What are some other antibody-drug conjugates [ADCs] being evaluated in patients with metastatic gastric cancer right now that we haven’t already discussed?

Elizabeth Prechtel Dunphy, DNP, CRNP, AOCN: 

There are 2 studies I’d like to mention. One is a phase 3 trial of…phenytoin, which is a HER2-targeting ADC comprised of a novel humanized anti-HER2 IgG1 [immunoglobulin G1] antibody and a microtubule inhibitor, MMAE, which is a monoclonal antibody of monomethyl auristatin E, conjugate. That’s being looked at in the metastatic setting. It’s a phase 3 study, randomized open-label, parallel-controlled study evaluating the efficacy of the recombinant humanized anti-HER2 monoclonal antibody, the MMAE conjugate, for patients who have HER2 overexpression. The overexpression for this study is defined as plus 2 or 3 score on IHC [immunohistochemistry] regardless of FISH [fluorescence in situ hybridization] status. There are 2 arms, which I found interesting.

One arm is with the RC48-ADC every 2 weeks IV [intravenous] vs physician choice. The physician choice was paclitaxel, irinotecan, and apatinib mesylate, or Aitan. I found that interesting because I wasn’t familiar with that being used here in the United States. So I did some investigating, and that is a multitargeted tyrosine kinase inhibitor that inhibits VEGF2. It’s approved in China for late-stage gastric carcinoma and has been in their armamentarium of treatments since 2004. The outcome is being looked at in this particular study as in other studies. The primary end point will be overall survival, progression free-survival, objective remission rate, duration of relief, and time to tumor progression. Patients had to have had progression or intolerance following at least 2 systemic therapies. And as I mentioned, the HER2-positive by IHC is 2+ or 3+.

There’s a second study that’s a phase 1 study that’s looking at ARX788, which I think you mentioned in breast cancer, a humanized anti-HER2 antibody, Amberstatin 269. This is a 2-part phase 1 study in which the ARX788 is given by infusion, and patients had to have received a prior treatment with trastuzumab.

Patients have to be FISH positive or IHC plus-3 HER2 positive, and it’s a dose-finding study. ARX788 is a next-generation, site-specific anti-HER2 ADC that utilizes non-natural amino-acid-enabled conjugation technology and a noncleavable Amberstatin drug linker to generate a homogenous ADC with a drug-to-antibody ratio of 1 to 9. It has a growth inhibitory effect on all 5 lines of HER2-positive cells that were tested. I wanted to investigate it a little further because I wasn’t certain myself what ARX788 was. So that’s my information that was gathered.

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Before closing out their discussion on HER2+ gastric cancer, experts review clinical trials investigating other novel ADC agents in this setting.

Novel Clinical Trials With ADCs in Gastric Cancer

Before we close, I would like to ask each one of you to share some pearls for your fellow nurses regarding toxicity management and antibody-drug conjugates [ADCs] in patients with metastatic breast cancer and gastric cancer. Jamie, why don’t you go first?

Sure. For breast cancer, if there’s any risk of stomatitis, or peripheral neuropathy, just think “freeze.” Freeze everything. Have them [patients] chew ice in the chemotherapy unit, have them stick their hands and their feet in Elasto-Gel mittens and booties. If you’re worried about alopecia, try cryotherapy to the head. Just think ice is never wrong.

Additionally, I do see where patients have dryness of the mouth and mucosal membranes. So I recommend XyliMelt, it’s a little disc they can put down under their cheek at night, and it helps stimulate the salivary gland. Or they can buy a $2 bag of Jolly Ranchers, and if they suck on those, that helps stimulate the salivary glands to help with their dry mouth.

What I would suggest is doing a very good initial assessment, whether you’re meeting the patient for the first time or you’re seeing them in follow-up. But I think in particular, before they start treatment, know where they are at baseline. My case study was about diarrhea, and so having that information prior to seeing the patient as they start treatment gives me good information. Secondly, I always like to, if I can, involve the caregiver because they are always the tattletale in the room. The patients don’t always like that, but I think it’s good to have someone who is in real time with the patient from day to day, being able to give their perspective. Obviously, they can’t tell you what the patient is feeling, but they can at least tell you what they are observing, which gives some added input to help you make decisions for the patient.

