The PALOMA-3 study, as everybody knows, is a randomised study comparing palbociclib and fulvestrant and fulvestrant placebo in patients that have progressed on endocrine therapy and also every pre-treated population. This study showed very early on efficacy results for the primary endpoint, that was the progression free survival, already presented and published in The New England Journal of Medicine 2015. We have continued to follow these patients for quality of life, safety and, of course, the overall survival secondary endpoint. So today we presented data on overall survival and this is also the first time that a CDK4/6 inhibitor in a phase III study is reporting overall survival data.
The results show that in the 521 patients randomised two to one to the treatments the patients that received the combination with palbociclib have an improvement in overall survival up to 6.9 months and this is maintaining the same improvement that was seen in the progression free survival. With regards to one of the stratification factors, particularly looking at endocrine sensitivity – patients who have responded to prior endocrine therapy in the metastatic setting or did not progress in the first two years of endocrine therapy in the adjuvant setting – this group of patients was the largest, by the way, of the 521 – more than 400 patients – had a different overall survival, improved overall survival of 10 months.
So the importance in the setting of metastatic breast cancer, particularly hormone receptor positive is relevant. First of all the triple negative breast cancer patients progress very quickly and have a shorter survival, not many treatment options. Hormone receptor positive metastatic breast cancer has many more options for treatment, that’s why it has been always difficult to prove an overall survival advantage, particularly in the first line setting. These patients were heavily pre-treated before and after they received the investigational treatment but relevant to this is the data we’ll be presenting with regard to the further patients that received the treatment, the investigational treatment with palbociclib, stay on the study for a longer time, had to wait much longer before going to chemotherapy. So overall this had an impact not only on quality of life, as I already mentioned, also clearly it contributed to an improvement in overall survival that we see. This is relevant because it’s also important to see, compared to other studies that have been presented, that this benefit that you gain early on with the treatment moves all the way to the end. There is no single treatment that will completely change the outcome of these patients but as an incremental contribution from various treatments. So having this treatment for patients at this time of their disease, as the study investigation was, is very relevant.
Taking these results forwards, is there anyone with HR positive advanced breast cancer who you would not recommend palbociclib for?
For the study patients, the patients who progressed on endocrine therapy, there is no patients for which we would not recommend. The reason being that if you look at the overall survival for the control group, if the patient in the general population was between 27.5-28 months but when you start to define a different subset, clinical subset, it was less than four months for the visceral metastases. So we know why endocrine therapy is indicated for patients with hormone receptor positive disease, you do not want to give endocrine therapy single agent in visceral metastases patients because it would be ineffective. The magnitude of benefit is seen also in bone disease and non-visceral so I don’t see any group of patients that would not benefit from the combination of this drug, palbociclib.
Then, I guess, all the approvals and availability and access needs to be in place for this to be standard of care?
Absolutely. In the US we are fortunate that the drug has been approved and it’s available to patients, it’s been already three years, particularly with the extension to the combination with fulvestrant. Clearly there are other countries that have to deal with the approval process.
Just to go back to the endocrine resistance, PALOMA-3 was very significant also allowing us to study the biomarker associated with endocrine resistance. We reported that, in fact, the patients that had the most common mutation associated with endocrine resistance not only benefit from the treatment combination but also probably do better. So if you have a 25% chance to have an oestrogen receptor mutation or 30% a PI3 kinase mutation you know that particularly in the advanced setting you cannot give a single agent, you must give a combination with palbociclib.
Finally if I could just ask for your thoughts and your experience with what CDK inhibitors and CDK therapy is doing to change the breast cancer space?
I’ve been using these agents in the advanced setting for several years because I’m fortunate enough to have FDA approval. I can see the patients do very well; the safety profile of palbociclib is incredible compared also to the others as well as the chemotherapy. There is minimum neutropenia, never associated with an increased risk of infections. This neutropenia is very well managed with dose reduction or dose delay. It usually happens in the first few months and then patients do well and just need to go back to the patient office once a month. So very well tolerated, patients are being treated for a long time and they respond; I have patients that have been more than two years on the treatment and they are responding and very stable.
Do you think that any emerging new generations of CDKs are going to improve on the results that we’ve seen or is it making the best of a good situation?
I think it’s very difficult to have the new agents, new CDK4/6, they have the same safety profile, the same efficacy. Of course it’s nice to have the first in class and there will be other agents that will come. Of course we are hoping that these agents will be successful soon in the adjuvant setting where certainly there is a need for better endocrine therapy to prevent resistance. Certainly we know that there is an investigation ongoing with HER2 targeted therapies for the triple positive tumours. So there will be other applications for this class of agents once we have established that these are safe and effective and in the future, of course, in combination with some other agent, maybe even the sequence with some agents if we learn a little bit more why some patients progress and how they’re going to be preventing the progression.