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Welcome to the Quick Consult podcast, brought to you by Metall. Before starting this podcast, please review the faculty information, disclosure statements, and learning objectives using the link in the episode description. To claim your CME credit, complete the evaluation using the link in the episode description. This podcast is a continuing education activity managed and accredited by Current Concepts Institute in collaboration with Metal. This activity is supported by an independent medical education grant from Pfizer. Welcome to the first line Focus Perspective series of the podcast. I'm your host, Doctor Phil McAulay, and in this series, we're focusing on optimizing first line BRAAF targeted treatment decisions in community oncology settings for patients with metastatic colorectal cancer and metastatic non-small cell lung cancer. In this first episode, Making the First Move, we'll discuss how to put all the critical patient information from clinical guidelines to molecular profiles into action to select the best initial therapy. Joining us is Doctor. Zev Weinberg, professor of medicine and co-director of gastrointestinal oncology at the UCLA School of Medicine. Dr. Weinberg, thank you for joining us. The recent breakwater data is practice changing. Could you briefly summarize why the combination of encarafenib, cetuximab, and chemotherapy is now considered the new standard of care for first line BRAF V600E mutant metastatic colorectal cancer, especially compared to chemotherapy alone. Thanks, Phil, and thanks for having me. You know, so BRAF represents about 8 to 10, 8 to 12, depending on what you read, percent of metastatic colorectal cancer. It's been around for a while, insofar as we've recognized that it represents a distinct subset. This became more relevant in the last number of years when drugs, particularly drugs that block both BRAF directly and down. Extreme EGFR were tested and shown to be promising in second line in what was called the Beacon study that was superseded in respect to a frontline study called the Breakwater study. The Breakwater study randomized patients with newly diagnosed metastatic colon cancer that was BRAF mutated to either chemotherapy plus bevacizumab, which would be considered at the time the standard of care, or To the combination of encarafenib, which is the BRAF inhibitor, cetuximab, the EGFR inhibitor, and FOLFOox chemotherapy, and suffice it to say that the results were very compelling. It showed a very significant improvement in overall survival in the group of patients who obviously lived longer, having been on the chemotherapy combination over the standard of care. Chemotherapy alone this was supported by increased response rates, increased progression free survival, and most importantly, overall survival. It was a hazard ratio of 0.49, which was highly statistically significant, and so it has changed the standard of care in essence to newly diagnosed patients with BRAF mutation should now get FOLFOX, encarafenib, and cetuxim. In metastatic non-small cell lung cancer, we have two FDA approved regimens, derefenib plus remetinib and encarafenib plus biummetinib. What key data, perhaps thinking of the fair off study and treatment naive patients, should community oncologists consider when choosing? A first line BRRAF MAC inhibitor combination in this disease setting. So in lung cancer represents a much smaller subgroup, it's probably 2 to 3%. Some even say 1 to 2% have a V600E mutation in non-small cell lung cancer. For a number of years, lung cancer with select point mutations has been treated by drugs like this with great success. Dorafenib tremetinib was the first one, as you mentioned, approved a number of years ago, and more. Recently, and a little more compelling was the FAA study, which was encarafenib and cetuximab. Um, this was a combination of, again, a BRAF inhibitor and carafenib, and uh binimetinib, in this case, not stuximab, which is a MEC inhibitor. Um, in that context, in the most updated analysis, which was pretty recently, response rate was 75% in newly diagnosed patients. And 46% in previously treated non-small cell lung cancer patients. So a very compelling response rate. The median PFS was 30 months in the group of patients who were treatment naive and 9 months in the group of patients who had been pre-treated. And most compellingly, the overall survival median hadn't been reached in the newly diagnosed patients. So because of that, I think most people consider that very compelling. And even in the absence of randomized data, people consider it the FAA regimen. And corafenib and binimettinib to do to be a good gold standard for newly diagnosed patients with BRAF mutant non-small cell lung cancer. Once a treatment regimen is chosen, how important are patient specific factors such as performance status or comorbidities in tailoring the final personalized first line plan for patients with BRAF V600E mutant, metastatic colorectal cancer or metastatic non-small cell lung cancer. So, I mean, the good thing. About most of these regimens is that they do tend to have a safety profile that is reasonably well tolerated. So even in patients who, in my opinion, are borderline performance status, one, you could still treat with great success. Now of course it's going to depend on individual patient characteristics. For example, some of these drugs cause a serious rash, so we have to be sure that the rash is treated accordingly. Other patients, for example, with FOLFOox, get. For neuropathy, so you're going to have to keep that in mind. I mean, obviously one of the key elements to any treatment regimen being a success is how the patients are tolerating it. However, given that a lot of the regimens are oral pills, this has made it a little easier and more practical to treat patients even who live at far distances and see if they work. The other point is, a lot of times with these new targeted therapies that are of great success, especially non-small cell lung cancer, but even Colorectal cancer as well. The response is immediate, so meaning the patients actually usually feel better after just a month or two on these drugs. So it's important to keep in mind that you're expecting a quick response very often. Given the complexity of modern multi-agent therapy, what's the single most important piece of practical advice you can give a community oncologist today about confidently initiating these BRAF targeted first. regimens. So I think the first thing is that I think the more and more we study these drugs, the more value there is in using them up front. So I think in my opinion, for example, we should be getting this information as soon as a diagnosis is established of advanced disease. We shouldn't be waiting till later. We should be finding out right away if they are BRAF mutants in this context, because the results have immediate practical implications. So for example, we see that if you give these drugs in front line, They do much better than you give them later on after they've been on chemotherapy. So even if you know, you're getting organized quickly, established diagnosis, I would, I would try to figure out ASAP if somebody has a BRAF mutation in colorectal and lung and implement the appropriate therapy quickly. Community oncologists are extraordinarily busy. They have to keep track of many, many different things, including many different cancers and what new data. I think to make it practical and easy, I, I always advise my referring physicians to send immediately for a next generation sequencing panel on all of these patients with solid tumors that will, and BRAFVD 600E is one of the first ones to read out. And so I find that to be the easiest and fastest way to get an answer. Doctor Weinberg, thank you so much for joining us and for clarifying the most current strategies for first line treatment. Join us for our next episode where we'll dive into proactive strategies to monitor and manage adverse events associated with BRAF targeted regimens. You can access more accredited CE resources on this very topic and others by visiting metaleducation.com. Thanks for listening. To claim your CME credit, complete the evaluation using the link in the episode description. See you next time on the Quick Consult podcast.