CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: April 04, 2024
Expiration: April 03, 2025
Introduction
In this module, Matthew Gubens, MD, MS, FASCO, discusses key adverse events (AEs) with investigational antibody‒drug conjugates (ADCs) targeting TROP-2—datopotamab deruxtecan (Dato-DXd) and sacituzumab govitecan—as well as prophylaxis and management strategies.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
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Datopotamab Deruxtecan: TROP-2‒Targeted ADC
Dato-DXd is a TROP-2‒targeted ADC being studied in active clinical trials. Dato-DXd includes a humanized TROP-2 monoclonal antibody with a cleavable linker to a topoisomerase 1 inhibitor payload. This payload has high potency, membrane permeability, and a short systemic half-life to optimize delivery to tumor cells while minimizing global toxicity to patients.1-4
Sacituzumab Govitecan: TROP-2‒Targeted ADC
Sacituzumab govitecan is another TROP-2‒targeted ADC that is in active development in NSCLC and already has FDA approval in 3 settings: locally advanced or metastatic triple-negative breast cancer, hormone receptor‒positive/HER2-negative metastatic breast cancer, and urothelial cancer.5 Like Dato-DXd, sacituzumab govitecan is composed of a humanized monoclonal antibody and cleavable linker, but with an SN38 payload. SN38 is a metabolite of irinotecan—a drug that we have used for many years—and the goal with this unique chemistry is to improve solubility and selectively deliver a higher-fold concentrated dose of the compound to the tumor, with the hope of sparing global toxicity in patients.5-7
Common and Notable Toxicities Associated With TROP-2‒Directed ADCs
It is important to note that different toxicity profiles are observed when comparing these TROP-2‒directed ADCs, and this does not relate to the antibody or linker; rather, it is dependent on the payload. We are learning more and more in the ADC field that the nature of the payload greatly influences the toxicities we see in patients.8 For sacituzumab govitecan, some of the more specific toxicities to monitor include neutropenia and diarrhea. For Dato-DXd, some of the unique toxicities include dry eye, stomatitis, and ILD.9,10 Understanding these differential toxicities can help us proactively counsel patients and provide them with prophylactic treatments to reduce the incidence and help them remain on therapy at effective doses.
Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan
Although stomatitis and mucositis can occur with many traditional chemotherapy regimens, it is important to proactively recognize the importance of managing these in Dato-DXd. Symptoms we should look out for include red lips and mucosa, visible sores on the oral mucosa, mouth pain that affects chewing and swallowing, and changes in ability to taste. These are, again, things that we talk about during chemotherapy education with many of our patients, but I think this warrants special attention with Dato-DXd.11 The more advanced the symptom, the more we consider delaying or reducing the dose. Certainly, proactive management is key here.
TROPION-PanTumor01 Substudy: Prophylactic Mouthwash for Mucositis/Stomatitis
There is an active investigation regarding prophylaxis for mucositis and stomatitis with Dato-DXd. The TROPION-PanTumor01 study is a large study that is still accruing.10 Of importance, there is a substudy aiming to evaluate whether the addition of prophylactic steroid mouthwash vs nonsteroid mouthwash affects the 8-week incidence and severity of mucositis and stomatitis associated with Dato-DXd (NCT03401385). In my personal practice, I have already implemented this. I consider use of prophylactic steroid mouthwash with drugs like Dato-DXd that have a higher incidence of stomatitis because prevention can help patients have a better quality of life and remain on treatment at higher doses. However, I look forward to the results of this substudy to quantitatively evaluate the difference between these preventive approaches.
Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan
Although AEs such as mucositis and neutropenia are common in medical oncology clinics and many of us are very comfortable with managing them, one aspect of Dato-DXd that warrants attention is the incidence of ocular surface toxicities,10 because these are less commonly encountered with other compounds, particularly in thoracic medical oncology. While monitoring for ocular toxicities, look for symptoms such as dry eye, including eye redness and stinging; keratitis with eye pain; excess tears or discharge; and difficulty opening the eyelid because of pain and irritation. Of course, when we hear of blurred or decreased vision, we must promptly address these reports.
To manage these symptoms, I find that it is important to have an ophthalmologist on call, which is sometimes challenging for medical oncology practices. Those clinics are busy, too, but it is important to know someone in this area so that when patients have these symptoms, they can receive attention quickly. For asymptomatic ocular findings, we can maintain the dose of Dato-DXd, encourage the use of artificial tears, and start a nonurgent referral to ophthalmology. As soon as patients report any kind of visual acuity change, however, they should see an ophthalmologist promptly. So, again, some logistical work on the part of clinics to ensure that they have a referral pattern is very important.
In the rare case that a patient experiences perforation or visual acuity of 20/200, that is a point where we would permanently discontinue the drug. For the more common, less-severe symptoms, proactive mitigation such as the use ophthalmology referrals to manage the toxicity and reducing the dose of Dato-DXd can help keep patients on this effective treatment.
