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ESMO19: Studies for Novartis suggest CDK4/6 inhibition boosts survival in advanced breast cancer

Detailed findings from two Phase III trials presented Sunday at the annual European Society for Medical Oncology (ESMO) meeting showed that treatment with a CDK4/6 inhibitor plus fulvestrant improves overall survival (OS) in women with HR+/HER2- advanced breast cancer, compared with fulvestrant and placebo. The 726-patient MONALEESA-3 study investigated Novartis' Kisqali (ribociclib) as a first- or second-line treatment in postmenopausal women, while MONARCH 2 evaluated Eli Lilly's Verzenio (abemaciclib) in 669 patients, regardless of menopausal status, after failure of endocrine therapy. 

"The results give the treating physician the full spectrum of choice of CDK4/6 inhibitor for each individual patient, although the two CDK4/6 inhibitors have slightly different management requirements and toxicity profiles," according to an ESMO statement. 

Novartis previously reported that MONALEESA-3 had met its primary endpoint, with the combination of Kisqali plus fulvestrant significantly improving progression-free survival (PFS) in HR+/HER2- advanced breast cancer. The latest results show that the trial has also met the secondary endpoint of OS, with a 28% reduction in the risk of death among Kisqali-treated patients. Novartis noted that patients randomised to fulvestrant alone had a median OS of 40 months, whereas OS was not yet reached in the Kisqali arm. The company said that at 42 months, estimated rates of survival were 58% for the Kisqali combination treatment and 46% for fulvestrant alone. 

Median PFS in the first-line setting was also reached at this analysis and demonstrated that Kisqali plus fulvestrant has a median PFS of 33.6 months compared to 19.2 months for placebo. Moreover, the need for chemotherapy was delayed in all patients who were prescribed Kisqali plus fulvestrant. "The remarkable results from MONALEESA-3 and MONALEESA-7 make Kisqali the CDK4/6 inhibitor with consistently superior overall survival," commented Susanne Schaffert, president of Novartis Oncology, while study author Dennis Slamon suggested the new data could be "practice-changing." 

Kisqali had $235 million in sales in 2018, well behind $4.1 billion for Pfizer's first-to-market CDK4/6 inhibitor Ibrance (palbociclib), although last year the latter drug failed to significantly extend survival in breast cancer patients in another late-stage trial. Analysts anticipate that Kisqali, priced at about $130,000 annually, will generate sales of roughly $1.2 billion per year by 2024. 

Meanwhile, in the MONARCH 2 trial, Eli Lilly said Verzenio plus fulvestrant significantly extended life by a median of 9.4 months, compared with placebo plus fulvestrant. The company previously reported that the combination had significantly improved PFS versus fulvestrant alone. The latest findings from the trial, which were also published in JAMA Oncology, were consistent across subgroups that included both pre/peri- and postmenopausal women, the drugmaker noted. 

Further, among women previously treated with endocrine therapy who went on to develop primary endocrine resistance, the data were consistent with the intent-to-treat population, while similar results were observed in women whose cancer metastasised. Meanwhile, an exploratory analysis revealed that Verzenio plus fulvestrant delayed the time to chemotherapy, with a median time to chemotherapy of 50.2 months versus 22.1 months for placebo. 

George Sledge, first author of MONARCH 2, suggested "the main take-home message from this study – and from other similar studies – is that CDK4/6 inhibitors significantly prolong the time patients remain in remission and significantly improve overall survival. Therefore it is very reasonable to think of these as standard-of-care options for patients with metastatic breast cancer." Results from the two studies follow a recent warning by the FDA about a rare, but severe lung inflammation with Ibrance, Kisqali and Verzenio for breast cancer.

Kisqali gained expanded approval last year in both Europe and the US in combination with fulvestrant for use in certain women with HR+/HER2- advanced or metastatic breast cancer as initial endocrine-based therapy and in women who have received prior endocrine therapy. Verzenio was approved by the FDA in 2017 also in combination with fulvestrant to treat woman with HR+/HER2- breast cancer after the disease has advanced on endocrine therapy. 

Written by: Anna Bratulic

Plublished in: September 29th, 2019

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