Theresa Wicklin Gillespie, PhD, MA, RN, FAAN: 

I have 2 points that I’d like to share or reinforce. The first is tagging a little from what Liz said about a baseline assessment. For me, it would be to do a thorough and careful assessment in terms of what might be a toxicity or some kind of sign or symptom the patient is experiencing, and trying to figure out for real, is this the drug? Is this the cancer? Is this the therapy? Because that’s all too often, perhaps, easy to mix up, and therefore that would influence the best intervention.

But the second point is just to remember that regardless of whatever the drug is, these patients have metastatic disease. And part and parcel with that is high anxiety. So, every single twinge or any symptom that they’re experiencing, to them, has to represent that this is progression of the disease, this is another site of metastasis. It influences and colors all of our interactions. And so, do whatever you as the provider can do to help both the patient and the caregiver or family member to recognize that, yes, this is metastatic disease, but something I said earlier about looking at it more as a marathon than a sprint. Because if you do look at those second- and third- and fifth-line options, in many cases there is lots and lots on the menu. That’s not a panacea, it’s just something that hopefully can be helpful.

Thanks, Theresa. For me, for a pearl to share, when I have patients who are going on a regimen that’s highly immunogenic, I of course want to prevent adverse effects as much as possible. For trastuzumab deruxtecan, we’ve had a lot of issues with nausea. So I make sure that they [my patients] have a lot of premedications, and I give them everything I listed earlier, with the aprepitant, and the 5-HT3 [5-hydroxytryptamine 3 receptor] inhibitor, and the dexamethasone, and whatever else I can add in there. But also I have been prescribing patients often olanzapine. It was shown to be effective for patients getting doxorubicin and cyclophosphamide, the early stage regimens we use for breast cancer, and it was shown to reduce and prevent nausea if they took it just for the first 5 nights. I’ve used that with trastuzumab deruxtecan quite a bit. So, I would recommend that to anybody.

Also, I do totally agree, Theresa, that everything is in the details with patients. Understanding what they’re experiencing every day and every moment of that day, and what they’re taking to deal with it, and how they manage, that helps you figure out what the cause is and how to treat it. Asking a lot of questions; I always think I drive my patients crazy but asking more questions is always better.

Thank you everyone for joining us. And to our viewing audience, thank you for joining us as well. We hope you found this 

 discussion to be useful and valuable in treating your patients with HER2-positive breast cancer and gastric cancer. Thank you all.

Shared practical advice on the management of toxicities associated with antibody drug conjugate therapy in both the breast cancer and GI cancer settings. 

Practice Pearls for Toxicity Management With ADC Therapy in Breast and Gastric Cancer

So how common is diarrhea in patients with gastric cancer receiving trastuzumab deruxtecan (T-DXd)? Which patients are at risk for diarrhea? Who would be developing this more so than somebody else? Theresa, do you have a sense of this in your practice?

I think Liz presented some of those data from at least the Gastric01 study, and it’s not uncommon. In fact, it I think was one of the top 3 toxicities that were reported in that study. And it depends on whether you’re just looking at all grades or grade 3 or more. But it’s certainly a fairly common thing. I wasn’t clear, Liz, if your patient was diagnosed with metastatic disease at the time of diagnosis. Is that correct?

So if patients are diagnosed when they don’t have metastatic disease and they may undergo surgery, either a partial or total gastrectomy, they may have diarrhea from that. They may have dumping syndrome. They may have nutritional dysfunctions and problems, and maybe they have a feeding tube and there are issues with that. So when you’re talking about how you are treating diarrhea, I think it goes back to some of our earlier discussions about distinguishing between what are drug-induced or drug-associated toxicities vs what may be cancer or other therapeutic-associated or induced toxicities, and being very careful with your assessment.

