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I'm Jeff Crawford, a medical oncologist at Duke University in North Carolina, and I'll be, uh, addressing an update in cancer cachexia focused on emerging therapies. If you haven't already seen it, I'd recommend you also, uh, listen to Doctor Laird's presentation. It's also on the web with Medal. Uh, it focuses more on an overview of cachexia and talks about recognizing the syndrome and how we manage it. Here are my disclosures relevant to today's talk. I'm on the uh clinical trial steering committee for both ActimMed and for uh Pfizer, and we'll be discussing some of their trials later. Learning objectives are shown here. Uh, we'll be talking about GDF 15 or growth differentiation factor 15 as a target for potential therapeutic intervention for cancer achexia. And we'll be doing that in the context of other clinical trials of emerging therapeutic options, uh, and the overall, uh, treatment strategies that may be applicable to you and your patients currently and patients with cancer cachexia. To start with the case, this is a woman I took care of a 72-year-old with cough, back pain, poor appetite, and unintentional 10 lb weight loss over 3 months. She presented with fatigue and actually had to close her law practice because of it. She had a past history of smoking, but no other significant comorbid disease. Uh, physical exam was actually unremarkable. Her BMI was actually slightly elevated. Her performance status was clearly impaired at 2. She was mildly anemic, had a low albumin. And the workup showed ultimately a stage 4 adenocarcinoma of the lung with a 6 centimeter right upper lobe mass, instinal adenopathy, and a 4 centimeter left adrenal mass, all of which were FDG avid on PET scan. Brain MRI was negative. Molecular markers were negative for any targeted approaches, and a PDL1 score was 10%. So we discussed treatment options with the patient and recommended carboplatin, pemetrexate, and pembrolizumab. Um, but we also want to refer her to a palliative care specialist. She had a number of symptoms with cough, back pain, poor appetite, weight loss, and fatigue, and actually by weight loss alone met criteria for cancer cachexia, which we'll be discussing further. Now, hopefully, most of you are aware of this data. It's now more than a decade old, but Doctor Temel did an important trial showing that in patients with lung cancer, randomized to early intervention with palliative care versus standard of care with the oncologist, there were multiple improvements in outcome for these patients in terms of quality of life and, and symptom management. But in addition, there was an improvement in survival. Now this has not been replicated in every study, but it does, uh, I think highlight. The really important aspects of early intervention on symptom management in addition to treating the cancer. Yes, cachexia has been defined in many ways, but the best known definition comes from an international consensus uh led by Doctor Fron that described cachexia as a multifactorial syndrome with an ongoing loss of skeletal muscle mass that can't be fully reversed by conventional nutritional support and leads to progressive functional impairment. Now, a decade later, this definition is being revised to take advantage of the fact that fat loss is part of this and quite important, as well as inflammatory components, uh, and the need to address different body compositions globally, um, in other patients. But the fear and criteria as we have described them are that the cachexia is defined by a loss of greater than 5% of body weight in 6 months, or if your BMI is less than 20, uh, A loss of greater than 2%. NCCN guidelines are shown here and they're not quite easy to read in the slide, but in essence, uh, because there's not a one standard fits all for how to manage cancer cachexia, uh, NCCN guidelines have recommended a detailed screening for conditions and symptoms that might interfere with food intake. That could be altered taste, it could be a dry mouth, it could be mucositis, it could be depression, it could be pain, nausea, and vomiting. Uh, constipation, that all of these issues really need to be addressed in the context of the patient losing weight. And if that doesn't resolve, and on the right side of the slide, they talked about dietary consultation, uh, and potential use of appetite stimulants, and we'll talk a little bit more about that, but it really is a multi-pronged approach, uh, that one needs to think about to reverse the weight loss in our patients. In 2020, ASCO convened a, a group of experts to try to develop management guidelines for cancer cachexia. And you'll see their very first recommendation is actually dietary counseling, which is the best validated approach to uh improving cancer cachexia. It can't be fully reversed with diet, but it can be ameliorated. Uh, they also said that there really wasn't a specific medication that they could recommend routinely for patients, but one could consider either progesterone analogs or corticosteroids as possible options. Subsequently, uh, they added to this list an additional agent shown here, olanzapine. This is a, a study, a randomized trial in patients with advanced GI and lung cancer, uh, and you can see in red. The continued loss of weight on the placebo arm versus weight gain in the, in the group getting olanzapine, low dose daily, so different than we would do with nausea and vomiting management, but more longer term. So this is an interesting option. And this is actually being studied right now for those of you in the US that may have access to NCTN trials. This is a randomized phase 3 trial of olanzapine versus Megestrol acetate for cancer associated anorexia being led by Doctor Jatoi. Uh, at the Mayo Clinic, uh, and we'll address importantly whether there is an actual improvement in anorexia and what the side effect profiles of these two different approaches are may help us, help guide future ideas on how to manage our patients. We look at ACO and ESO treatment considerations overall, these are not firm recommendations but options. Uh one can see they've listed the same agents of the gastrol acetate, olanzapine, and corticosteroids. All three of these agents have shown some reversal of weight loss and or improvement in appetite, but none are approved for use for cancer cachexia, and none have shown a quality of life benefit or functional improvement. And all have some side effects that are potentially significant, so. Uh, while we have options that we can use for our patients, in addition to tailored, uh, approaches that I mentioned from NCCN, um, we don't have a, a, a gold standard of what to do for our patients. So clearly, uh, we have to look to the future and we have to look to clinical trials to improve outcomes for our patients. One other important approach and, uh, I think, uh, very important to incorporate in our practice is a multimodal intervention. The MENAC trial was reported last year at ASCO in 2024. This is an open label phase three multi-center trial that looked at a combination of exercise, nutrition, and an anti-inflammatory medication over a number of weeks in patients with advanced longer pancreatic cancer. What was seen in this study was that weight was stabilized in patients that got the multimodal intervention versus standard of care. But it wasn't reversed, so patients had less weight loss going forward, but not, uh, not resurrection or correction of the uh cachexia. There were no significant difference in muscle mass or physical activity. So again, uh, there's potential benefit, but, uh, not what we'd like it to be. This is supported by a couple of other phase two studies, the miracle trial done in Korea, and the next 2, the next act 2 trial of nutrition exercise done in Japan. And I think all of these. Tell us the same thing and that's that, we have to take a multi-modal approach to our patients, nutrition, exercise, and a tailored involvement of specific um agents that may help uh, an individual patient's situation, but we also need to look to the future for better agents. To that end, uh, a clinical trials working group in cachexia led by Doctor Barry Laird and Richard Skipworth at the University of Edinburgh have, uh, looked at uh systematic literature reviews of a number of different endpoints have been studied in cancer cachexia clinical trials, including physical function, appetite, quality of life, body weight, and composition, and biomarkers to give us sort of a landscape of what the options are and what the outcomes have been. As an example, this is a slide showing uh the relationship of different measures of body weight and composition compared to the intervention of exercise, multimodal interventions, nutritional interventions, and pharmacologic interventions. One can see the number of studies, the size, whether they were significant or not, um, but it gives us an idea of what potential, uh, endpoints might look like and what the outcomes might be. Of course, that's gonna be very dependent on the intervention, whether it's successful or not, but Quite important to understand what the different Uh, outcomes might be, we think are relevant for our patient population. It's also important to get an idea of the overall landscape of uh the field. There are a number of agents that have been in development both pre-clinically and clinically, that really try to address the central feature of muscle atrophy, and shown here are a number of different approaches.