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Medicine Matters oncology

So if you look at the two trials, PALLAS and monarchE-- in general, these trials had similar but not quite identical populations. MonarchE specifically looked at what I think is a somewhat higher-risk population. That is to say patients had have four or more positive nodes or one to three nodes. And if they had one to three positive nodes, then they had to have an additional risk factor. This could include either a tumor greater than five centimeters in size, a high-grade tumor, or a tumor that had a higher proliferation rate as measured by Ki67.



So for instance, if you look at patients who have four or more positive nodes, there is about a 20% greater rate of this in monarchE than there was in PALLAS. So while both would have been considered traditionally high-risk populations, I think monarchE was at least slightly higher-risk than PALLAS. And perhaps that contributed to this. It certainly allows you to have a lot of events, and to have a lot of events with a relatively short follow-up to test number one.



The other question that's related would be when a trial fails, is it failing because there's a study design problem? Or is it failing perhaps because there's a difference in the drugs? Now, I would have said coming into these trials that because in the metastatic trials, in general, the results were pretty similar-- both in the frontline and in the second-line settings-- that there was no particular expectation that there would be a huge difference in the adjuvant setting.



Now, having said that, there are some differences in the drugs. If you look at abemaciclib versus palbociclib, abemaciclib has relatively greater potency against CDK4 than does palbociclib. It's not a huge difference. Both are in the relatively low nanomolar range. But perhaps that makes some difference.



There are differences in terms of how the drugs are administered. Because palbociclib has relatively more in the way of neutropenia, in the early trials with it, it was decided that treatment should be given three weeks on and one week off. Abemaciclib had relatively less in the way of neutropenia, but relatively more in the way of diarrhea. So it was possible to give it as a continuous medication. Is there perhaps a difference between giving a drug continuously and giving the drug intermittently that could affect the outcome?



And then finally, if you look at what actually happened in the trials themselves-- there was a greater than 40% discontinuation rate in the PALLAS trial with palbociclib. The discontinuation rate with abemaciclib was, as I recall, somewhere around 16%. Now, that may not be a fair comparison because patients have not been followed as long in the monarchE trial as they have in the PALLAS trials.



So maybe-- and indeed likely-- we'll see more drug discontinuations over time in the monarchE trial. But at least to date, there appears to be a higher discontinuation rate in the PALLAS trial than in the monarchE trial. And you know, it is a certainty that one cannot benefit from a drug that one does not take.



So for all those reasons, either individually or collectively, those may explain the differences that we're seeing in terms of the outcomes of the trial.



The ribociclib adjuvant trial-- which is a trial run by the TRIO organization. It's called the NATALEE trial-- is still accruing patients. It was actually close to its accrual goal. I've been told that that trial based on what went on with PALLAS and monarchE, has been amended to include a higher-risk population of patients.



And so they'll be accruing more patients with four or more positive lymph nodes in hopes of that being the explanation for the difference in the trials. And therefore, based upon that, allowing the trial to have more events and perhaps see a better separation of the curves. So that's a case where a trial has been altered based on the presumed explanation that the underlay went on in the other two trials.



Now, as I mentioned, the other possibility, of course, is that there might be differences in the drugs. And therefore, if that were the case, then I don't think we have any good sense of how ribociclib would perform.



Now, it is important to point out that in the metastatic setting, ribociclib, like abemaciclib in a very similar setting in combination with fulvestrant has shown improvements in overall survival. And there again, the expectation based on that would be that one would hopefully see similar benefits in the adjuvant setting. But of course, that's why we do the trials. We don't know the answers.