From Approval to Practice: Managing Side Effects of Antibody Drug Conjugates (ADC) in Cancer

Intro Hello and welcome back to another episode of The Oncology Brothers. I'm Rahul Ghossein, here with my brother and Co host Rohit Ghossein. Today we're kicking off a new series focusing not just on drug approvals, but rather on managing side effects of approved agents in our community settings. Speaker 2 Rahul, you're right. It's not just about knowing these approvals, but rather to get comfortable and managing some of these side effects. Today we'll be talking about antibody drug conjugates. We will touch on three important antibody drug conjugate and fortumab bedotin, sasituzumab and prestuzumab Deroxycan given the approval of all these antibody drug conjugates from multiple different disease sites. We are joined by Doctor Tian Zhang, A Gu medical oncologist from UT Southwestern and Dr. Erica Hamilton from Sarah Cannon Research Institute. Tian and Erica welcome. Speaker 3 Thanks for having us. Thanks. Speaker 1 Arka Tian, thank you so much for joining us. As Rohit mentioned, there's a lot of excitement with antibody drug conjugates where we're getting more sophisticated in attacking the cancer cells in this space. Infertumab Can we start off with infertumab where the target is Nectin 4? This was initially approved in metastatic bladder cancer in second line. But then at ESMO 2023, we saw infertumab and pembrolizumab doubling the overall survival for bladder cancer in first line. This is now our standard of care for this disease. The side effects from infortumab are not trivial, be it skin toxicities, hyperglycemia, neuropathy or fatigue TN. Can you touch on some of these common side effects with infortumab and some clinical pearls around this agent? Is it those reductions skipping day eight? What does it really look like in your clinic? Speaker 3 Sure. Thanks so much for highlighting it. EV and pembrolismab certainly has changed our practices for metastatic bladder cancer. We've been involved with the clinical development of fortimafedotin ever since the monotherapy trials. So EV 103, EV 201, an expanded access form and even early on as monotherapy we saw some of the skin toxicities. The rashes are steroid responsive and they are also responsive to early holding of treatment and early dose reduction. I also warn our patients about the neuropathy it tends to build up over the cycles of treatment to out four to six cycles on EV alone or on EV with pembrolizumab we start to develop more of the sensory and sometimes the motor neuropathies. So as those come on, I'm, I'm one to consider early dose reduction, but also one to drop day 8 of EV alone when we're sort of in the standard of care setting. And you know, the, the cytopenias are often are not so, so bad with our EV. We've had some transient neutropenias, but they usually bounce back. We're really focused on skin and nerve toxicities. The hyperglycemia is also an adverse event of special interest with hyperglycemia over 250, we hold in for Tam epidotin for that day. So if somebody does have underlying diabetes, we we watch your sugars pretty carefully, opt for more aggressive glucose control and really try to get them through so that they can actually see more of them for to map but don't. But those are the three that I kind of harp on for our patient populations. I have seen pretty severe skin toxicities, the black box warning around Stevens, Johnsons and 10 certainly there for a reason. But if we do some early dose reduction, if we do some skipping of day 8, those tend to be more at Bay. And in the last three years at least, I haven't personally caused an SJSTEN syndrome. But it does require some early awareness. If any blistering rashes, holding a treatment is quite prudent. Speaker 2 Thanks for going over that TN. Well, I hope no one really goes to the level of SJS or TEN because this can be devastating with regards to when you have these blisters or rash. Do you get them started on steroids and of course dermatological involvement but do you re challenge them with that or just you stop after the patient has not developed SJS or TN but almost getting there? Speaker 3 Yeah, I, I certainly hold while they're recovering, as we taper off the steroids, we have that conversation of what are the risks and benefits for re challenge. These skin toxicities can worsen over time with re challenge. If anybody re challenges, I often go at a lower dose, OK, Those are the ways to mitigate. And when those blisters come up, I want to really try to hold off as long as we can until they improve with steroids, mostly if they develop really