Now, I'd like to introduce my uh colleague and friend, uh Doctor Suki Pada, uh Vice Chair of Medical Oncology. Fox Chase Cancer Center at Temple University Hospital Professor and clinical investigator, track thoracic and Phase One oncology at Fox Chase to talk to us about KRSDK 11 and keep one mutations as a special patient population. Doctor Pater. Hi, everyone. Thanks so much for staying till the very end. And I know we're running behind as well. So we'll talk about special populations uh trying to be even more selective in how we deliver therapies for our patients using molecular alterations. The focus of this talk is K ras mutations STK 11 mutations and keep one mutations. So the objectives are to define what these mutations are. Review the impact of these mutations on immunotherapy outcomes looking both at real world data as well as clinical trial data. And then is there a role for precision therapy for STK 11 and keep one mutations? So let's start with the definitions. So we know ras mutations are a problem in cancer. So if we look at lung cancer, specifically, the dominant ras mutation that we're dealing with is K ras mutations impacting almost one third of our patients, but it's more heterogeneous than that. So, if we look at the types of ras mutations that occur in lung cancer, the dominant ones are G to T trans versions often associated with tobacco history including G 12 C followed by G 12 V and then a very different type of KRS mutation, uh KRG 12 D. So it's not enough just to say KRS mutation, you actually have to be very specific about what you're talking about because we also have krag 12 C inhibitors uh approved. So when there's a ras mutation, obviously, it turns on constitutive activation of downstream pathways including the map kinase pathway and P A three Kase pathway which allow the cancer cells to survive and grow. So now what about uh STK 11, keep one mutations, perhaps you perhaps you've heard of rass but not have heard of these. So STK 11 is the sine three and in Kase that inhibits Mtor via activation of AMP kinas as is demonstrated in this figure and it's very important in cellular energy metabolism. And so STK 11 is a tumor suppressor. So when it is lost, it leads to M to activation. And SDK 11 mutations are associated with worse outcomes with immunotherapy and are often associated with additional commutations including keep one. So now let's go to keep one. So what is keep one, keep one binds and negatively regulates NRF two under homeostatic uh cell conditions. And NRF two is really there to protect the cell. So keep, one is also a tumor suppressor loss leads to activation of NRF two and resistance to oxidative stress to allow the cell to survive. So, keep one mutations are associated with worse prognosis and resistance to multiple types of treatments. So, uh chemo radiation targeted therapies as well. So what do we know about the frequency of these mutations in lung cancer? Uh They're a little bit different between non squamous and squamous. So, SDK 11 mutations tend to be more common in non squamous uh than squamous around 10 to 20%. Well, keep one in FNFE two L two mutations or NRF two mutations are more evenly distributed between the two right around uh 20% for non squamous and 20 to 30% for squamous. So, they are important for lung cancer. So now let's review the impact of these mutations on immunotherapy outcomes since we now know what these mutations are. So, starting from Real World data, this is from Doctor Boer, who you heard from and uh colleagues including doctor treat, looking at the Flat Iron Real World Database and looking at a variety of driver alterations and how it impacts immunotherapy outcomes. And what we can see in the middle is for um Real World progression free survival with immunotherapy. BR and KRS mutations tend to do better with immunotherapy than Egfr Elk, for example, but that's not the whole story we just heard from Doctor Borga that PDL one is also important. So if we're looking, then at K ras mutations, if you look at those that express high PDL one, those are the ones that derive the most benefit from immunotherapy. So now things are getting really, really complicated and we've only now just talked about PDL one expression and K ras mutations, we haven't yet even talked about STK 11 and keep one. So how do these all interplay? So this is another uh collaboration actually between uh Fox Chase and Penn uh led by doctor Sun and colleagues looking at the interaction of the different PDL one strata and these different mutations. So generally, for PDL one high expression, when you see a K ras mutation, it's often exclusive, 80% will not have a commutation in STK 11 or keep one while if you look at PDL one negative or that PDL one low range, you see much more frequent STK 11 and keep one commutations with KR almost half of them. So basically STK 11 and keep one mutations are associated with negative or low PDL one expression. And in fact, in this real world data set again from flat iron, those patients who did the worst had PDL 10-K ras mutation commuted with keep one and SDK 11. So now the story is getting even more complicated how we select therapies for our patients. So commutations impact on immunotherapy, looking at PD one PDL one inhibition may also depend on the Kras context. So this is a multi institutional uh cohort study including uh Dana Farber Memorial and MD Anderson. And if we look on the left or keep one mutations and overall survival, keep one mutations with immunotherapy are only detrimental in the setting of a Kras mutation, not Kras wild type on the right panel. The same story holds true for STK 11 mutations. So it depends on what genomic context you are seeing uh these tumor suppressor mutations. So as I mentioned earlier, STK 11 often cours with keep one mutations as well. So what if you try to control and look at exclusive STK 11 mutations or exclusive, keep one mutations? The survival is still uh worse in the setting of uh KR in terms of overall survival. And again, if that bottom left panel, that green curve right, that the worst overall survival curve represents those with K ras mutation SDK 11 mutation and keep one mutation. So these mutations are all sort of interacting with each other in terms of impacting response on immunotherapy. So now we talked about real world data as it relates to those mutations. Now let's move to clinical trials. So this was a big meta analysis of first line immunotherapy clinical trials. 