And then it becomes very complicated because some of the foods that Liz was talking about, they may be contraindicated as well if you have had a partial gastrectomy, you’re having dumping syndrome or something like that. But there may be other foods that maybe are the only ones that a particular patient may tolerate, and that’s very important for their overall nutritional status. So it does get a little tricky, and I think the first thing is to be very careful with your assessment. And the second thing is to be very thoughtful about the intervention.

And I just have to ask Liz. What did you think was the reason this gentleman didn’t report his symptoms? I love the comment from his wife, “I told you so.” But that’s a pretty profound symptom if you’re having diarrhea 8 times a day. Could you discern why he never reported that?

Elizabeth Prechtel Dunphy, DNP, CRNP, AOCN:

 He said in his conversation with me “Well, we discussed this, and you talk about it every time I come. And so I just thought it was what I should expect.” So I tried to reinforce that yes, it is a side effect, but we do need to know if it’s happening beyond this amount of times a day because we don’t want him to get dehydrated, the low count of the low potassium. There are consequences to that, and I guess he didn’t hear that part. He only heard that I said it would happen and went with that. At least that’s what he told me, and I took from the conversation.

I think sometimes it can be because of embarrassment. The last thing you want to do is call in and tell somebody you’ve got diarrhea. Nausea is one thing. Diarrhea is another. Nobody really wants to talk about it. I’m wondering if, for this gentleman, he just thought: “I’ll deal with it, it’s fine. I don’t want to call in and bother anybody with my symptoms.”

That could be the case. I like to say to our patients while working with the GI [gastrointestinal] cancer population, I’m probably the one person who wants to hear all about your stools. I want to know what they look like and their consistency. And I do get the head shaking a lot from the patients, particularly if there’s a caregiver with them. But I tell them I want to know because I need to know. I guess trying to be transparent with the patient regarding that in a good way so that there’s an open line of communication is a good thing.

 Liz, what are the monitoring parameters that you consider in these patients that you’re starting on trastuzumab deruxtecan to mitigate their risk of worsening diarrhea or diarrhea altogether? What kind of questions do you ask them, and how much detail are you asking them about their bowel movements, perhaps?

I try as we’re starting the medication, to get a baseline of what their normal bowel movements are, how many times a day, what is the consistency. And then I also like to ask if they’ve had issues with bowel movements in the past with their prior treatments. And then some of the things that Theresa said we need to take into consideration, particularly if they are having feeding tubes. What is the nutritional supplement they’re using? And because of that, their bowel consistency isn’t what we would maybe normally expect. And does that happen? Has that happened off of treatment? Have you had changes. So that you can have a really good assessment of what their baseline is so that you know going forward, is it related to their cancer and their subsequent—if they’ve had surgery or comorbidities—or is it truly related to the treatment? So that way you can treat appropriately.

 Based on that, how do you counsel them on how to report their diarrhea? When to report it, what to do? What are you telling your patients, Theresa?

Theresa Wicklin Gillespie, PhD, MA, RN, FAAN:

 I also want to go back to your earlier question, Sarah. I don’t think I answered it fully. But in terms of just how often diarrhea is seen or at what rates, I think we talked about the Gastric01 study and that was around 32% of all grades and about 2% of grade 3. It was not seen at that high rate in the Gastric02 study, and there were very few or no grade 3s reported. I looked at the lung study because the same drug has been used in non–small cell lung cancer. And interestingly, the rate for diarrhea in all grades was around 32% there too, so that seems to be pretty stable. Maybe a third of the patients are having some diarrhea.

But to piggyback on what Liz said and on what I said earlier, when you’re counseling patients about diarrhea, you do have to put it in the context of what other issues are they dealing with. Are there post-surgical nutritional and GI problems? All the different things that come into play with GI cancer and GI toxicities. There’s a lot of overlap, and we have difficulty in discerning. It’s hard to just draw the line and say, “This is therapy, this is a disease, this is surgery.” But we do definitely want the patients to report any kinds of changes in their bowel habits. And that includes, even though they may be anticipating some diarrhea, certainly if they’re having 8 stools a day, to make sure they’re reporting that. Maybe we need to emphasize that more on the significant other, the caregiver too, if they know that’s what you should be doing. So there’s a lot of stuff going on from a GI perspective and nutritional perspective with these patients.

