One of the things that I think has become increasingly apparent to those of us who’ve been working in this field now over the last five to 10 years is that it’s unlikely that a one-size-fits-all approach is going to work in this post-CDK4/6 setting because there are such diverse mechanisms. We have some of the cell cycle regulatory elements that we just talked about...
One of the things that I think has become increasingly apparent to those of us who’ve been working in this field now over the last five to 10 years is that it’s unlikely that a one-size-fits-all approach is going to work in this post-CDK4/6 setting because there are such diverse mechanisms. We have some of the cell cycle regulatory elements that we just talked about. We have some of the oncogenic signal transduction pathways that we talked about. Now, there is some overlap between those things, inhibitors, next-generation cell cycle regulatory blockers, for example, aurora kinase inhibitors. And so I think we have to have an understanding at each individual patient level of what some of these resistance mutations might be so that we can identify either currently available drugs or clinical trial opportunities for patients to participate in that make sense based upon the genomic and molecular changes that are happening in the tumor. In the same way that we recognize ESR1 as a measurement or a surrogate for ER dependence and as a marker of potential response to next-generation antiestrogens, we need to take that logic into the post-CDK4/6 space to help identify patients who should go on CDK2 blockade, patients who should go down the road of AKT-PI3 kinase blockade, patients who may be better suited for RAS or MAP kinase, FGFR, HER2 targeting therapies. And I think we’ll have examples of all of those. And again, that may change over time. If you have one dependency and you target that, a new dependency might emerge later. That again, we need to repeat the process and think about deploying some of our emerging sequencing technologies to dynamically change therapy in these patients. Of course, we have opportunities for ADC therapy and chemotherapy, but that comes with more toxicity, with requirements for IV treatment, et cetera. And so we’d like to be able to use oral, well-tolerated, targeted drugs that I think are better suited to the individual molecular and genomic changes in specific patients.
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