severe skin toxicities. These are patients who we treat in the hospital. We tend to use plasmapheresis and IVIG for some of these folks. Hopefully we don't get there. Yep. Speaker 2 With regards to hyperglycemia, because the trial only enrolled patients who HBA 1C less than 8, do you check baseline HBA 1C or how do you manage that? Hyperglycemia We do, we watch their A1 CS, but if you know they're borderline like they are 8.18 point 2, I, I don't, you know, avoid, but rather we try to help with glycemic control and to manage your sugars as much as we can during the treatment course. Speaker 2 Sounds good. Thank you. Well, from 1 bladder cancer drug to another Sasatusumab govitican where the target is in fact truck to Sasatusumab was initially granted accelerated approval for bladder cancer, but recently the approval was pulled away. But clinically we have seen some meaningful benefit even in bladder cancer setting. Sasatusumab is also approved in triple negative and metastatic hormone receptor positive breast cancer. But when it comes to side effects, we have to worry about neutropenia, diarrhea, fatigue. Erika, can you touch on some of these important side effects and how to manage these? And as we know that these all Adcs are not similar with terms of side effect profile. Speaker 4 Yeah. If there's one thing I want to leave listeners with today is to not think about these antibody drug conjugates as a class. I was really struck listening to 10 talk about infortamab, which is a drug as a breast medical oncologist I've not had the opportunity to use. But the three big side effects there, the hyperglycemia, the rash and the neuropathy are side effects that we don't anticipate to see with the two AD CS that we're going to be talking about in the breast realm. Although these are AD CS, they're really individual drugs. I think it's hard for community oncology just because you have to think about each of these individually. You're right, Sassituzumab, like infortumab, is also an ADC that's dosed on a day one, day 8, and then you have day 15 off. This ends up being quite challenging for this drug because the biggest side effect that we anticipate to see is neutropenia. And because of that day 8 dose, we can't use a pegylated GCSF product after day one because they need to come back and get that day 8. And so I think that's really the most challenging issue. We can use something short acting like a Neupogen. I think that's hard for patients because a lot of times we can't get that approved for insurance for home and who has time to be coming into the clinic for three days for a shot administration. So a lot of times we use a Neulasta or a pegylated GCSF product after day 8 and really try to boost those counts up high enough that they survive the next cycle through day one, day 8 to get the GCSF in a pegylated form again. I'd say that's our first way of managing it. If we can't manage that, we'd have two choices. We can either dose reduce the drug a bit so we don't end up with the white blood cell count so low, or a lot of times I see people switching to a day one day 15 administration. Q 28 days. That way you have two weeks between each administration. And if you need to, you could use a pegylated GCSF product. The other big side effect from saskatuzumab is diarrhea. Diarrhea And I guess I'll say I see this diarrhea a little bit different than diarrhea from other drugs. It's not universal like ATKI, you know, it's not a neuratinib or lepatinib or nabimicyclob. Or you really expect most patients to have some form of diarrhea? I find it to be very binary. People either really struggle with diarrhea like 3 drugs and tincture of opium struggle or they don't really have diarrhea at all. And I'm not sure what it is about individual GI tracts of how people react, but some people just don't struggle. Mustard all and some people struggle a lot. I think it's also just important to highlight which antibody drug conjugates can have some alopecia. Sasatuzumab Govatekin We can see alopecia with sasatuzumab Govatekin, there is no more mad patient than a patient who loses their hair that you forgot to tell them that might. So I just want to point that out. And otherwise, you know, I think this is a drug that's really challenged the way we think about breast cancer. In some ways we were so set in our dogma of dividing her 2 positive, triple negative and hormone receptor positive. But with these AD CS we're really seeing hormone receptor positive and triple negative group together with some more broad approvals. It is encouraging. Speaker 1 Erica, thank you so much for going over that. I'm actually