25 contra trials included over 15,000 patients. And in general, although patients with keep one or STK 11 mutations have worse outcomes with immunotherapy, they still benefit from immunotherapy. So on the left, you have trials that looked at immunotherapy versus a chemotherapy in the front line setting. And on the right, you have combination chemo immunotherapy chemotherapy and all those hazard ratios for overall survival across STK 11. Uh and keep one mutations still demonstrate benefit with immunotherapy. So it's not that we should omit immunotherapy use from these patients. We just start to expect probably less than ideal outcomes. So let's talk, take a couple of uh key trials and uh dig a little bit deeper. This is a keynote 189 trial, first line carbo pem uh Pember, looking at overall survival across these different uh mutations and overall the hazard ratios for overall survival uh show uh benefit of addition of immunotherapy. But if you look at the point estimates of the hazard ratio between wild type and mutation amongst Krass STK I and keep one, perhaps the hazard ratios are not as robust in those who are mutated. You heard from Doctor B Borga about the potential importance of utility of CTL A four inhibition for those uh tumors that are PDL one negative. We know CTL A four in inhibition is much earlier on in T cell activation. So you could be uh producing a more diverse uh T cell uh repertoire. In addition, they also deplete regulatory T cells. So have quite a different uh mechanism of action compared to PD one or PDL one inhibition. So this is checkmate 227, looking at the PD one CTL A four combination of Nevo IY across STK 11 and I keep one mutations for STK 11, uh didn't seem the greatest benefit uh with this combination. But if we look at keep one mutated sub set, the hazard ratio for progression free survival was 0.25 and for overall survival was 0.31. So maybe this is a useful combination for those patients who have keep one mutations. This is Poseidon uh looking at a different uh CTL A four PDL one inhibition combination with uh chemotherapy as well. And if we look across STK 11 mutations uh with the combination of this dual IO plus chemo, we see a benefit in progression free survival, overall survival as as well as best response rate for those with STK 11 mutations. Similar story for keep one mutations, maybe doesn't hold true for the efficacy, end point for for progression free survival. Uh But we see it for overall survival and response rate. So maybe CTL A four inhibition could be beneficial in these cold tumors often indicated by the presence of STK 11 or keep one. So, is there a role for precision therapy uh for the subtypes based on this data I've just shown. So this is a uh table uh in the blue far right side. Those are all CTL A four inhibition containing uh clinical trials. And on the left are those uh with combination with chemo or single agent immunotherapy with PD one or PDL one. And what we can see is maybe for keep one mutations, we see more robust hazard ratios for those clinical trials that include CTL A four inhibition compared to those that include PD one or PDL one therapies. Uh STK 11, that's a little bit all over the place. The point is these are exploratory analysis. The sample sizes are limited and the data is mixed. If you really look across each of those uh hazard ratios, you can see it kind of goes up and down depending on the clinical trial. So this is not definitive. I think it's absolutely hypothesis generating. Uh This is a bubble plot a sort of another way to look at the benefit of CTL A four inhibition. And I've circled the trials in red. On the left, we have SDK 11 mutations on the Y axis. You have overall survival hazard ratios uh versus chemotherapy on, on the X axis, you have the median overall survival. So that top right quadrant are basically the trials that performing the best. And so if we look at SDK 11 mutations, we see the CTL A four inhibition containing trials are kind of all over the plot. Well, maybe and keep one mutated lung cancer on the right panel. Uh We can see a little bit more CTL A four containing trials in the upper right quadrant. So maybe, maybe so there is a clinical trial that's ongoing, trying to really definitively answer this question, the Triton trial uh looking at uh Dorve trami chemotherapy. So that dual IO versus chemo IO and they're including patients with KRSTK 11 and keep one mutations with a primary endpoint of overall survival. So hopefully we'll have some kind of definitive answer on whether there's a precision immunotherapy approach for this group of patients. So in conclusion, next generation sequencing, we're using it all the time is providing more rich information on our genomic landscape. What do we do with it? Is it prognostic? Is it predictive? I'm really not sure. CTL A four inhibition may have a role in SDK 11 and keep one mutated lung cancer. But still a question that needs to be definitively answers. And there's other strategies that we need to look at to make cold tumors like keep one or SDK 11 mutated tumors which are often PDL one negative, convert them into hot tumors. So there's other strategies being explored. Excell inhibition, il six inhibition, uh maybe DNA damaged repair uh may also be an important pathway to target here. So I thank you for your time.
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