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Optimising Disease Control in Metastatic Breast Cancer

M.E. Cazzaniga (Italy)

SlotAE-4 Cazzaniga, M.E.

Presentation by the Dr. Marina Cazzaniga of the current and futures strategies to optimise disease control in Metastatic Breast Cancer

Transcription

Summary of topics

I will offer a brief summary of available strategies to achieve disease control.  We will have an overview of clinical data of oral vinorelbine in HER2-negative metastatic breast cancer patients and finally I will share with you the results of the studies published until now about metronomic vinorelbine in breast cancer.

Full transcription

Full transcription

Summary of topics

I will offer a brief summary of available strategies to achieve disease control.  We will have an overview of clinical data of oral vinorelbine in HER2-negative metastatic breast cancer patients and finally I will share with you the results of the studies published until now about metronomic vinorelbine in breast cancer.

Disease control = Make cancer a chronic disease

Matti has told us that the disease control is a key point for the success of our patients and disease control means make cancer a chronic disease.

How can we achieve this goal?

How can we achieve this goal, the goal of disease control and the goal of chronicising the cancer?

I think that there are three possible options. 

How can we achieve this goal?

The first one is the administration of potent maximum tolerated dose regiments for a fixed period.

The second option is the administration of biological drugs together with cytotoxic regimens continuously until progression occurs.  But in my opinion there is a third option which is the possibility to administer better tolerated regiments for a prolonged time.

How can we achieve this goal?

In my opinion the first option is not suitable.

MTD regimens for a fixed period

The lessons from the past

 The lessons from the past told us that MTD regimens, prolonged treatment with these kinds of regimens is unrealistic because of cumulative toxicity, so I think it’s time to move from the idea of administration for a fixed period of treatment and to move to prolonged treatment which is the idea of maintenance strategy.

How can we achieve this new paradigm?

The second option.

How can we achieve this new paradigm?

All we know is that there are recent data about the administration of biological agents with cytotoxic chemotherapy backbone.  In my opinion, I think this is not a good way.

IMELDA: Evaluation of prolonged treatment with maintenance chemotherapy

Why?  All of you know the IMELDA study recently published.  All of you know that this study demonstrated impressive results in terms of progression-free and overall survival but the toxicity remains a major limiter of this design.

IMELDA: Most common Grade ≥3 AEs (≥2% of patients in either arm)

You can see here that hand-foot syndrome occurred in approximately 30% of the patients and this side effect is clearly related to standard dose and schedule of capecitabine leading to a discontinuation rate of 10% of the patients.

Biological agents together with cytotoxic regimens

But I think that the most important lesson the IMELDA trial told us is that the switching from an initial MTD regimen to a better tolerated one provides sustained disease control and that this switch maintenance approach may help disease progression which finally leads to disease control.

How can we achieve this new paradigm?

The third option - the administration of better tolerated regimens for the prolonged period of time.

How can we achieve this new paradigm?

I think this is a very good option.

Association between duration of treatment and progression-free survival

We know that prolonged treatment is strictly associated and related to improved disease-free –

Association between duration of treatment and overall survival [Two separate slides]

- and overall survival.

Treatment regimens with improved safety that can be given for longer are needed

We have to think about the potential strategies to increase treatment duration.  One option is the administration of sequential different single agent therapies but for a planned number of cycles, but I think that there is another option which is the administration of the same drugs, perhaps old drugs, in a different and more fashionable way.

Which is the “ideal” drug for prolonged treatment?

If I ask you which is the ideal drug for prolonged treatment, I think you will agree with me that it must be a drug with a proven clinical activity in metastatic breast cancer, preferably oral because we have more and more tried to avoid admission of patients to the hospital with no cumulative side effects, otherwise we have the same results of the IMELDA study and perhaps which allows a better quality of life preservation.

Single agent oral VNR in MBC

Overview of activity

Let’s have a look at the single agent oral standard schedule – I underline standard schedule – of oral vinorelbine in metastatic breast cancer.

In this published overview by our Chairman, you can see that oral vinorelbine is one of the recommended agents by the ABC guidelines, by different guidelines too with an overall response rate of up to 40% and interesting results about the progression-free and overall survival.

Single agent oral VNR in MBC

Overview of toxicity

But also in this case, toxicity of standard schedule and those of oral vinorelbine is a major need because you can see on this slide that leukopenia grades 3 and 4 occurs in approximately 12% of the patients as well as neutropenia, febrile neutropenia, nausea and vomiting.

Is standard schedule VNR the “ideal drug” for maintenance?

So is standard schedule vinorelbine the ideal drug for maintenance?  I think that the answer is no, but everything is different when we have the metronomic approach.

