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HER2 ADCs in Gynecologic Cancers

CME

Emerging HER2-Targeted Antibody–Drug Conjugates in Gynecologic Cancers

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: May 09, 2024

Expiration: November 08, 2024

Kathleen N. Moore
Kathleen N. Moore, MD, MS, FASCO
CME/CE Information

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Administration Considerations for T-DXd in Gynecologic Cancers

Nausea is the most common toxicity we have observed with ADCs in gynecologic cancers. These drugs can be emetogenic, and I recommend considering premedication with antiemetics for nausea and vomiting when using T-DXd or DB-1303. DB-1303 is being evaluated in clinical trials, so these will help identify how any premedications are given.  

The table summarizes the starting dose for T-DXd—5.4 mg/kg intravenously every 3 weeks—and the recommended dose reductions for adverse events, along with how to monitor and manage adverse events of special interest.

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Strategies to Manage ILD Associated With HER2-Directed ADCs

The slide summarizes what HCPs should do when they suspect ILD/pneumonitis in a patient receiving T-DXd.

In patients with suspected asymptomatic ILD/pneumonitis, we must hold the drug, assess symptoms, and use a CT scan for confirmation and/or involve a pulmonologist. The key is to rule out an alternative cause, such as pneumonia (eg, with blood cultures, bronchoscopy). For confirmed ILD/pneumonitis of any grade, drug should be held and corticosteroids considered (prednisolone 0.5 mg/kg/day). T-DXd can be restarted if symptoms resolve within 28 days of onset. For those in whom ILD/pneumonitis persists beyond 28 days, treatment should be done only with caution after full resolution and at a reduced dose. However, for grade 1 ILD that has not resolved within 49 days from last infusion, as well as for grade 2-4 ILD, the drug must be permanently discontinued and systemic corticosteroid treatment initiated promptly (eg, prednisolone ≥1 mg/kg/day or equivalent for ≥14 days, followed by taper for ≥4 weeks).23,24

In addition, we want to monitor for new ground glass opacity on lung imaging, inflammatory vs infective change clinically correlate, patchy changes, or fibrotic linear changes. All of these descriptions, which in some of your patients you may have seen before, sort of waxing and waning ground glass opacity, just based on your region of the country and prior exposure, and it may not have been previously called pneumonitis.

With asymptomatic ILD/pneumonitis, your patient is going to feel great, and they are going to have a normal O2 saturation—so, unless you see those “clues on the CT scan” and recognize that as potential pneumonitis, you could miss it. That is the biggest learning curve of this drug. If you see anything new on the chest CT scan—certainly a new tumor that is different, but anything new—you need to hold the medication, which your patient will not want to do.

Next, get an opinion from a pulmonologist who has some understanding of pneumonitis with the use of deruxtecan payloads. This is key, because not all pulmonologists do, although I do believe pulmonologists are getting more educated on this issue. Also, this will take a phone call to a pulmonologist, because they are going to see a referral for a “ground glass opacity” in a patient with no symptoms and not see them for a month. So, you need to call the pulmonologist and say something like: “I have a patient on a medication that has a known association with pneumonitis, and I need her assessed as soon as possible to see whether you feel it is real. I have to hold the medication until I know.” Pulmonologists will look back on previous CT scans (if available), and sometimes they will see things that were there that you did not see.

My takeaway is to hold medication early when you recognize anything that is new on the CT scan that should warrant a second look and to get an opinion from pulmonology before you continue that medication. If your pulmonologist says this is not consistent with pneumonitis, and there are things on the imaging that are more likely related to environmental exposures—certainly as we have seen with COVID-19 and other things—they will tell you that, and then you can resume treatment. However, if they say, “Yes, this looks very different, and this is probably a new occurrence of pneumonitis, and the patient is asymptomatic,” that is grade 1, and drug needs to be held until it has resolved. Once you have documentation that the pneumonitis has resolved, you can restart at a dose modification, but you need to follow the patient very closely.

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Final Thoughts and Takeaways

It is a very exciting time in the field of HER2-targeted ADCs for the treatment of gynecologic cancers. HCPs are going to be able to leverage IHC testing for HER2 into available therapies for patients with aggressive gynecologic tumors and potentially find a trial match for certain patients going forward. Even now, many of these trials are enrolling, so I think if HCPs want to change one thing in their practices today, it would be to know the HER2 IHC status of all their patients with gynecologic cancer. Populating these trials would help investigators assess efficacy in larger cohorts of patients to further validate these highly encouraging preliminary findings.

For more on the evolving status of HER2 testing and HER2-targeted ADCs in other malignancies, including gastrointestinal and genitourinary cancers, visit the program page here.

The phase II DESTINY-PanTumor02 trial evaluated trastuzumab deruxtecan (T-DXd) monotherapy in patients with advanced HER2-positive solid tumors who were not eligible for curative treatment and progressed after prior therapy or were without satisfactory alternative therapy options. Which of the following efficacy results were reported for T-DXd in the patient population with gynecologic cancer?

Which of the following would you recommend for a patient receiving T-DXd for recurrent HER2-positive endometrial cancer who develops treatment-related asymptomatic grade 1 pneumonitis?

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