ESMO 2016

Ribociclib improves progression-free survival in advanced breast cancer

Prof Gabriel Hortobagyi - University of Texas MD Anderson Cancer Center, Houston, US

I’m going to present to you today a summary of the findings of the MONALEESA2 clinical trial. Just to give you a little background as to why this is important, about two-thirds of breast cancers happen to be what we call hormone dependent – we think that they develop on the basis of abnormal hormonal exposure. For these patients hormonal or endocrine treatments represent the treatment of choice both in the primary and in the metastatic setting but, especially in the metastatic setting, after several months of exposure breast cancer becomes resistant to endocrine therapy and there has been a rich area of research in breast cancer trying to develop strategies to overcome or prevent or reverse resistance to endocrine or hormonal therapy.

One of the most promising lines of research in this direction has been the development of cyclin-dependent kinase inhibitors and I’ll explain that a little bit more. On this cartoon I show you how the cell prepares for dividing and for proliferating. So there are a number of external factors shown on the top left part, some of them growth factors, some of them a variety of other proteins, that influence a signalling pathway that focusses on cyclin D and the cyclin dependent kinases, in this case described as CDK4 and 6. Now this complex governs the release of a factor called E2F that you see on the lower right side and separates it from the retinoblastoma protein or RB. Once that happens then gene transcription starts, the cell goes from the G1 or G0 part of the cell cycle into S1 which is the synthesis of DNA and then proliferation and cell division continues.

Many investigators in our group have felt that blocking this process of releasing the E2F factor would be an important way to interfere with this process. Now this is important because phosphorylation of RB by CDK4/6 is what precipitates the cell cycle progression and increased cell cycle, or CDK 4/6 activity, driven by perturbations of other aspects of cell life is associated with endocrine therapy resistance and there’s a very rich area of literature about that. Now, ribociclib is one small molecule that is orally available and it is a selective inhibitor of cyclin dependant kinase 4/6. This line of research has been going on for over 15-20 years but only recently have the selective CDK 4/6 inhibitors become available.

This is the design of the MONALEESA2 study, so it recruited patients who were postmenopausal and had hormone receptor positive, HER2 negative advanced breast cancer or metastatic breast cancer who had received no prior therapy for advanced disease. They were randomly assigned to either letrozole, which is a commonly used endocrine therapy, plus placebo or letrozole plus ribociclib, the CDK 4/6 inhibitor. The primary endpoint of this study was progression free survival as well as a number of secondary endpoints such as survival, response rate, clinical benefit rate etc.  The study was supposed to recruit 668 patients, which it did, they were evenly distributed in the two arms and the analysis, the first analysis, was planned when about 70% of 302 progression free survival events had been reached.

I mentioned the enrolment criteria, patients who had received prior systemic therapy for the advanced disease or those who had inflammatory breast cancer or a history of cardiac disease were not eligible for participation. This is the main result of the trial: at the interim analysis, so when only 70% of the expected events have occurred, there was such a significant difference between the two curves in terms of progression survival that it was declared that statistically the study had met its primary endpoint. As shown on this slide, there was a hazard ratio of 0.556 or about a 44% reduction in progression free events with a median follow-up of 15.3 months. As you can tell from these curves, they start to separate very early and the separation continues and expands. The median progression free survival for the control group was 14.7 months which is actually better than what we have seen historically with endocrine therapy alone. In the investigational arm with ribociclib the median has not been reached, the data will need to be followed until further maturity but it is expected that it will far exceed what the control arm did.

Adverse events were commonly seen but were mostly uncomplicated and asymptomatic hematologic changes, especially mylosuppression, neutropenia, leukopenia, anaemia and thrombocytopenia. To a much lesser extent nausea, vomiting, diarrhoea, alopecia, rash and in a small number of patients elevations on liver function tests were also reported. Most of these were grade 1 and 2, grade 3 and 4 were uncommon and very few patients discontinued treatment on the basis of adverse events. The side effects or asymptomatic toxicities were managed with dose interruptions and dose reductions but the great majority of patients were able to continue and complete therapy.

So, on the basis of these results, we concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progression free survival compared to letrozole plus placebo or letrozole alone, again with the hazard ratio and a very powerful p-value included in parentheses. The treatment benefit, I did not show you this but we did a number of pre-planned subset analyses and the treatment benefit was present in all subsets, regardless of age, performance status, extent or location of metastases and other secondary endpoints such as response rate and clinical benefit rate also favoured the combination. Ribociclib was well tolerated and the side effects and toxicities that I described were well managed by dose interruptions and reductions.

It is our conclusion that this combination represents an important advance for patients with metastatic hormone receptor positive breast cancer. I might mention that two other clinical trials with this same agent have completed accrual in different subsets of patients with hormone dependent breast cancer and we are expecting the data to mature to round out the role of this combination in the management of advanced breast cancer. Thank you very much.