Danielle Roman, PharmD, BCOP:
We will now discuss AE profiles associated with ADCs, how to identify AEs, how to prevent AEs, and how to manage them when they occur.

This slide compares the HER2-targeted ADCs T-DM1 vs T-DXd.

Fatigue is a common AE associated with T-DM1.^5,12,16  T-DM1 has a low risk of infusion reaction and a low risk of interstitial lung disease (ILD) or pneumonitis at just 1%. The risk of left ventricular ejection (LVEF) dysfunction is low at less than 2% with T-DM1 but should be monitored and there is a black box warning for decreased LVEF. There is also a black box warning for hepatotoxicity. T-DM1 therapy frequently results in increased aspartate transaminase (AST) and alanine transaminase (ALT) (29% to 32%), hyperbilirubinemia (17%), and a low incidence of rare toxicity of nodular regenerative hyperplasia of the liver.

Nausea occurs in approximately 40% of patients receiving T-DM1 but there is a low risk of vomiting. The National Comprehensive Cancer Network (NCCN) classifies T-DM1 as a low emetic risk, thus giving a premedication is recommended.⁴⁹ There is some cytotoxicity associated with T-DM1 with thrombocytopenia occurring in approximately 30% of patients. Peripheral neuropathy is also observed due to the cytotoxic microtubule inhibitor component of T-DM1.

Like T-DM1, fatigue is also a common with T-DXd.^6,22,27  Alopecia is experienced by 21%-46% of patients receiving T-DXd. One of the most serious AEs associated with T-DXd is ILD or pneumonitis occurring in 9%-12% of patients and there is a black box warning for ILD/pneumonitis. Also like T-DM1, T-DXd has a low risk of decreased LVEF. T-DXd results in increased AST and ALT in 42% to 48% of cases but unlike T-DM1 there is no black box warning for hepatotoxicity. Nausea rates are high with T-DXd. The deruxtecan component causes some neutropenia and thrombocytopenia. 

Danielle Roman, PharmD, BCOP:
ILD/pneumonitis is associated with several ADCs, as well as with other agents such as taxanes and anthracyclines.⁵⁰ It is also observed with some targeted therapies including CDK4/6 inhibitors and osimertinib, and with other agents targeting HER2.

The interstitium is the space between the alveoli of the lung and the capillaries where oxygen exchange occurs. ILD is damage to the interstitium via disruption of alveoli structures and fibrosis that limits gas exchange. How ADCs induce ILD is not well elucidated. One option is alveolar macrophage uptake and redistribution of the ADC. ILD could also be related to the bystander effect of the released payload and damage from the circulating payload after release.

The table shows the risk of ILD from 4 different ADCs as seen in clinical trials. Sacituzumab govitecan has a very limited to no risk of ILD.^36,39,51 Both T-DM1 and Dato-DXd have a very small risk of ILD.^15,16,42 The highest risk is with T-DXd with up to a 15% incidence observed in some of the breast cancer trials.^{20,22,24,27,52} Of importance, there were cases of grade 5 or fatal ILD in some of these clinical trials. After the initial trials, intense monitoring was incorporated into later trials and although fatality rates decreased, there were still some fatalities on later trials. ILD is a serious AE associated with T-DXd and one that needs close monitoring.

Danielle Roman, PharmD, BCOP:
In a pooled analysis of 9 phase I and II trials of T-DXd in solid tumors, the overall incidence of ILD was approximately 15%, so a significant risk.⁵³ However, most cases were grade 1/2, and most of the events occurred within the first year of therapy. The risk does carry beyond 1 year but intense monitoring in the first year to detect cases early as low-grade events is recommended.

This pooled analysis also examined subgroups hoping to identify risk factors associated with the highest risk for ILD. They identified the following potential risk factors—patients who were younger than 65 years old; patients treated in Japan; patients with lung comorbidities at baseline; patients with moderate to severe renal dysfunction as determined by the Cockroft-Gault formula; patients who were more than 4 years from their diagnosis; patients with low baseline oxygen levels, and patients receiving a higher dose of T-DXd. Of note, the higher dose referred to doses greater than 6.4 mg/kg, which was used predominantly in gastric cancer.

These risk factors can potentially identify higher-risk patients. There are not currently specific screening strategies for these factors but for patients who have 1 or more of these baseline risk factors, HCPs may want to consider more frequent monitoring and intense patient and caregiver education.