Comprehensive insight on the optimal management of diarrhea associated with ADC therapy, with regard to patient education and monitoring during treatment.

T-DXd in HER2+ Gastric Cancer: Educating Patients About Risk of Diarrhea

How does your broader health care team, where you practice, participate in the management of these toxicities in patients with trastuzumab deruxtecan in metastatic gastric cancer. Theresa?

We do have very good pharmacy support. We have Pharm Ds [doctors of pharmacy] that are part of the team. And if the regimen that Liz Elizabeth Prechtel Dunphy, DNP, CRNP, AOCN went over, perhaps, is not effective in a particular patient, or they have some other things going on, that input may be very valuable. And then, absolutely, nutritional support. We have dietitians who are very engaged with these patients and their families in terms of helping them to work through these nutritional issues. And so they would be, I would say, top of the list in terms of the broader health care providers who would need to be involved with these patients.

I definitely agree. We have clinical pharmacists on our care teams. Our clinical RNs [registered nurses] obviously play a pivotal role in talking with patients about toxicities. They do our education prior to the patient starting a new therapy. They’re that frontline when a patient messages into the care team. So the nurses do a lot of our toxicity management for our patients.

We have a similar setup where we are. We call them our triage nurses that are the first line in hearing about changes in bowel movements.

Panelists share their perspective on the role of the broader, multidisciplinary healthcare team in managing toxicity associated with trastuzumab deruxtecan therapy.

Role of the Broader Healthcare Team in Managing AEs Associated With T-DXd 

Theresa, what are some of the other ongoing trials with trastuzumab deruxtecan in patients with metastatic gastric cancer?

I think we’ve mentioned before, the DESTINY-GASTRIC01 trial (NCT03329690); that was the first one that was done, in Japan and Korea. And I think Liz may have cited some of those data. But that really set the stage in terms of using these drugs and how people might be experiencing them in terms of toxicity profile. I think I mentioned earlier that some of the adverse effects were a little elevated, and there was some thought that perhaps that was seen primarily in the Japanese testing site.

The second trial, which was the DESTINY-Gastric02 (NCT04014075), was done with European and U.S. patients. There were only 79 patients in that study. That was a monotherapy, and so the same dosage of 6.4 mg/kg every 3 weeks was prescribed. They did see a very promising, about 38%, response rate. And median progression-free survival was about 3.5 months, and that lasted about 4.3 months in some cases. So that we have some preliminary data from. And again, this was from a Western population, so there’s thought that perhaps those findings are maybe a little more applicable. I will say that there was, I think for our population, a high incidence of pneumonitis and ILD [Interstitial Lung Disease], about 4% of pneumonitis and 2.5% of ILD. And those are not small numbers for such serious side effects. They obviously were not as high as what was reported in the Gastric01 study with Japanese patients, but those toxicities are occurring. Since then, there’s been the DESTINY-Gastric03 trial (NCT04379596).

It’s a phase 1B-2 trial looking at monotherapy and then other combination therapies in a dose escalation and expansion trial. That will be very interesting to see the other kinds of combinations. In oncology, more is always better, and so we don’t want to just give 1 drug if we can give 2 or 3 or 5 drugs. But this trial will help us determine if that is the case in terms of efficacy. And then the other study is the DESTINY-Gastric04 (NCT04704934). This is a randomized phase 3 study, and this is a head-to-head study. So that will give us some very interesting data in terms of comparative data, and overall survival is the primary outcome there. So I think that will be very important in really evaluating this particular type of therapy and its application in the gastric cancer population.

Panelists briefly review ongoing clinical trials with trastuzumab deruxtecan in the setting of HER2+ gastric cancers.