Management of Interstitial Lung Disease Associated With Datopotamab Deruxtecan
With all ADCs, we should be mindful of the risk of ILD, especially with ADCs that have a topoisomerase 1 inhibitor payload—all those with the “deruxtecan” designation—and Dato-DXd is no different. We also have had this conversation with trastuzumab deruxtecan.12 What we want to consider in a patient with lung cancer, specifically, is any new report of shortness of breath on exertion, dry cough, or chest discomfort.13 Now, in lung cancer, unlike breast cancer, the differential diagnosis is broad because these symptoms can suggest ILD or disease progression, especially with lymphangitic carcinomatosis, pleural effusion, or infection. So, we must have a high index of suspicion for new symptoms, especially hypoxia.
Borrowing from other drugs with a topoisomerase 1 inhibitor payload, we have a rubric for managing ILD.12 When I see asymptomatic (grade 1) ILD, which means there are infiltrates on imaging but no active symptoms of ILD, sometimes I will watch the patient and hold the ADC with the hope that on the next scan (with follow-up at 4-6 weeks), the infiltrates will have resolved and treatment can be resumed. As soon as a patient develops symptoms or hypoxia, however, I am obliged to hold treatment and initiate steroids.
If patients are nonhypoxic but symptomatic (grade 2), I typically start with oral prednisone in the outpatient setting with close follow-up. If patients have significant hypoxia or symptoms limiting self-care ADLs (grade 3), however, that is where one should consider early hospitalization, selection of IV steroids vs oral steroids, and pulmonary consultation to help assess the differential diagnosis and optimally manage these cases. If the symptoms are related to disease progression, then certainly therapy would need to be discontinued; however, if the symptoms are resulting from ILD, initiation of steroids and symptom management would be crucial, as well.
Also of note, for patients who have ILD refractory to oral or IV steroid treatment, multidisciplinary coordinated care is imperative—whether they be outpatient or inpatient pulmonology teams—to consider other immunomodulatory treatments such as infliximab, mycophenolate mofetil, IV immunoglobulin, and tocilizumab.13 Because the respiratory status of patients may change rapidly, it is critical to monitor very closely for improvement in or worsening of symptoms.
Management of Diarrhea Associated With Sacituzumab Govitecan
When considering AEs with sacituzumab govitecan, it is important to remember that because its payload (SN38) is a derivative of irinotecan, one of its specific adverse events is diarrhea, which may occur very acutely or with delayed onset. As with irinotecan, it is important to have atropine available in the infusion center to administer quickly in the event of severe early-onset diarrhea due to cholinergic syndrome. This is a symptom that we see in the infusion center that can be managed in real time and does not necessitate a change in the dose of sacituzumab govitecan. Certainly, if a patient experiences diarrhea with the initial dose of sacituzumab govitecan, one should incorporate atropine prophylaxis into the premedication regimen for future infusions.5
One also should be cognizant of the fact that even if patients do not have acute cholinergic diarrhea, they are more susceptible to delayed-onset diarrhea throughout the course of their treatment. Therefore, one should ensure that in addition to counseling on dietary management, patients have loperamide available at home and understand to continue the agent until their last episode of diarrhea is complete. There are patients for whom we must use high-dose loperamide, and when diarrhea is refractory to that, one must consider octreotide and/or bring them in for fluid and electrolyte replacement on a frequent basis.
Of course, if a patient has profuse diarrhea affecting self-care ADLs, which would be reflective of grade 3-4 toxicity, then one may need to consider hospital admission, IV fluids, and octreotide in the inpatient setting to ensure that their diarrhea is controlled. Then one should be mindful about whether to rechallenge with sacituzumab govitecan, with or without a dose reduction.14
Management of Neutropenia Associated With Sacituzumab Govitecan
Based on the SN38 payload, one should expect a higher level of neutropenia with sacituzumab govitecan than some other ADCs. Like other chemotherapies that carry a high risk of neutropenia, one should be mindful of following the absolute neutrophil count on Day 1 and Day 8 of each 21-day cycle and should promptly evaluate any reports of fever.
With sacituzumab govitecan, it is reasonable to use granulocyte colony-stimulating factor (G-CSF) support and consider dose reduction at first, second, and third incidences of significant and durable neutropenia. In practice, I do find this to be a manageable toxicity and typically can maintain patients on effective treatment with G-CSF support.5
Summary
In summary, TROP-2‒targeted ADCs represent a new frontier in the treatment of NSCLC for patients with or without actionable genomic alterations. I anticipate much phase III trial data within the next year or so in the first-, second-, and third-line settings. As we begin to think about incorporating these therapies into the NSCLC treatment paradigm, healthcare professionals must understand the toxicity profiles and their specific, unique aspects so they can effectively care for patients receiving these agents in clinical practice.
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