I presented the first results of a randomised phase III trial entitled MONALEESA 7. This was a trial that tested a new class of compounds that’s been around now for about two years called cyclin dependent kinase 4/6 inhibitors. Three of these drugs have now been approved for the treatment of women with hormone receptor positive, HER negative breast cancers. All of the trials have been in patients that are postmenopausal. These drugs work in part in combination with aromatase inhibitors which really are only effective in postmenopausal patients. However, about 20% of patients diagnosed in this country are premenopausal, that number is even higher in other parts of the world, and we don’t have clear data on how to manage those patients. This study was designed to enrol those patients and to suppress the ovaries, to put them in a postmenopausal state, and to test the standard hormonal therapy, aromatase inhibitors with or without ribociclib, with suppression of the ovaries. It was also novel in the sense that it tested tamoxifen or an aromatase inhibitor, as patients and their physicians could choose between the two, and there were certain rules that might guide you to one or the other.
We didn’t have this type of information before to reassure us that when we do at the time of diagnosis suppress the ovaries, get the same results that have been seen before. The results ended up confirming that the benefit in terms of prolonging progression-free survival, nearly doubling it, was about the same that has been seen in the postmenopausal trial, so that was very reassuring that we can in fact treat premenopausal patients with ovarian blockade and the similar treatments that have been tested before. It also, for the first time, tested the commonly used drug tamoxifen and showed that the benefits were similar with that drug as they were with aromatase inhibitors.
I made a note of the overall response rates as being quite something as well.
Yes. In the past we have not seen really high response rates with hormonal therapy alone and with the addition of ribociclib we saw a response rate of 41% and it was actually around 50% in the subset of patients with measurable disease.
When it comes to the toxicity profile of these drugs?
The toxicity profile of these drugs was similar as what has been seen in other studies, we didn’t see any new signals. For CDK4/6 inhibitors typically include neutropenia, however, neutropenia to the point that it was associated with fever was infrequent, only 2.5% of the patients had that. There were other side effects that are typically seen with tamoxifen and aromatase inhibitors such as muscle aches and joint pains and we did see that. There was also prolongation of the QT interval, something that many drugs can cause, and this was seen in about 7% of patients but it was typically asymptomatic, and only one patient on the ribociclib arm had to actually come off of it because it was prolonged enough by the protocol. None of these were associated with any arrhythmias or any other clinical events.
Were there any planned follow-ups to assess if there was any long-term impact on patient fertility?
We expect that patient fertility is going to be suppressed because patients are having a blockade of ovarian function. However, after the block of the ovarian function is removed patients generally will remain fertile. In this population of patients, however, because it’s not a curable disease, many patients may not put fertility as a high priority, but it’s possible that some might. There has never been any testing of this, at least to a large extent, to see if active treatment with CDK4/6 inhibitors is contraindicated in pregnancy. Obviously, since we don’t know, it is contraindicated until we have safety data, but because these drugs are being used in advanced breast cancer and other advanced cancers it’s probably not going to be as big an issue as it might be with the drugs that we use, say, for early stage breast cancer where many of these patients are going to survive and live a long time.
Is that something that you would advise doctors possibly looking forward to applying ribociclib in the clinic, something that they should be aware of having conversations with these patients, raising it before treatment?
Oh, absolutely. We feel that any cancer treatment has to be fully explained – why are you using it, what are the options, and then of course what are the side effects, both the short term and long term side effects. Many of the cancer drugs we use are not compatible with being pregnant and patients have to be advised of that. In fact, some of the drugs may permanently cause cessation of ovarian function – not goserelin, but there are other drugs that can and of course that has to be discussed, absolutely.
The take-home message of ribociclib success is one of triumph, then?
Yes, this was a triumph in the sense that it addressed an unmet need. We have very little data on how to treat premenopausal patients. We have assumed that we would just block ovarian function and use the same drugs we use in all of the postmenopausal trials, and in fact that’s probably what many physicians did do when they came across that. But now we actually have confidence that that strategy gives the same effect as we saw in the postmenopausal trials, and, in addition, we now know that tamoxifen can be used as well as an aromatase inhibitor. Aromatase inhibitors have some distinct side effects that for some patients may be intolerable and switching to tamoxifen oftentimes can help. We now know that that is actually an effective endocrine therapy to be partnered with CDK4/6 inhibitors.