Danielle Roman, PharmD, BCOP:
Early identification of ILD is very important.^6,54 Patients and caregivers should be counseled to immediately report any changes in breathing, new onset cough, dyspnea, fever, and any new or worsening respiratory symptoms. When a patient presents with symptoms of possible ILD, high-resolution CT is the preferred test to confirm a diagnosis of ILD. Other tests are recommended to rule out other potential causes of respiratory changes such as infectious agents. Consults with colleagues from pulmonary and infectious diseases should be considered.

Upon confirmation of ILD or pneumonitis, management is based on whether patients are asymptomatic or symptomatic. For patients with asymptomatic (grade 1) ILD, the recommendation is to hold the drug until ILD is resolved to grade 0. Corticosteroid treatment can be considered, usually prednisone 0.5 mg/kg, or potentially up to 1 mg/kg.

For patients who have symptomatic ILD (grade 2 or greater), the recommendation is to permanently discontinue the drug. These patients should initiate systemic corticosteroid treatment with 1 mg/kg of prednisone or equivalent for at least 2 weeks of treatment, followed by a taper for at least 4 weeks. For symptomatic patients, there is no rechallenge with T-DXd.

Patients with grade 1, asymptomatic disease often can resume therapy upon resolution. If resolution occurs at 28 days or less from the onset of ILD, the patient can resume therapy at the same dose. For patients whose ILD takes more than 28 days from symptom onset to resolve, the recommendation is resume at a lower dose. Once the T-DXd dose is reduced, it is not recommended to re-escalate. Dose reductions vary by indication but in all cases if a third dose reduction is needed, the recommendation is to permanently discontinue T-DXd.

There are no specific recommendations for monitoring, other than high-resolution CT scans from every 6 to every 12 weeks. Currently, in my practice, we are checking high-resolution CTs every 9 weeks, which is about the time we are assessing for disease response to therapy.

I want to stress that patient education is very important regarding ILD. Emphasizing with patients and caregivers the importance of early reporting any changes in their pulmonary status, any new coughs or shortness of breath to their healthcare team. The goal is to identify ILD as a grade 1 toxicity, retaining the possibility of restarting therapy upon resolution. Any changes reported by the patient or caregiver should prompt an immediate workup for ILD. 

Danielle Roman, PharmD, BCOP:
The  5 "S" rules for detecting and managing T-DXd related ILD can assist HCPs.⁵⁵

Screening patients carefully for therapy is an important component of treatment.

Scan: Ensure that patients receive high-resolution CT scans every 6-12 weeks throughout therapy.

Synergy: Use a team approach to identify and manage AEs. This includes the patient and caregiver team; the oncology care team, including nurses who work closely with patients in the infusion centers; clinic teams; and pulmonary and infectious disease teams.

The fourth "S" is suspending treatment. Stop the drug immediately if ILD is suspected and only resuming treatment if a patient has fully resolved, grade 1 disease.

The fifth "S" is steroids. Steroids are a consideration for grade 1 disease, and in my experience it is often used in that setting. Steroids are a necessary component of management for any patient that has symptomatic ILD. 

Danielle Roman, PharmD, BCOP:
Another consideration with T-DXd is the significant risk of nausea and vomiting.⁶ T-DXd is categorized as highly emetogenic by NCCN guidelines, and premedication with a 3-4 drug regimen is recommended to prevent treatment-induced nausea and vomiting.^49,56 This drug regimen generally consists of a steroid, a 5-HT₃ receptor antagonist, and an NK1 receptor antagonist with or without olanzapine. Of note, nausea and vomiting may be delayed. Patients need prophylactic antiemetics not only on Day 1 of treatment, but for approximately the first 4 days after treatment. Patients should receive a take-home antiemetic to use as needed.

Danielle Roman, PharmD, BCOP:
Neutropenia is another important AE with T-DXd.⁶ Management is similar to other anticancer therapies.^56,57 When educating patients on the potential for neutropenia, it is important to note that it is usually low-grade with a low risk of febrile neutropenia. Patients should be monitored by a CBC with differential before starting treatment, before each dose (every 3 weeks), and as clinically indicated. The median onset for neutropenia is 2-3 weeks after starting treatment.

Recommendations for management include dose holding and/or reductions and potential use of G-CSF. It is recommended to hold the drug if the patient's absolute neutrophil count (ANC) is less than 1000 or if they have neutropenic fever. Dose reductions are warranted for patients with grade 4 neutropenia or grade 3 febrile neutropenia. Discontinuation is recommended for patients by the third dose reduction. G‑CSF is a consideration for patients who present with neutropenia as secondary prophylaxis and for patients who have a significant history of prior neutropenia complications.

