So mucosal melanoma is an uncommon extracutaneous subset of melanoma. We'll see about 1500 cases a year in the United States. About half of those arise from the head and neck. So again, oral cavity, sino nasal, uh, about a quar quarter will arise from the anorectal region, quarter will arise from the lob of vaginal region. And as you might imagine, um, these are diseases that arise in areas that don't get a lot of UV radiation, uh, which is the primary driver and etiology of cutaneous melanoma. Uh, and I think because of that, you know, the underlying biology of this disease is very different, right? So when we look at just the, the genomics of mucosa melanoma, um, When we think of cutaneous disease, we think high mutation burden, right? A lot of UV sun damage signature, um, in terms of the DNA mutations. Um, mucosal melanoma, not UV related, uh, we'll see about tenfold fewer number of mutations, so it's a lower mutation burden. And there's a higher number of structural rearrangements, um, um. Amplifications, losses, and so forth. So just the the genome is is very, very different. Um, this is a disease for which there's no Uh, again, there are no approved therapies, um, and no defined standard of care, I would say. And so when we see these patients in clinic, um, you know, these are the patients we are always thinking about um clinical trials, even as frontline. Um, The, um, and actually let me step back a little bit and because I am talking about metastatic disease, but you know, when patients are diagnosed with a primary lesion, right, in the anorectal region or the, you know, maybe a, a, a vaginal melanoma. Um, even with primary treatment, which can be surgery or, or sometimes radiation, or sometimes a combination, um, there's a very high risk of recurrence. So when we look at the 5-year overall survival of all patients with mucosal melanoma, um, from the time of diagnosis, um, regardless of stage, right, um, the 5 year overall survival is under 20%. Which means that even if we're able to do surgery with curative intent, the likelihood of there being micrometacial disease is, is um is quite high. Um, and we don't have proven preventative strategies like adjuvant therapies, right? In cutaneous melanoma, um, are high risk stage 3 patients, for instance, if we do a year of anti PD1 or if the patient has a BRAF mutation, we do BATE for a year. We know we significantly decrease the likelihood of recurrence, and that's not the case for mucosa melanoma. And so all too often, for those of us who see these patients, um, even at the time of diagnosis, there's a high concern for the development of metastatic disease and that's um the situation we see far too often. And so when we see patients with metastatic disease, um, because of the limited efficacy of our standard therapies, you know, checkpoint blockade can work, a response rate on the order of 25-30% perhaps, but no real durability. Um Um, I think we're always thinking about clinical trials. I think for patients for whom we don't have a good clinical trial, checkpoint blockade tends to be the first, um, uh, kind of therapeutic step. For a long time, many of us were doing dual checkpoint blockade as our first line therapies, a combination illimumab and evolumab, and that was based off of some um studies um pulled from the BMS experience looking at the patients with mucous melanoma treated on the BMS trials of PD1 or IPO. And in those data sets, um, the patients who got IPNEO seemed to do better than patients who got single agent PD1 alone. Um, since that time there have been uh larger retrospective studies of over 500 patients, international collaboration putting these data sets together, um, in, um, in Western populations, Asian populations, and so forth, where, um, there's absolutely no difference in outcomes in terms of patients treated with single agent PD1 versus IPO. And so frontline therapy outside the clinical product for these patients is checkpoint blockade, um, whether it's single agent or combination, um, depends on um um various clinical features and uh discussion with the patients and, and the, the primary uh physician. Um, as with other diseases, the idea of targeted therapies is really important. Unlike cutaneous melanoma, which has a relatively high predominance of activating BRAF mutations, which are sensitive to our BAME inhibitors, um, although we can see BRAF mutations a little bit less frequent, about 20% in the mucosal melanomas. Um, NRAS mutations a little bit higher, um, and in about 10 to 15% of patients will find activated mutations in CIT, sometimes some amplifications in CIT which can be responsive to to some of the kit inhibitors like aatinib, and so that's something that we think about as well. Um In terms of next line after that, then we start falling back on things like chemotherapy, um, and, and, um, and there is some data um supporting the use of antiangiogenic agents like Bevacizumab in in combination with chemotherapy. So, so kind of third line we'll think about chemotherapy, maybe carbotaxol with or without bevacizumab. Uh, and that's, that's kind of in terms of therapeutic options where we're at.
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