Ongoing Clinical Trials With T-DXd in HER2+ Gastric Cancer

I am going to present case 4. Patient number 4 is JD. He’s a 66-year-old male with metastatic HER2-positive gastric cancer that spread to the liver, lymph nodes, and lungs. He was initially treated with FOLFOX/trastuzumab for 12 cycles. When he had progressive disease, he was switched to paclitaxel/ramucirumab for 5 cycles. He again developed progressive disease, and at that point, we had to consider treating him with trastuzumab deruxtecan, which is what he started taking. He’s currently on this treatment regimen, and he is seen by the advanced practice provider prior to cycle 3 of treatment. 

He comes to the clinic complaining of nausea, diarrhea, and fatigue. His blood pressure is 118 over 65. His heart rate’s 116, respirations are 18, temperature is 98.7, oxygen saturation is 98 on room air, and his weight is 156 pounds. He’s found to have lost 6 pounds since his last visit, in part because of…nausea and diarrhea. He says that his nausea when he uses the antiemetics is fairly well controlled, and he hasn’t had any vomiting. He denies any elevated temperatures at home, but he does state that the diarrhea has occurred up to 8 times a day over the last week. We questioned him to find out why he didn’t notify the office or call to ask advice if that was something to be expected, even though we had reviewed that at his initial visit. But he really wasn’t clear as to why he didn’t call the office to discuss the symptoms and possible interventions. He’s accompanied by his wife, who says: "I told you so, you should’ve called."

In doing my assessment with the patient, I reviewed the patient’s medical history, diet history, recent travel, current medications, and supplement use. With his assessment of the frequency and duration of stools being 8 times per day for a case, that’s considered a grade 3 AE. And as Jamie Carroll, APRN, CNP, MSN mentioned, it’s important to try to grade that in case you’re not the provider that sees the patient in the follow-up visit. I asked if he had any exacerbating factors or anything that alleviated his symptoms, and he couldn’t describe anything that made his symptoms worse or better. I also assessed to see if he had attempted any interventions being he didn’t call the office, and he said he took milk of magnesia once and it didn’t work, so he didn’t try it again. And I also assessed what effect it was having on his quality of life, and he was reporting more fatigue because he is spending a lot of time getting up and making sure he was close to a restroom. In part of my assessment, I did some lab studies, which we would do prior to his treatment, but also with him having these symptoms. And I included the complete metabolic panel, a CBC [complete blood count], and magnesium level. The CBC showed a white count of 4, an ANC [absolute neutrophil count] of 1,600, and platelets of 156,000, so pretty good. I don’t have his hemoglobin listed there, but it was around 10.6. And that was stable for him. His creatinine level was 1.4, and I wanted to assess that to see if he was dehydrated. I also checked his potassium level being he’s had the diarrhea for almost a week that he’s reported, and his potassium level was 3. His magnesium level I also wanted to assess because of the diarrhea and it was 1.9, which was within the normal limits. And then I was thinking could this be infectious, and do I need to consider an infectious workup?

Other symptoms that I also wanted to assess were some of the symptoms and sequelae for the diarrhea, particularly symptoms of dizziness, orthostasis, lethargy, any cramping, and abdominal pain. We did ask and talk about the nausea, vomiting, and fever. Was he having any rectal bleeding? In addition, did he notice any difference in his urinary output? One of the labs was assessing for hypokalemia if he’s having diarrhea, because that could be a sequela. And his potassium level, as we said, was 3. And then for hydration, he did have an elevated creatinine of 1.4.

We’ve mentioned this before. In the DESTINY-Gastric01 study (NCT03329690), the incidence of grade 3 or 4 diarrhea was 2.4%. All grades were 32%. And diarrhea occurred in greater than 2% of patients which led to a dose interruption. Part of our management for this particular patient was talking about maintaining hydration and then treating symptoms. In discussing and maintaining adequate hydration, we talked about hydration at home, but also considering IV [intravenous] fluids in the office or through a home infusion company if the patient is not able to adequately hydrate at home. And for our case, we administer IV fluids in our office twice a week, and repeated his labs weekly while he was here for that. We also discussed some dietary considerations, making sure he was adding foods to his diet that can help to make the stools more solid, discussing a low-fiber diet, and then talking about those foods to avoid—some of the regular diarrhea management that we would recommend if someone else came in with another agent that was causing diarrhea: avoiding lactose-containing foods, spicy foods, alcohol, caffeine-containing foods and beverages, certain fruit juices, gas-forming foods, high-fiber foods, and high-fat foods.