Danielle Roman, PharmD, BCOP:
Monitoring for decreased LVEF associated with other HER2-targeted therapies is familiar to most HCPs. Although the risk of decreased LVEF is low (2%-8%) with T-DXd, monitoring LVEF prior to initiation of T-DXd, either with an echocardiogram or a MUGA scan, and at regular intervals throughout treatment is recommended.^6,57 In my clinical practice, as we initiate the drug, we monitor every 3 months. We occasionally lengthen that time frame if patients are stable on T-DXd for long periods of time.

The recommendations for management for decreased LVEF are based on the absolute LVEF and comparison with baseline values. It is important that the same technology be used each time—if you start with a MUGA, ideally you continue with that, similarly if you start monitoring with an echocardiogram continue with an echocardiogram so that you are comparing data from consistent technologies.

For patients with an LVEF of 40%‑45% and an absolute decrease from baseline of 10%-20%, the recommendation is to hold the drug and reassess the LVEF within 3 weeks. If the patient has not recovered to within 10% of baseline, the drug should be discontinued. If the patient has recovered to within 10% from baseline, treatment can resume at the same dose.

For patients who either have an LVEF of less than 40% or an absolute decrease from baseline greater than 20%, the recommendation is to hold therapy and reassess within 3 weeks. If LVEF remains the same, discontinuation of the T-DXd is recommended. For patients diagnosed with chronic heart failure, it is recommended to discontinue T-DXd.

Danielle Roman, PharmD, BCOP:
Considering AEs associated with TROP-2–targeted ADCs, this slide compares sacituzumab govitecan on the left with Dato-DXd on the right.

Of note, with sacituzumab govitecan there is a significant risk of fatigue occurring in 51% to 68% of patients.^7,36,39 Hypersensitivity reactions are observed in 35% and alopecia is observed in up to 50%. Gastrointestinal AEs include nausea, vomiting, and diarrhea. Diarrhea is the most serious of these AEs, seen in up to 72% of patients. Sacituzumab govitecan also carries a significant risk of neutropenia as observed in 64% of patients. Sacituzumab govitecan has a black box warning for neutropenia and diarrhea.

For AEs associated with Dato-DXd alopecia is found in up to 40% of patients.^8,42 There are some different AEs that we have not yet discussed with other agents including a risk of ocular events and stomatitis. There is a low risk of ILD (4.2%). Nausea and fatigue are also common with Dato-DXd but there appears to be a lower risk of hypersensitivity reactions vs sacituzumab govitecan.

Danielle Roman, PharmD, BCOP:
Of note, the prescribing information for sacituzumab govitecan mentions UGT1A1 testing.^7,58 UGT1A1 is an enzyme that breaks down the SN-38 payload, and genetic polymorphisms in UGT1A1 can result in reduced enzyme activity and therefore increased toxicity. Patients who have the *28/*28 diplotype metabolize sacituzumab govitecan poorly. Early identification of the *28/*28 diplotype may be helpful to identify patients who may be at greater risk for toxicity and may need early dose reductions. Testing could be at baseline as patients start therapy, but certainly for patients who are presenting with excessive toxicity, consider checking for this particular genetic polymorphism.

Danielle Roman, PharmD, BCOP:
Diarrhea is an AE of interest with sacituzumab govitecan.^7,59 Grading diarrhea is important for management and is based on the number of stools over baseline. For patients with grade 1 or 2 diarrhea, 6 or fewer stools over baseline, the next consideration is the time frame in which the diarrhea is occurring. An onset during or shortly after infusion is considered early or acute diarrhea that is associated with cholinergic syndrome like what is seen with irinotecan. Primary prophylaxis does not necessarily need to be atropine, but atropine should be the drug of choice when patients experience this AE. If patients need prophylaxis with atropine, then atropine prophylaxis is recommended for future infusions while continuing sacituzumab govitecan at the same dose.

For patients with grade 1 or 2 delayed-onset diarrhea, loperamide and dietary management should be considered. In patients whose diarrhea does not resolve, loperamide can be escalated to 4 mg at the time of first loose stool and then 2 mg every 2 hours. If diarrhea does not resolve within 24 hours, then octreotide can be prescribed for refractory diarrhea. It is important to consider infectious causes of diarrhea.

