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My name is Mark Pegram. I'm a professor of medical oncology at Stanford University in Palo Alto, California, and I'm pleased to present this lecture to you. On the topic of post CDK 46 sequencing in hormone receptor-positive HER2 negative metastatic breast cancer based on clinical and molecular resistance patterns. Please keep in mind my disclosures of financial relationships within the past 24 months and take these into consideration as you listen to my remarks today. The learning objectives for this segment include implement appropriate post-CDK 46 sequencing. In ER positive HER2 negative metastatic breast cancer based on clinical and molecular resistance patterns to identify clinical indications and resistance mechanisms following CDK 46 inhibitor progression in ER positive HER2 negative metastatic disease, apply evidence from the latest clinical trials and patient characteristics to guide personalized sequencing decisions in the metastatic setting. And finally, to construct individualized post-CDK46 management plans that reflect both guideline-based and emerging therapeutic options for metastatic breast cancer. You will all recall the exciting final overall survival analysis of the first-line AI with or without ribociclib phase 3 Mona Lisa 2 trial. This is again in first-line metastatic breast cancer that's hormone receptor positive and HER2 negative. You can see a very nice efficacy, uh, advantage in terms of OS with a hazard ratio of 0.76 and a significant P value of 0.008. Ribocyclin plus letrozole showed a significant OS benefit with a one-year improvement over placebo in hormone receptor-positive HER2 negative advanced breast cancer. And this is a new benchmark for OS in the first-line setting, um, since other phase three trials of other CDK46 inhibitors. Did not reach statistical significance for the OSN point. Although I will admit the Abemaiclib trial came very close with a marginal P value of 0.06. Perhaps if that trial had been a little bit larger, we may have seen an OS benefit. And to make that point and perhaps underscore the point, um, if you look at this real-world data presented, uh, uh, this year by Doctor Hope Rugo and colleagues. Um, this is a real-world, uh, flatiron database claims analysis of patients who received a babocyclop plus AI, ribocyclin plus AI, or, um, uh, uh, halociclib plus AI. And if you look at the Kaplan-Myer plot on the far right-hand side of the slide, you'd be hard pressed to see that there's any difference in the overall survival endpoint for either of these three. Mind you, this is a 9,146 patient database. Including over 6800 treated with palbociclib, over 1200 treated with ribo, and over 1000 treated with a benbocycllib. So these are big numbers. And the uh point estimate hazard ratios for all three are 0.95 or above. So, in the real world, there's probably no difference in OS irrespective of which CDK46 inhibitor you choose to use in the first line. Moreover, uh, the vagaries of the study designs may account for the fact that two of the trials did not reach statistical significance. Some of which had a high fraction of crossover, and one of which at least that had many patients, double-digit percentage that were lost to follow-up indeed. Mechanisms of resistance to CDK 46 inhibition have been described extensively in the literature, and they involve many different mechanisms. There's not just one that dominates. Hyperactivation of a target, for example, the hippo fat signaling pathway can directly activate activate CDK 6, Increase in CDK6 expression can lead to resistance P10 loss, map kinase pathway dysregulation, parallel receptor kinase activation like FGF receptor gene amplification, for example. It can also uh uh result from loss of target. For example, if you lose RB you cannot possibly respond to a CDK46 uh inhibitor. Um, also, bypass mechanisms of, uh, increased cyclin E can lead to CDK 46. Inhibitor resistance. Also, P53 loss or MDM2 gene application, of course, MDM2 is an endogenous inhibitor of P53 mechanism. Consequently, that has a, uh, a mechanism that phenocopies P53 gene loss. Now, We don't use any of these known mechanisms really in the clinic. There's no drug for RB loss. There are drugs for FGFR gene amplification, um, some of which have been approved for, um, hepatobiliary cancers and, uh, bladder cancers, uh, but none that have yet, uh, reached approval for, uh, treatment of CDK 4-6 inhibitor resistant breast cancer. So future studies will be needed to capitalize on any of these mechanisms. But I will, uh, in this, uh, presentation show you other alterations, molecular alterations that are still targetable in these CDK46 inhibitor resistant patients who have progressed on first-line therapy with these agents. One of those pathways is the PI3 kinase pathway. PI3 kinase can be mutated in a high fraction of breast cancers. Overall, PI3 kinase gene mutations are the second most common mutation, about 40% in hormone receptor-positive breast cancers. Um, second, only the P53 mutations which are more frequent in triple negative breast cancers. PI3 kinase mutations are higher in luminal tumors, whereas P53 tumors are most frequent in basal-like and also in HER2 positive tumors. There are FDA approved companion diagnostics for detection of PI3 kinase gene mutations. Um, but there are a number of commercially available assays that are highly similar to the FDA approved companion diagnostics. So, many of the big Uh, diagnostic houses in the US offer PI3 kinase gene sequence analysis by NGS testing, uh, including CTDNA analysis. And so, in the clinic, um, uh, one can choose any one of those commercially available assays in order to detect these mutations. Um, there are common hotspots in the PI3 kinase gene that are sites of mutation. Um, and they are non-random, uh, kind of on a statistical basis. They hit the kinase domain, obviously, but also the helical domain and the, uh, C2 domain, which is a, uh, uh, phospholipid binding domain, whereas the helical domain, uh, actually binds to RAS GTP. I'd like to present, uh, new data from the Anavo 120 phase 3 randomized double-blind placebo-controlled clinical trial testing the PI3 kinase inhibitor in volaib. In combination with palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIC3CA mutated hormone receptor positive HER2 negative advanced breast cancer, bicentral CTDNA testing or local tissue uh DNA testing, measurable disease, progression during or within 12 months of adjuvant endocrine therapy completion. No prior therapy for advanced disease and fasting glucose less than 126 and hemoglobin A1C less than 6%. Uh, involoib is a P PIC 3CA alpha inhibitor with a high degree of selectivity over the beta and gamma and delta isoforms of the PI3 kinase protein. The primary endpoints are investigator assessed PFS and the secondary endpoints are shown for reference as well as the stratification factors at the bottom of the slide. This study met its primary endpoint with statistical confidence. It also met the key secondary endpoint of overall survival with statistical confidence. This is the first time overall survival has been significantly improved by a, by a PI3 kinase pathway targeted drug in breast cancer. Uh, the PFS, uh, data set updated with the newest data presented at this year's ASCO, uh, is shown on the left. Again, with longer follow-up, highly statistically significant superiority in the intervals of randomized subjects compared to placebo. And then the overall survival data is shown for your reference on the right-hand side of the slide. Uh, the most common adverse events involving at least 20% of patients, including laboratory abnormalities were cytopenias. Increase fasting glucose, um, Stomatitis, diarrhea, hypocalcemia, fatigue, hypokalemia, uh, increased creatinine. Nausea Increase in serum sodium, hypomagnesemia, rash, uh, anorexia, COVID-19 infection, and headache. Hyperglycemia, stomatitis, and dry eye, and blurred vision were reported at the higher frequency also in the invulsive group, but discontinuation rates, despite these adverse events were low in the study. This is also a clinically important endpoint that is time to first subsequent chemotherapy. We work hard in the clinic to try to prolong the time to Use of chemotherapy in order to uh mitigate against chemo-related side effects such as alopecia, cytopenias, nausea, vomiting, diarrhea, etc. fatigue. Uh, so, um, this I think is a, a really important endpoint and I'm glad this is captured in this data set. Um, time to first subsequent chemotherapy was much prolonged, uh, 35.5 months compared to just over a year in the control arm. Uh, and again, in favor of those patients randomized to interulsive.