going to turn the clock back a little and jump on the same bandwagon as you and Rohit. These are different ADC's. Even though falls in the same class as community oncologist. This is not immunotherapy or Tkis where we can lump all these side effects. Yeah, there might be some overlap. Alopecia, we see it with Sassy, we see it somewhere TDXT, but they all have their unique side effects. This was approved in bladder Cancer. Anything you would like to add in this space so that I can continue to feel more comfortable in the community settings day one? Day 8. Do you feel comfortable skipping day 8 like what we tend to do for Enforzimab? Anything on your end? Similar story for diarrhea, primary or secondary prophylactics that you might consider. Speaker 3 Thanks. I would note that the confirmatory trial was negative. Most recently, Gilead withdrew their registration for Sassafus Magobatican in bladder cancer. That said, we've seen some efficacy for some patients, certainly a stability of disease in select patient populations and we weren't selecting them for Troop 2 expression. So maybe a population effect. But I would echo a lot of what Erica said about sesame gravity. Can you know we're, we're focused on the cytopenias and there are some patients who I will give growth factor to. I also don't hesitate in skipping day 8 if we run into a toxicity, but these are definitely different drugs and for each drug we need to manage the side effects appropriately. Speaker 1 OK, so now on to another ADC that initially got approved in breast cancer. Trastuzumab Durextacan But recently we've seen a bucket approval Trastism after XT can and here the target is. Her two common side effects here are nausea, fatigue, alopecia. We touched on that, but ILD is something where the mortality is associated with. Erica, your thoughts here? Speaker 4 Yeah, absolutely. So a different ADC for sure. Our biggest side effect that we see day-to-day with trastuzumab durextacan is nausea. It's almost universal nausea. Now in the initial trials, Destiny breast O1, Destiny breast O 2346 etcetera, mandatory anti medics were not required. They were suggested per protocol. And so I do want to highlight that because I think we're doing a little bit of a better job with nausea in the real world than we did in the studies because in CCN, ASCO, etcetera, guidelines are acknowledging that this is at least a moderately if not highly a metagenic drug. And so their recommendations are at least a 2 drug, if not a three drug anti emetic prophylactic regimen. In my clinic, universally we use a three drug anti emetic regimen. So this consists of dexamethasone A5, HT 3 like ondansetron as well as an NK1. For patients that still have nausea. I borrowed a little bit from the GI literature and I give olanzapine at night. This works really well for my patients, my patients that aren't struggling very much with nausea. I dropped that NK one out. I've not had anyone that's had to stop this drug or hasn't been able to tolerate this drug for nausea. But I would caution you, don't just start the drug and say I'll add nausea drugs later if we need it. We really should be using prophylactic nausea drugs. I think you brought up a really important point about ILD. ILD This garnered a lot of tension years ago with the DBO 1 presentation where we saw fatal grade 5 ILD on and off throughout the subsequent studies. We have seen a couple cases in each trial. It's interesting. We don't see a lot of grade 3 or grade 4 ILD. We see quite a bit of grade one, grade two, more mild, but it really looks like if it progresses to more severe ILD, ultimately it's hard to turn those cases around and they could end up being fatal. So we see about a 10 to 15% ILD pneumonitis across all studies, but we have managed to get kind of fatal ILD kind of into this half a percent category, so much more rare. I want to caution the community oncologists that are used to looking for ILD with other drugs that we treat ILD differently with trastuzumab drugs to can with immunotherapy where we maybe don't think much about it until grade 3 where we're stopping drugs etcetera. This is different with trastuzumab drugs to can even for grade 2 ILD. So any symptoms, cough, shortness of breath, anything that is supposed to not be re challenged with drug and even for Grade 1 completely asymptomatic seen only on an incidental staging scan, we're stopping drug and waiting for this to resolve before we re challenge with drug. So really a different that threshold around ILD with this drug and with that increased guidance and threshold and we've been able to eliminate fatal cases. But don't