Patients who have 7 or more stools over baseline, grade 3 or grade 4 diarrhea, need more aggressive intervention. Hospital admission with IV fluids should be strongly considered along with octreotide and possibly antibiotic therapy. Dose reductions are needed if patients do not recover within 2-3 weeks or for those with grade 4 diarrhea.

Danielle Roman, PharmD, BCOP:
The other serious AE associated with sacituzumab govitecan is neutropenia.^7,59,60 Onset of neutropenia is approximately 2-3 weeks after treatment with a median duration of 6 days. A CBC with differential should be measured before each dose on Days 1 and 8 of each cycle. The drug should be held for patients who have an ANC count of less than 1500/μL on Day 1, less than 1000/μL on Day 8, or who present with neutropenic fever. Manage neutropenia with G-CSF and consider anti-infective therapy for patients with febrile neutropenia.

Dose reductions are dependent on the length of time it takes for the patient's ANC to recover. If the patient has a grade greater than 3 neutropenia and dosing is delayed by 2-3 weeks, then a dose reduction would be warranted.

Danielle Roman, PharmD, BCOP:
Additional toxicities associated with sacituzumab govitecan include hypersensitivity reactions and nausea and/or vomiting.^7,49,60 Premedication is important to mitigate the risk of hypersensitivity reactions. A prolonged first infusion at 3 hours is warranted with close observation. Nausea and vomiting are also quite common so a 3 or 4 drug regimen, as previously noted for T-DXd, is also appropriate for this agent.

Danielle Roman, PharmD, BCOP:
Dato-DXd is associated with stomatitis and mucositis.⁸ Prevention strategies include advising the patient to use a steroid-containing mouthwash 4 times per day.⁶¹ Another important strategy is cryotherapy, by holding ice chips or ice water in the patient's mouth during drug infusion to limit blood flow to the mucosa.

Signs of stomatitis/mucositis are visible sores on the oral mucosa, lips and mucosa redder than normal, mouth pain, and changes in taste.

Management and dose modifications are by grade. Supportive care includes continuing steroid mouthwashes, pain management, bland mouthwashes, and referral to a dentist, oral surgeon, or dermatologist for persistent or severe cases. Dato-DXd should be held for grade 2 or 3 stomatitis/mucositis and discontinued for grade 4. Upon resolution of grade 2 to grade less than 1, the drug may be resumed at the same dose but dose reductions should be considered for recurrent grade 2 events. For grade 3 stomatitis/mucositis, the dose should be reduced upon resolution to grade less than 1.

Danielle Roman, PharmD, BCOP:
Patient counseling strategies are similar to those  recommended for other drugs with the mucositis risk.⁶² These include avoiding spicy and acidic foods, consuming a soft or liquid diet, and use of artificial saliva. Topical anesthetics can provide some relief as well as bland mouth washes. As noted previously, patients should be counseled to use a steroid mouthwash 4 times per day.

Danielle Roman, PharmD, BCOP:
Ocular toxicity is an AE associated with Dato-DXd but not with other ADCs discussed in this module.^8,61 An ophthalmologic exam is recommended at baseline and annually while on treatment. Patients should also use a preservative-free lubricant eye drop at least 4 times per day and up to 8 times per day. It is recommended that patients avoid contact lenses. Ocular toxicities include dry eye, blepharitis, conjunctivitis, keratitis, and blurred vision.

The median onset of keratitis is approximately 2 months and most events are grade 1 or 2. Dose modifications may be required based on severity of keratitis.

Danielle Roman, PharmD, BCOP:
There is a risk of hypersensitivity with Dato-DXd, so premedication is necessary.^8,61 Nausea and vomiting are also common with Dato-DXd and it is in the NCCN high emetic risk category.⁴⁹ I would recommend a 3 or 4 drug regimen. There is a low risk of ILD with Dato-DXd but management mirrors that discussed for T-DXd.

Danielle Roman, PharmD, BCOP:
A brief mention of the AEs associated with patritumab deruxtecan.⁴⁷ Toxicities that are seen with this agent in clinical trials are predominantly nausea and thrombocytopenia. ILD was observed in 5.3% of patients.

Danielle Roman, PharmD, BCOP:
In summary, ADCs have an expanding role in the management of a number of different solid tumors, including tumor agnostic indications. ADCs have unique AEs that HCPs should be aware of including ILD, ocular toxicities, and gastrointestinal toxicities. A number of ADCs are currently in development as well as novel ADC-containing combination approaches, thus new agents and additional indications are likely to be approved in the future.