And then most importantly, discussing the use of antidiarrheal and their dosing schedules. We initially in our practice will start with loperamide or Imodium, 2 mg tablets. I advise the patients to take 2 tablets with their first episode of diarrhea or watery stools, followed by 1 thereafter with each continued loose stool for a maximum of 16 mg or 8 tablets a day. And hopefully, that is usually successful for most patients not reaching that maximum of 8 tablets a day. But there are some patients where that may not be enough, and so you may need to consider adding in or switching to something like Lomotil 1 to 2 tablets 4 times a day as needed. So, we prescribed for this patient loperamide with a plan to check in in 2 days and advised him to call the office should his symptoms worsen, and reinforce that with his family member who was with him. One other thing to consider is adding probiotics. So, for this patient, for his total management, we initiated an antidiarrheal, loperamide. We initiated IV fluids in the office because we weren’t convinced that he was able to adequately maintain hydration at home, and then set up a follow-up schedule with him to check in since he wasn’t very readily calling the office.

In addition to that management, we also were looking to treat the sequelae, including the hypokalemia. So, with his IV fluids, we added and started him on an oral potassium supplement with a plan to repeat labs in 1 week when he comes back for that additional hydration. And because of his having this side effect, we considered and initiated a dose delay, not a dose reduction, but a dose delay, to get those symptoms under better control. And in our case, his treatment was only delayed 1 week.

Shifting focus to the second patient profile of HER2+ gastric cancer, key opinion leaders highlight the risk and management of diarrhea in this setting.

Patient Profile 4: A Patient with HER2+ Gastric Cancer Treated With T-DXd Who Develops Diarrhea 

What are the front-line treatment options for patients with HER2-positive gastric cancer? Liz, do you know? I think we went over this earlier. Do you mind going over it again with us?

Yes. Per the NCCN [National Comprehensive Cancer Network] guidelines, a fluoropyrimidine, such as fluorouracil, and capecitabine with oxaliplatin and trastuzumab. FOLFOX [folinic acid, fluorouracil, and oxaliplatin] or CAPOX [capecitabine and oxaliplatin] with trastuzumab or fluoropyrimidine, again, the 5-FU [fluorouracil] or capecitabine, with cisplatin and trastuzumab. And with both of those, depending on their PD-L1 status, pembrolizumab could be added.

Other regimens that could be considered are fluorouracil and irinotecan. Paclitaxel, with or without cisplatin, or in combination with carboplatin. Docetaxel, with or without cisplatin. 5-FU or capecitabine alone. Docetaxel, cisplatin, or oxaliplatin and fluorouracil, or docetaxel, carboplatin and fluorouracil. The last ones, from fluorouracil with irinotecan, are other recommended regimens. The primary regimens usually recommended are FOLFOX or CAPOX with trastuzumab, or fluorouracil with cisplatin or trastuzumab, plus or minus pembrolizumab.

After progression on that first-line regimen, whichever one is chosen, what is the recommended treatment approach in a second-line setting, and what are the data available to support it?

As Theresa mentioned earlier, treatment for our patients with gastric cancer depends on their prior therapies, performance status, and their comorbidities. The NCCN preferred regimens are: ramucirumab and paclitaxel, trastuzumab deruxtecan, docetaxel, single-agent paclitaxel, single-agent irinotecan, single-agent combination of fluorouracil and irinotecan. And then possibly in the third line, Lonsurf, or trifluridine and tipiracil, which is an oral agent.

