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Hello, I'm Doctor Joshua Sabari, thoracic Medical Oncology at NYU Langone Health Perlmutter Cancer Center. These are my disclosures. This is the outline of the discussion today. We're gonna focus on side effects of PD1 and PDL1 VEGF bi-specific monoclonal antibodies, uh, specifically looking at some of the VEGF associated side effects. We'll also look at some of the PD1 or PDL1 associated immune-related adverse events and how to think about managing these in the clinical practice setting. I'm gonna spotlight two agents here, Ivanesimab, formerly known as AKT 112, uh, uh, and we'll also look at poitummi, uh, formerly known as BNT 327, and we'll talk about how to manage these side effects in the clinical practice setting. We'll also comment on the importance of managing adverse events in clinical practice utilizing a multidisciplinary team. You know, it takes a village to take care of patients, and we'll end with some conclusions in this space. So to get us going, the objective for this discussion today is proactive monitoring and management protocols. How to deploy multi-disciplinary team coordination to optimize patient outcomes. So as we know, bi-specific antibodies are molecules that are designed to recognize two different epitopes or antigens. And this is a dramatic improvement over historic monoclonal antibodies. Uh, we have many monoclonal antibodies approved for non-small cell lung cancer, including in the frontline setting. Embrolizumab, a PD1 inhibitor, as well as PDL1 inhibitors with emiblimab or otezallizumab in the frontline setting. Here, we're looking at using a bi-specific antibody. So we're looking at two epitopes targeting both VEGF as well as PD1 or PDL1 expression. And we know that some of the common adverse events that we see from utilizing these bi-specific antibodies, particularly targeting VEGF and PD1 or PDL1, are unique, uh, to these molecules. Again, we have a lot of experience using PD1 and PDL1 inhibitors. We also have a lot of historical experience using, uh, VEGF inhibitors, medications such as bevacizumab, for example. Or Ramisurumab in clinical practice. It's interesting to note that by using a bio-specific antibody, you actually do limit the toxicity profile compared to using a PD1 inhibitor plus a VEGF inhibitor alone. Uh, interesting to think about the specificity of these agents. So what are some of the common side effects that we've seen in some of the phase +12, and 3 studies? Well, Some of the VEGF-mediated side effects such as hypertension, uh, we know that BP management is important both in primary care, but also in oncologic care. You know, monitoring patients and understanding, you know, pressures with systolics less than 140, uh, our goal. Also looking at diastolics less than 1000 or 90 millimeters of mercury are gonna be important. So I oftentimes will monitor these patients' BP and if you See it rising, you can co-manage with a, a cardiologist, nephrologist, or a hypertension specialist. Uh, usually starting low-dose antihypertensives. I'd like to start with, uh, medications that are vasodilators, uh, such as amlodipine, for example, 2.5 or 5 mg, and then move, uh, to ACE or ARB inhibitors, uh, that improve, uh, BP in this patient population. We also wanna look out for proteinuria. Proteinuria is seeing protein in the urine, quite common with hypertension as well as diabetes, and some of our patients may have some baseline proteinuria. So it's important to get urine analysis in these patients, uh, and if they do have elevated protein to actually quantify it using 24 hour urine. I oftentimes will refer my patients with proteinuria to nephrology to help manage the side effect in the clinical practice setting. There are ways to manage proteinuria. In particular, managing the renal function and, and making sure the BP is under very good control. We sometimes do need to dose hold uh the PD1, uh, PDL1 VEGF by specifics in this setting. The next set of side effects that we can see are immune-related adverse events or known as IRAEs, and this is really uh stimulating the immune system to such an extent where it technically will recognize and attack normal tissues in the body. And we'll go through a lot of the immune-mediated side effects, but some of the common ones that we can see are thyroiditis. Which can be monitored by checking TSH and T4, as well as starting, uh, you know, levothyroxine in patients who have, uh, TSH, uh, that is rising. I oftentimes will refer these patients to endocrinology, and this can be very useful in monitoring and managing hypothyroidism and the setting of thyroiditis in this patient population. It's also not uncommon to see skin or cutaneous adverse events, uh, such as, uh, a rash or dermatitis, or, you know, sort of, uh, uh, pruritis or itching. These are patients that we can manage with topical