Clinical studies with metronomic

Oral Vinorelbine

There is an increasing amount of data in the literature about metronomic oral vinorelbine in metastatic breast cancer.  Until now two single agent studies have been published mainly in an elderly population and we have now four different combination studies in different subgroups. I will focus my presentation on the results of the VICTOR-1 study.

To be presented at ECCO: VEX study

I invite all of you to attend the Monday morning poster session when the VEX study results will be shown.

VICTOR-1: Evaluation of metronomic Oral VNR with capecitabine in pre-treated locally advanced or metastatic breast cancer

Let’s move to the results of the VICTOR-1 study.  VICTOR-1 was a Phase I/II study evaluating the role of metronomic vinorelbine together with metronomic capecitabine in locally advanced or metastatic breast cancer patients.

The study demonstrated that 50mg three times a week was not the good dose for a combination and demonstrated that 40mg on fixed days during the week is the ideal dose for this kind of combination and is the warranted dose for future studies.

VICTOR-1 Phase I-II study: Patients’ characteristics

About patients’ characteristics, this was a phase I/II study.  We enrolled 34 patients.  Approximately 10%, the vast majority was HR-positive and the 15% of the patients have never already been treated, it was first-line therapy.

Safety – Phase II (1)

Safety results – we analysed a total of 187 cycles, each of them composed by three weeks and here are the results.  These are the results about non-haematological toxicity and you can see that the incidence of grade 3, 4 nausea-vomiting and hand-foot syndrome for example or neuropathy which are clearly dependent on capecitabine standard schedule, vinorelbine standard schedule, the incidence was very, very low – 1.6%.

About haematological toxicity, the incidence was very low as well and if you look at the same results when we use standard schedule and doses of the same drugs, we obtain deeply different results.

VICTOR-1, Phase II: Clinical benefit with Oral VNR plus capecitabine

What about efficacy?  We have said that the drug must have a clinically demonstrated activity in metastatic breast cancer.  The clinical benefit that we obtained was obtained in approximately 60% of the patients and the median time to progression was 18.5 months.

Learnings from VICTOR-1

Which are the learnings from the VICTOR-1 study?  The metronomic combination of these two drugs warrants the delivery of a similar dose intensity than the weekly schedule of Oral VNR but it was feasible and well tolerated also during prolonged treatment.

Multicenter Phase II study – VICTOR-2 (closed, April 2015)

We have just closed the VICTOR-2 study in April.  The VICTOR-2 was a Phase II study with the aims of confirming the data coming from the VICTOR-1.  We enrolled 85 patients and until now 669 cycles are evaluable for toxicity.

The primary objective was the clinical benefit and now this evening I show you for the first time the results about the toxicity.

Toxicity incidence is very, very mild and similar to the results obtained in the VICTOR-1 study.

VICTOR-2: Multicenter Phase II study (closed, April 2015)

Data about quality of life preservation has been accepted as a poster presentation at the upcoming ABC Congress in Lisbon but I can anticipate you that there is no deterioration in quality of life.

HR+ patients

My last three slides.  I just wanted to share with you some allocation for the metronomic schedule.

One option could be in HR positive patients, oral single agent metronomic VNR could be the ideal drug after a failure of a first-line endocrine therapy when the disease becomes symptomatic.

HR+ patients

One could say ‘Okay, but you have no data about that’. 

The TEMPO-BREAST trial is now ongoing.  It will be a study of first-line treatment and in this study there will be a direct comparison.  It is Phase II, a comparison between the weekly schedule, the standard schedule and the metronomic one.

HR- patients

What about triple negative breast cancer patients?  I think that there could be a role for the VICTOR combination in this subpopulation of patients.

HR- patients

Here I present you the VICTOR-3 Study design which will be a trial in triple negative breast cancer patients treated with a chemotherapy regimen, an MTD regimen for a fixed number of cycles.  Those patients not progressive at the end of this fixed number of cycles will be randomised to receive the VICTOR combination or the oral metronomic single agent vinorelbine.

The primary endpoint will be the PD rate after 12 weeks of treatment and the study has been designed to determine if both schedules will go up to the minimum required number of patients without progressive disease to better select and to determine if a single agent or a combination is better in these kinds of patients.

Take Home messages

Take-home messages and I have finished.  I think that disease control cannot be achieved by using the MTD approach.  Maintenance strategy preferably must be done with well tolerated and possibly oral drugs.

The metronomic philosophy I think is the ideal approach and perhaps we can realise the dream of cancer control.

Thank you very much!!

Thank you very much for your attention.