Some of the data that can be provided for the second-line therapy particular to trastuzumab deruxtecan come from the DESTINY-Gastric01 study, where 187 patients were treated. Approximately 125 of the patients received trastuzumab deruxtecan and 62 were on a physician’s choice chemotherapy, and that was either irinotecan or paclitaxel. The breakdown was 55 patients had irinotecan and 7 had paclitaxel. The overall survival was 12.5 vs 8.9 months in the trastuzumab deruxtecan arm compared to the physician’s choice chemotherapy arm. The overall responses were 51.3% vs 14.3%, respectively. Disease-control rate was also improved in the trastuzumab deruxtecan arm, being 85.7% vs 62.5%. And the duration of response was also improved, with the trastuzumab deruxtecan arm being 12.5 vs 3.9 months. The median progression-free survival was 5.6 vs 3.5 months. So, each of those end points was improved in the patients who were on the trastuzumab deruxtecan arm of the study.

A broad overview of the treatment armamentarium for patients receiving first- or second-line therapy for HER2+ gastric cancer.

First- and Second-Line Treatment Options for HER2+ Gastric Cancer

How common is neutropenia in patients with gastric cancer receiving T-DXd [trastuzumab deruxtecan], Theresa? I think you told us it was very common, but how common, really, is it? Which patients are at risk and are you more worried about?

As I mentioned, myelosuppression across the board is rather common. In the DESTINY-Gastric01 trial, which was done in Asia, those patients had really high rates of neutropenia, around 70% or 71% of all grades, and about 58% of grade 3, so that’s pretty significant. And close to 5% had febrile neutropenia. In subsequent studies, those numbers are less, and we don’t see quite that many in our own practice. But there are some risk factors that we do need to keep in mind, and when we talk about gastric cancer, these definitely tend to apply.

One factor would be age, and as I mentioned previously, in gastric cancer, most of these patients are older; you don’t see a lot of 40-year-olds with gastric cancer. So, age is already a risk factor overall with gastric cancer. The kind of gastric cancer they’re having is also associated with it, as well as previous therapies that they might have had that perhaps left their bone marrow a little beat up from previous regimens. But the other things are comorbidities. There are lots of comorbid conditions, including obesity, diabetes, congestive heart failure, COPD [chronic obstructive pulmonary disease], rheumatoid arthritis or osteoarthritis, as well as HIV. All of those are considered risk factors for neutropenia. Like with other systemic therapies that also have the risk of neutropenia, you want to make sure you’re educating the patients. And of course, we’re monitoring their CBC [complete blood count] and ANC [absolute neutrophil count] regularly.

To add to what Theresa was saying, in breast cancer, just over 40 patients have any grade neutropenia with T-DXd, or trastuzumab deruxtecan. I would agree that many patients are at risk, including what Theresa was saying, and then in addition, I think patients who have known bone marrow involvement, they’re at increased risk for neutropenia or myelosuppression from treatment.

They might be the patients you’re getting white blood cell, your G-CSF [granulocyte colony-stimulating factor] ordered for. And in this case, since this medication is given once every 3 weeks, you could consider something longer acting. What choice are you using for your white blood cell support? Maybe Theresa can answer first, as far as what sort of treatment do you usually use?

That’s a bit of physician’s choice, so I can’t say we have a strict policy on that. And we don’t usually see a lot of patients who have marrow involvement with gastric cancer. Liz may see it in her own practice, but that’s not normally something we would see a lot.

We haven’t seen a terrible amount of this either in our practice, so we haven’t had the instance where we have had to use growth-factor support, but I imagine if that were to be the case, again, as Theresa said, that’s a physician choice. I would think that they would use a long-acting growth-support factor, but we haven’t had that incidence yet.

Are there any parameters that are considered in a patient with metastatic gastric cancer who is started on trastuzumab deruxtecan, to reduce the risk of neutropenia? Is there anything we can do prior to prevent it?

I don’t know if there’s anything we can do prior to prevent it, except that we have good monitoring. We consider those risk factors that Theresa mentioned when we’re looking at our patients, and how heavily pretreated they are. So we’re maybe getting a sense of how compromised their bone marrow is, and keeping those facts in mind when prescribing this for a patient. And the education comes in, with not only the patient but their caregiver, to make sure they know when to call the provider should they start feeling unwell or develop a temperature or other signs and symptoms of infection.