steroids. I also sometimes use oral Benadryl, uh, or antihistamines, and these are patients that we can refer to oncodermatology or dermatology to help manage some of these adverse events in the clinical practice setting. Some of the less common or more rare side effects of vanneumab and poitomi can be bleeding. Uh, and we know that central tumors, particularly squamous tumors that may be vascular or necrotic, have higher rates of bleeding. Uh, these are usually VEGF mediated side effects, and if you see a patient that has even low volume hemoptysis, so sort of small amounts of blood. Admixed with sputum, it's important to get interventional pulmonology involved to consider doing a bronchoscopy to understand if there's anything that we can intervene on, uh, cauterization-wise or potentially embolization, uh, in these tumors, particularly those tumors that are central, uh, eroding or invading into the airway and invading into vasculature. Large volume hemopathy. greater than 1/4 cup of blood, bright red blood is a medical emergency, and I do recommend patients obviously presenting to the emergency room for urgent intervention either with thoracic surgery or interventional pulmonology to consider uh embolization or interventional radiology to consider embolization uh to that bleeding vessel. Stomatitiss and ocular toxicities are actually quite rare with these therapies but can occur. Stomatitiss, you know, mouth sores or inflammation of the GI tract, you know, patients can oftentimes be referred to GI or gastrointestinal, uh, uh, um, uh, providers in order to help manage the side effects. And lastly, ocular toxicity, quite uncommon. Common, uh, with these agents, mostly immune-mediated, uh, in my patient population. And using topical, uh, eye drops, for example, uh, that moisturize the eye can be very helpful. Uh, and then also thinking about, you know, uh, ophthalmology as a referral if these side effects are persistent or worsening in the clinical practice setting. So let's really focus in on some of these adverse events in more uh detail. So starting with the VEGF inhibitor-associated adverse events. You know, these are quite common in our clinical practice and it's really important to assess the patient upfront to understand their risk of developing some of these VEGF associated symptoms. So, who am I worried about? A patient with coronary artery disease, uh, neurovascular disease, history of stroke, for example, history of baseline proteinuria or Hypertension, I'd be much more cautious in utilizing these agents in that patient population. And I would really want to have my sub-specialist on board, uh, from initiation of therapy. I remember a patient recently started on, uh, one of these trials, uh, on therapy. Uh, I had them see nephrology upfront to make sure that if their BP was elevated or if they develop worsening proteinuria, that we would have a team approach, uh, that could get this under control, uh, very quickly. And then again, hemorrhage, I think is critical, uh, to really be thoughtful about which patients we're enrolling on to these trials, which patients in the future will be treating with these therapies. In patients with very centralized tumors who have active hemoptysis, I would recommend against using ivanneumab and pitomi in patients with high degree of vascular invasion, I'd be at high concern uh for, for bleeding, as well as tumors that have significant In central necrosis. Imagine you're a squamous cell histology patient in their 70s, heavy smoking history with this large bulky central tumor. You may want them to see interventional radiology or interventional pulmonology upfront. Perhaps even thoracic surgery upfront to sort of think about strategies that if they have bleeding or worsening bleeding on these therapies, uh, we can mitigate this appropriately and aggressively in our patient population. Digging in deeper into some of the PD1 and PDL1 associated adverse events, there are many that can occur and we don't have time to go through all of them. Again, it really takes a village today uh to manage a patient with these, uh, um, uh, therapies. But again, I will comment that the rate of immune-related adverse events seem to be better with Therapies like Ivanesimab and pitami leading to increased sort of specificity by binding both PD1 and VEGF or PDL1 and VEGFA as opposed to using a single agent PD1 inhibitor. Uh, some of the side effects that we've talked about already, endocrine being the most common, hypothyroidism occurring in greater than 10%, these patients Patients can be co-managed appropriately with endocrinology. We can see some respiratory side effects that are quite rare in this patient population, but pneumonitis, being one that obviously worries us in clinical practice, uh, any new cough, any shortness of breath really should trigger a dedicated CT scan of the chest and even grade one.