The final overall survival (OS) analysis of the Phase III MONALEESA-2 trial demonstrated that endocrine therapy plus CDK 4/6 inhibition with Novartis' Kisqali (ribociclib) prolonged OS by over 12 months compared to placebo in postmenopausal women with HR+/HER2- advanced breast cancer in the first-line setting. Novartis said the results, unveiled Sunday at the European Society for Medical Oncology (ESMO) congress, make Kisqali the only CDK4/6 inhibitor with proven OS benefit across all three Phase III trials of the MONALEESA programme with different endocrine therapy partners, regardless of menopausal status or line of therapy.
MONALEESA-2 randomised 668 patients to Kisqali or placebo, both in combination with the aromatase inhibitor letrozole. Patients were excluded if they had previously received a CDK 4/6 inhibitor, chemotherapy or endocrine therapy in the advanced setting. In 2016, Novartis reported that the study had met its primary endpoint of progression-free survival (PFS), with a median PFS of 25.3 months for Kisqali plus letrozole, and 16 months for letrozole alone. The data were used to support US and EU approval of the drug as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor.
"PFS benefit has been shown many, many times," noted study author Gabriel Hortobagyi, but "we have rarely observed an improvement in OS," largely due to the development of resistance. As a results, patients typically have to use multiple different types of treatment over the course of their disease, and these dilute the effect of the first therapy, he added.
At Sunday's ESMO conference, researchers said OS was evaluated after 400 deaths and showed a median duration of 63.9 months for Kisqali-treated patients, compared with 51.4 months for placebo, translating to a 24% reduction in the risk of death. Novartis noted that the analysis is based on a median follow-up of over 6.5 years, the "longest for any CDK 4/6 inhibitor trial to date."
The estimated six-year OS rate in MONALEESA-2 was 44.2% for Kisqali patients, versus 32% for placebo. Moreover, Kisqali patients went a median 50.6 months before they underwent chemotherapy, a delay of roughly 12 months compared to those taking letrozole alone. Novartis said it plans to submit the data to global health authorities to support label updates.
Hortobagyi noted that research is ongoing to examine whether there are any subgroups in the study that benefitted more or less from treatment. "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 said, although no new safety signals were observed in MONALEESA-2. Hortobagyi added that "while this is the only CDK 4/6 inhibitor to demonstrate an OS benefit in this patient population so far, we are still waiting for results" of trials for Pfizer's Ibrance (palbociclib) and Eli Lilly's Verzenio (abemaciclib).
Novartis unveiled OS results from the Phase III MONALEESA-7 and MONALEESA-3 trials in 2019, with updated exploratory analyses demonstrating Kisqali plus endocrine therapy significantly extended life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer – an indication for which the drug is also cleared. The company reported in July that Kisqali sales were up 42% in the second quarter to $225 million.
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