Ribociclib Offers 'Paradigm Shift' in Advanced Breast Cancer

COPENHAGEN — The investigational drug ribociclib (formerly LEE011, Novartis) added to letrozole in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer showed significant improvement in progression-free survival (PFS) compared with letrozole alone, new results show.

Interim results from the MONALEESA-2 study indicate that adding ribociclib to letrozole improves progression-free survival (PFS) by 44% and significantly improves overall response to therapy.  The results were presented here at the 2016 European Society for Medical Oncology (ESMO) Congress and simultaneously published in the New England Journal of Medicine. Novartis reports it will use the data as the basis of worldwide regulatory filings.

Ribociclib is a selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition has been shown to overcome or delay resistance to endocrine therapy and has become an established treatment strategy, with palbociclib (Ibrance, Pfizer) the first drug in the class approved by the US Food and Drug Administration last year, as reported by Medscape Medical News.

Discussing the potential impact of the findings on clinical practice, lead investigator Gabriel Hortobagyi, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, commented that the results for both palbociclib and now ribociclib are "paradigm changing in the sense that, historically, there have not been studies in metastatic breast cancer with this magnitude of benefit," but he added, "further study is required to determine which patients will benefit most from treatment."

He told a press conference, "The problem is that we don't have biomarkers. We do not know whether 100% of patients benefit, or 50% or 30% or 20%, so we cannot select a patient population to enrich. We are working very hard on developing such biomarkers, but those do not exist at this point."

He continued, "I think there's room today for patients with asymptomatic HR+ metastatic breast cancer, perhaps especially those with comorbidities, to be treated with endocrine therapy alone, but that's not an evidence-based recommendation."

"I think if you want the maximum benefit in metastatic HR+ breast cancer, you are pretty much going to select a combination with a CDK4/6 inhibitor as your first choice."

Dr Hortobagyi concluded, "I think this is a practice-changing study, and when [ribociclib] is approved by the appropriate regulatory agencies, it will be one of the major choices."

Commenting in an ESMO press release, Giuseppe Curigliano, MD, PhD, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, "I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib and abemaciclib."

Study Details

MONALEESA-2 is an ongoing double-blind, randomized, phase 3 trial examining the efficacy and safety of first-line ribociclib plus letrozole in postmenopausal women with HR+, human epidermal growth factor receptor 2 negative advanced breast cancer.

In the study, 668 women not previously treated for advanced disease were randomized to ribociclib 600 mg/day or placebo for 3 weeks, followed by 1 week off, plus letrozole 2.5 mg/day. Tumor assessments were made every 8 weeks for 18 months, and then every 12 weeks. Data were presented from the pre-planned interim analysis after 243 PFS events.

After a median follow-up of 15.3 months, ribociclib was associated with a significant improvement in PFS, with a hazard ratio of 0.556 (P = 3.29 x 10^-6). This corresponded with a median PFS of 14.7 months in the placebo arm, while median PFS was not reached in the ribociclib arm.

Among patients with measurable disease at baseline, the overall response rate was 52.7% with ribociclib vs 37.1% with placebo (P < .001). The clinical benefit rate was 80% and 72%, respectively (P = .02).

The most common grade 3/4 adverse events reported by at least 5% of ribociclib and placebo patients, respectively, were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase (9% vs 1%). Discontinuation rates because of adverse events were 7.5% and 2.1%, respectively.

A Game Changer?

Discussing the findings following the presentation, Stephen Johnston, MD, PhD, Professor of Breast Cancer Medicine at the Royal Marsden Hospital NHS Foundation Trust in London, UK, reminded the audience that endocrine therapy is the first-line therapy in this patient group, which achieves a median PFS of 10 to 13 months.

He added, however, that the rationale for using CDK4/6 inhibitors is “strong” and there has been a “rapid development” in terms of clinical trials — there have now been three clinical trials with palbociclib (PALOMA 1–3) and a phase 3 abemaciclib trial (MONARCH-2) (Lilly). The data published so far on these drugs indicates that, unlike endocrine therapy, the therapeutic benefit is seen earlier and across patient groups.

Turning to the MONALEESA-2 data, he said that ribociclib similarly achieved “very impressive separation of the curves” early in treatment, resulting in a “very significant improvement in benefit and efficacy.”

Dr Johnston added that the toxicity “is good” and the “benefit was seen across all subgroups, just as in the PALOMA-2 study for palbociclib.”

In view of these data, he asked whether this means that CDK4/6 inhibition is a game changer in the treatment of advanced breast cancer.

“It probably is,” he said.

The next question is whether clinicians should use their “clinical nous” to determine which patients should receive endocrine therapy or whether targeted combination therapy should be available across the board. He said that affordability “will be an issue, so there may still be a role for endocrine therapy, and it may still work after a CDK4/6 inhibitor.”

Nevertheless, he concluded that, overall, CDK4/6 inhibitor therapies will have a “big impact” on clinical practice.

The study was funded by Novartis. Dr Hortobagyi received grants and personal fees during the conduct of the study from Novartis and personal fees outside the submitted work from Eli Lilly and Pfizer. Some coauthors were employees of Lilly. Disclosures for the coauthors are listed in the article.

European Society for Medical Oncology (ESMO) Congress. Abstract LBA1_PR. Presented October 8, 2016.

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Cite this: Ribociclib Offers 'Paradigm Shift' in Advanced Breast Cancer - Medscape - Oct 08, 2016.