedImmune; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Macrogenics; Financial Interests, Institutional, Other, Payment to institution for expert testimony performed by Dr. Burris : Novartis; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Lilly; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Seattle Genetics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Merck; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Aglos; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Jounce Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Moderna Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : CytomX Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Verastem; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Tesaro; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : BioMed Valley Discoveries; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : TG Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Vertex; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : eFFECTOR Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Janssen; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Gilead Sciences; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : BioAtla; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : CicloMed; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Harpoon Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Arch; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Arvinas; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Revolution Medicines; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Array BioPharma; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Bayer; Non-Financial Interests, Personal, Other, Non-compensated consulting services performed by Dr. Burris : Bayer, Pfizer, Novartis; Financial Interests, Institutional, Invited Speaker, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : BIND Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Kyocera; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : miRNA Therapeutics; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Pfizer; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Takeda/Millennium; Financial Interests, Institutional, Principal Investigator, Payment to institution for conduct of clinical trial in which Dr. Burris served as PI. : Foundation Medicine; Non-Financial Interests, Personal, Other, Uncompensated consulting work: Daiichi Sankyo; Financial Interests, Personal and Institutional, Full or part-time Employment: HCA Healthcare/Sarah Cannon; Financial Interests, Personal and Institutional, Leadership Role: HCA Healthcare/Sarah Cannon; Financial Interests, Personal and Institutional, Stocks/Shares: HCA Healthcare/Sarah Cannon; Non-Financial Interests, Personal, Other, Non-compensated consulting services performed by Dr. Burris : GRAIL. Y.S. Yap: Financial Interests, Personal, Other, not specified: Novartis; Non-Financial Interests, Personal, Other, not specified: Novartis; Financial Interests, Personal, Other, not specified: Pfizer; Non-Financial Interests, Personal, Other, not specified: Pfizer; Financial Interests, Personal, Other, not specified: Lilly; Non-Financial Interests, Personal, Other, not specified: Lilly; Financial Interests, Personal, Other, not specified: Astra Zeneca; Non-Financial Interests, Personal, Other, not specified: Astra Zeneca; Financial Interests, Personal, Other, not specified: Roche; Non-Financial Interests, Personal, Other, not specified: Roche; Financial Interests, Personal, Other, not specified: Eisai; Non-Financial Interests, Personal, Other, not specified: Eisai; Financial Interests, Personal, Other, not specified: MSD; Financial Interests, Personal, Other, not specified: Inivata. G.S. Sonke: Financial Interests, Institutional, Other, Institutional reimbursement for patient accrual: Novartis; Financial Interests, Institutional, Other, Institutional reimbursement for education and steering committee activities: Novartis; Non-Financial Interests, Institutional, Other, Institutional research support: Merck; Non-Financial Interests, Institutional, Other, Institutional research support: Astra Zeneca; Non-Financial Interests, Institutional, Other, Institutional research support: Roche. L. Hart: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Speaker’s Bureau: Novartis. M. Campone: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Astra Zeneca; Financial Interests, Personal, Advisory Board: Eli Lilly. K. Petrakova: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Astra Zeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: BMS. E.P. Winer: Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Tessaro; Financial Interests, Personal, Advisory Board: Leap; Financial Interests, Institutional, Research Grant, Research funding (institution): Merck; Financial Interests, Institutional, Research Grant, Research funding (institution): Genentech. W. Janni: Financial Interests, Personal and Institutional, Research Grant: Novartis. P.F. Conte: Financial Interests, Personal, Writing Engagements: Novartis. D. Cameron: Financial Interests, Institutional, Advisory Board, Institution reimbursed for my time on advisory boards: Novartis; Financial Interests, Institutional, Advisory Board, Institution reimbursed for my time on advisory boards: Pfizer; Financial Interests, Institutional, Other, Institution reimbursed for my time on an IDMC: Lilly. F. André: Financial Interests, Institutional, Funding, Research funding (institution): Astra Zeneca; Financial Interests, Institutional, Funding, Research funding (institution): Lilly; Financial Interests, Institutional, Funding, Research funding (institution): Novartis; Financial Interests, Institutional, Funding, Research funding (institution): Pfizer; Financial Interests, Institutional, Funding, Research funding (institution): Roche. C. Arteaga: Financial Interests, Institutional, Research Grant, Research funding : Pfizer; Financial Interests, Institutional, Research Grant, Research funding : Lilly; Financial Interests, Institutional, Research Grant, Research funding : Takeda; Financial Interests, Institutional, Research Grant, Research funding : Radius; Financial Interests, Institutional, Research Grant, Research funding : PUMA Technology; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Symphogen; Financial Interests, Personal, Advisory Board: TAIHO Oncology; Financial Interests, Personal, Advisory Board: PUMA Technology; Financial Interests, Personal, Advisory Board: RADIUS; Financial Interests, Personal, Advisory Board: H3Biomedicine; Financial Interests, Personal, Advisory Board: OrigiMed; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. J.P. Zarate: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. A. Chakravartty: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. T. Taran: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. F. Le Gac: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. P. Serra: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal and Institutional, Stocks/Shares: Novartis. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Astra Zeneca; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Novartis; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Lilly; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Merck; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Seattle Genetics. |
Journal
Annals of Oncology