Late-breaking data of the final overall survival (OS) analysis of the Phase III MONALEESA-2 study, which evaluated ribociclib (Kisqali®; Novartis) in combination with letrozole (Femara®; Novartis) compared to placebo plus letrozole in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer with no prior systemic treatment for advanced disease were presented at the European Society for Medical Oncology (ESMO) Congress 2021 (#LBA17).[1]

Ribociclib, which was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals, in combination with letrozole met its key secondary endpoint of OS, demonstrating a statistically significant and clinically meaningful improvement in survival (median 63.9 vs. 51.4 months; HR=0.76; 95% CI: 0.63-0.93; p=0.004). [1] The analysis found that after a median follow-up of over six and a half years, the longest for any CDK4/6 inhibitor trial to date, the improvement in the median OS was over one year. [1]

The MONALEESA-2 study showed that after five years, patients treated with ribociclib in combination with letrozole had more than a 50% chance of survival (52.3% vs. 43.9%; 95% CI: 46.5-57.7 vs. 38.3-49.4). [1]

“These remarkable ribociclib overall survival data are highly encouraging and represent the longest reported median survival from a randomized trial in HR+/HER2- advanced breast cancer. This extension of life is great news for our patients and the building block for further progress,” noted Gabriel N. Hortobagyi, MD, FACP, professor of medicine with The University of Texas MD Anderson Cancer Center.

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“I have spent the last 45 years researching and increasing our scientific understanding of breast cancer, so it is incredibly rewarding to see just how far we’ve come,” Hortobagyi added.

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MONALEESA-2 study
In MONALEESA-2, a 12-month delay in time to chemotherapy was observed with ribociclib (median 50.6 vs. 38.9 months; HR=0.74; 95% CI: 0.61-0.91) compared to those taking letrozole alone [1]. With this longer follow-up, no new safety signals were observed; adverse events were consistent with previously reported Phase III trial results for ribociclib.

Gabriel N. Hortobagyi, MD, FACP – Professor of medicine with The University of Texas MD Anderson Cancer Center.

“As we reimagine medicine and strive for cures, our MONALEESA program continues to push boundaries by demonstrating that ribociclib is unique in its ability to give people living with advanced breast cancer more time,” said Susanne Schaffert, Ph.D., President, Novartis Oncology.

“Our mission is to improve and extend the lives of those with cancer. For people with HR+/HER2- advanced breast cancer, these data are not just numbers and may mean more life milestones — yet, we will not rest as we continue to investigate the full potential that Kisqali can bring to patients.”

In MONALEESA-2, the primary endpoint progression-free survival (PFS) was met at the initial analysis [median PFS; 95% CI (19.3 months – not reached) vs. 14.7 months (13.0 – 16.5 months); HR=0.556; p=0.00000329] [5]. These new OS results mark the third statistically significant and clinically meaningful survival benefit achieved by Kisqali in the MONALEESA program. Novartis is expected to submit the data to global health authorities to support label updates.

Longest ever reported
“When treatment offers long overall survival—and in this case, the longest ever reported in HR+/HER2- advanced breast cancer—patients have more time to be with family and loved ones and to pursue whatever makes them happy. These data offer new hope for people with advanced or metastatic breast cancer, which remains the leading cause of cancer death in women worldwide,” explained Shirley A. Mertz, President, Metastatic Breast Cancer Network (MBCN).

Ribociclibis the CDK4/6 inhibitor with the largest body of clinical trial evidence demonstrating consistent and superior overall survival benefit compared to endocrine therapy alone.

Overall survival results from MONALEESA-7 and MONALEESA-3 were presented at ASCO 2019 and ESMO 2019 respectively, as well as published in the New England Journal of Medicine, with updated exploratory analyses presented at SABCS 2020 and ASCO 2021, demonstrating Kisqali plus endocrine therapy significantly extends life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer. [2][3][4][5][6][7]

Clinical trials
A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer (NATALEE). – NCT03701334.

Highlights of prescribing information
Ribociclib (Kisqali®; Novartis)(Prescribing Information)
Letrozole (Femara®; Novartis)(Prescribing Information)

References
[1] Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke G, Hart L, Campone M, et al. Overall survival (OS) results from the Phase III MONALEESA-2 (ML)-2 trial of postmenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Presented at the European Society of Medical Oncology (ESMO) Congress, September 16-21, 2021, (Abstract #LBA17).
[2] Im, S. A. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381:307-316.
[3] Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im S-A, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514–24.
[4] Hortobagyi G, Stemmer S, Burris H, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375:1738-1748.
[5] Slamon D, Neven P, Chia S, et al. Updated overall survival (OS) results from the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2− advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, June 5, 2021, (Abstract #1001).
[6] Tripathy D, Im S-A, Colleoni M, et al, Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Presented at the San Antonio Breast Cancer Symposium, December 9, 2020. Abstract #PD2-04.
[7] Ferlay, J, et al. Global Cancer Observatory: Cancer Today. International Agency for Research on Cancer. Online. Last accessed on August 18, 2021.

Featured image: ESMO 2017.  Photo courtesy: ESMO/European Society for Medical Oncology. Used with permission

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