underestimate this. We really have to maintain vigilance. Speaker 2 Thanks for summarizing that, Erica. With regards to nausea, certainly the community oncologist, we are used to this side effect profile, but managing with dual or triplet therapy is extremely important to manage some of these side effects. With regards to ILD, as you stated with Grade 1, you can certainly reach challenge and with regards to grade two, grade 3 and grade 4, definitely not. ILD in Grade 2 But grade 2, do you reach out in some of these patients post ILD is resolved? Speaker 4 Yeah, the formal answer is no, we're not supposed to have I ever. Yes, I have. And I think that grade 2 ILD is not all created equal. You know, grade 3 is kind of requiring hospitalization. Grade 1 is no symptoms. And as you can imagine in this grade 2 bucket is somebody that says that maybe they had a little bit of cough but had no shortness of breath, didn't need oxygen, you know, anything like that. And so for some of these patients that are very mild, I have re challenged. I wouldn't do this universally for grade 2. Anybody that had hypoxia or any drop in oxygen, I have not done it for. I think it's just a little bit too dangerous. But again, we're talking about a drug that PFS can be upwards of two years and otherwise these patients really have a quite poor prognosis. And so I've been very upfront with patients about the risk, but some of them are saying, you know, please don't take the drug away from me. I understand the risk. I'm willing to take it. But you know, I I also have a cancer that I'm not gonna make it through, and it's a fatal cancer, so I'm willing to take on more risk. Speaker 2 Patient shared decision making is extremely important, but again, keeping the side effect profile, especially when you're talking about quality of life when palliative measures are involved. So it's important. TN the prevalence of her 2 positive and Geo malignancy is low. Have you utilized this agent yet and your thoughts here? Speaker 3 And it's a great agent to have for a pen tumor approval. I have a couple of patients in my practice. There's one in particular with a very differentiated scrotal tumor that was her two turned out to be her two overexpressing. And we gave him, I was metastatic and we gave him D and he had a beautiful response. So far, I've been quite pleased with the effect and also the side effect profile. He's tolerated very well. We haven't run into the ILD issues thankfully yet, but they do tend to have some of the dwindles when these payloads are delivering chemotherapy drugs. Patients can feel poorly while they're on it and. Speaker 2 Before we close, just one last question. Cold therapy for neuropathy and alopecia Any utilization of cold therapy, whether that's for neuropathy or alopecia, have you seen any changes or rather benefits from that? Speaker 4 That's a great question. I don't think we have, there's been a couple of patients that have tried it. But really the benefits of cryotherapy, whether we're talking about, you know, hair preservation or for neuropathy really depends on the half life of the drug. And so if you have a very high half life because you're kind of administering naked chemo as I like to call it, that's gonna work because by the time they walk out of your infusion suite, the concentrations are much lower. A drug like trastuzumab, Durexacam that's only given every three weeks and actually has a quite long half life, it's not going to help us in the same way. So this is not a place where I say that cryotherapy is really going to benefit our patients. Speaker 1 Absolutely, Thank you both for these invaluable insights as we hope that these discussions will help us navigate to complexities of managing toxicities of these ADC's in our practice. Outro For our listeners, let's go over a quick recap. Speaker 2 In today's discussion with Doctor Erica Hamilton, a breast medical oncologist and Dr. Tien Zhang, a Geomedical oncologist. We had a chance to focus on how to manage side effects of three common antibody drug conjugates and Fortimab, sasituzumab and TDXD. Speaker 1 Keeping common side effects in mind is important, but recognizing and acting on the ones where mortality is associated is equally, if not more critical. With and fortimab skin toxicities, hyperglycemia and neuropathy should be on your radar, whereas with sasituzumab, neutropenia, diarrhea, and fatigue are some to keep in mind. We also touched on TDXD where nausea, fatigue, and ILD are critical. Thanks for joining us. Make sure to check out more of these discussions around toxicity management. We are the oncology brothers.