To piggyback on what Jamie said earlier, about how patients may be reluctant to report certain symptoms, I guess you could say the good thing about neutropenia is that there’s a laboratory test, so it’s not like they can pretend that, “Oh, I don’t have an ANC of 600” or whatever. But they do have to be educated and have it reinforced in terms of if they develop a fever or any other signs or symptoms of an infection.

As I mentioned, these patients can be quite ill, and so they may have a lot going on with them, and something that could be homed-in on if you don’t have a lot of other symptoms you’re dealing with. That may be overlooked when you’re dealing with some of the problems that our patients with gastric cancer have. So, think about some of the surgeries they have had and the nutritional consequences of that, trying to get enough nutrition, particularly if they’ve had significant surgery or a total gastrectomy, for example. A lot of times their focus is on the day-to-day. “How many calories am I getting in in a day?” Or “how am I going to be feeling and quality of life?” So, you have to make sure you’re reinforcing every time, maybe sounding like a broken record, but to make sure they’re hearing that, and their caregivers and family members are hearing that, too. We try to emphasize this is not something we mess around with. This is something that is really important, that you report that, and report it at the earliest time that it’s observed.

Are you seeing similar patients on docetaxel, carboplatin regimens, or on your doxorubicin, cyclophosphamide regimens, where when they become neutropenic, they’re having oral sores, on trastuzumab deruxtecan? I haven’t had that experience with this medication in patients with breast cancer myself, so just curious.

You mean like mucositis?No, that has not been a prominent problem. Liz?

For patients with breast cancer on trastuzumab deruxtecan, I think we counsel patients similarly, Jamie, do you agree, as far as neutropenia goes?

I agree. I think this is one area where COVID-19 has helped. Because prior to COVID-19, if someone was wearing a mask out in public, everyone would look at them, but now that’s a common thing. So, if you are neutropenic and we’re worried about the development of neutropenic fever or dose delays, holds, anything like that, patients can wear a mask out in public. I counsel them not to kiss or hug someone with a known infection. Then if you’re going to be inside in a crowded area, it might not be a bad idea to wear a mask.

I am really all about quality of life, though, so when patients ask me about neutropenia, and we know they’re going to be neutropenic maybe from day 7 to 11 in a cycle, they say, “Should I stay home? Should I not go anywhere?” And for me, it’s really about quality of life. I don’t want them to be fearful of living their life. They have a metastatic diagnosis, and although we hope that with metastatic breast cancer they are alive for several years, I don’t want those years to be low quality because they’re fearful of leaving their home, because of development of infection, or because they’re neutropenic. I try to strive for them to go out and do the things that bring them joy, the things that they like to do. That’s part of what I counsel when we’re discussing the adverse effects of treatment.

Focused discussion on the management of antibody drug conjugate–related adverse events in gastric cancer, with a focus on neutropenia. 

T-DXd in HER2+ Gastric Cancer: Managing Neutropenia and Other AEs 

One of the trials in progress with ADCs [antibody-drug conjugates] in breast cancer that could further impact the landscape is the HER2CLIMB trial, which has tucatinib plus trastuzumab deruxtecan. That’s ongoing for patients with metastatic breast cancer with and without brain metastases. Hopefully, the study will show improvement not only in the brain but also elsewhere. It’s super promising.

In addition, there’s a trial with a new antibody-drug conjugate called ARX788, and that will be studied in patients with metastatic breast cancer who have been refractory to TDM-1 [trastuzumab emtansine] or trastuzumab deruxtecan or tucatinib-containing regimens, like the HER2CLIMB regimen. We have a lot of new research happening, and hopefully more treatments for these patients are coming up.

Before closing out their discussion on antibody drug conjugate use in breast cancer management, panelists consider ongoing clinical trials in this setting. 

A Brief Review of Ongoing Clinical Trials of ADCs in Breast Cancer

Centering discussion on a patient profile of HER2+ gastric cancer, experts in oncology discuss the occurrence of neutropenia with trastuzumab deruxtecan therapy.

Sarah Donahue, MPH, NP, AOCNP

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