T-DXd Use in HER2+ Breast Cancer Influenced by Site of Metastases and AE Monitoring

Aditya Bardia, MD, MPH, FASCO

Professor, Department of Medicine, Division of Hematology/Oncology

Director of Translational Research Integration

UCLA Health Jonsson Comprehensive Cancer Center

Los Angeles, CA

KEY TAKEAWAYS FROM ADITYA BARDIA, MD, MPH​, FASCO

• Trastuzumab deruxtecan (T-DXd) continued to show benefit in the updated data from the DESTINY-Breast03 trial (NCT03529110).
• Special attention should be paid to the toxicities of nausea and pneumonitis with T-DXd, according to Bardia.
• Tucatinib (Tukysa) demonstrated improved intracranial efficacy in patients with active brain metastases; similar data for T-DXd have been published but not from randomized trials.

Targeted Oncology: What sequence of systemic therapy options is recommended by the National Comprehensive Cancer Network for stage IV HER2-positive metastatic breast cancer?

Aditya Bardia, MD, MPH​, FASCO: In terms of guidelines, the first line is trastuzumab [Herceptin], pertuzumab [Perjeta], and [either docetaxel or paclitaxel].¹ The second line is T-DXd. The third line [can be] tucatinib plus trastuzumab plus capecitabine or trastuzumab emtamsine [T-DM1]. You can use T-DM1 after T-DXd [but physicians] generally like to use a ‘sandwich’ technique in which you use T-DXd, then use tucatinib, capecitabine, and trastuzumab, and then after that bring in T-DM1 so you're not using antibody-drug conjugate [ADC] after ADC, but we don't have much evidence. You can use T-DM1 after T-DXd if you want. There was a trial combining T-DM1 with tucatinib that showed better results, but not much, so it's not something that we would use in clinical practice. Then after that, [one can use] pretty much any option. You can combine trastuzumab with something: trastuzumab plus capecitabine, docetaxel, vinorelbine, eribulin—you just combine anti-HER2 therapy with chemotherapy. Neratinib [Nerlynx] is another option in the third-line setting [and beyond].

What led to the indication for T-DXd following HER2-targeted first-line treatment in this setting, and what are the most recent updates to these data?

This was based on Destiny-Breast03. It was in the second-line setting with randomization to T-DXd vs T-DM1, so one ADC vs another. It included patients who had disease progression within 6 months after completing adjuvant therapy.

[With 43 months median follow-up], there was very impressive improvement in progression-free survival [PFS] with an HR of 0.3 [95% CI, 0.24-0.38].² We don't generally see this in the field of oncology [as a whole], not just breast oncology. In terms of overall response rate [ORR], there was a nearly 80% ORR [with T-DXd vs 36.9% with T-DM1]. That's why, if a patient has liver disease or symptomatic disease, this is the go-to medication, including in estrogen receptor–positive breast cancer when a patient has HER2-low disease or a lot of disease burden. T-DXd is a good medication in that circumstance. There was improvement in overall survival as well [HR, 0.73; 95% CI, 0.56-0.94].

In terms of adverse events [AEs], 3 common AEs seen with T-DXd included nausea, myelosuppression, and alopecia, and pneumonitis as well [less commonly].³

Nausea is the No.1 AE with T-DXd. If you look at guidelines, they say you can use a 2-drug or 3-drug antiemetic regimen.⁴ I usually use a 3-drug antiemetic regimen to start with, and if a patient does very well, then I back off. The other trick is to use olanzapine [Zyprexa]. For some reason, it tends to work very well with breakthrough nausea with T-DXd, as well as with sacituzumab govitecan [Trodelvy]. If none of this works…[you can] do dose reduction. It is somewhat dose related, and if you reduce the dose, the patient can feel better.

Pneumonitis is a very serious AEs with T-DXd; there have been deaths in clinical trials. You can imagine [with the patient population treated] in routine clinical practice it will be worse, and the key is early recognition. But sometimes, despite that, we tend to see severe pneumonitis.

[In terms of] AEs of special interest, we know about pneumonitis as well as decrease in left ventricular ejection fraction. That's less of a problem in terms of monitoring in HER2-positive disease, because those patients know about EKGs, and they're used to getting EKGs. This is something important to remember when T-DXd is used in hormone receptor–positive breast cancer in the HER2-low setting. Often those patients have not had EKGs before, so it’s just important to remember to get an EKG in that circumstance.

Does the presence of lung metastasis or the use of radiotherapy in the lungs increases the risk of pneumonitis?

In pooled analysis of clinical studies, they've not seen it to be a major risk factor. The risk factors are history of lung injury [such as] smoking and prior history of lung disease, or impaired renal function; that appears to be a risk factor as well, in terms of pneumonitis from T-DXd.⁵ Maybe it's because you have more payload that circulates around, it's usually in the first few months and the majority occurred in the first year. That's why, early on, it's important to get scans. Some would say every 8 weeks, but definitely every 12 weeks…in terms of scans initially with T-DXd.

Would you change from trastuzumab/pertuzumab to T-DXd in a patient with bone-only metastases that could be irradiated?

If you're just seeing 2 spots in the bone, and everything [else] is under control, you could consider radiation. If you just are seeing disease in the brain and everywhere else the disease is under control, you could do stereotactic radiosurgery and then continue trastuzumab/pertuzumab.

What data support treatment selection for patients with brain metastases?

There have been clinical trials looking at T-DXd in patients with brain metastases in Destiny-Breast02 [NCT03523585] and Destiny-Breast03, but it was in patients with stable brain metastases, not patients with active brain metastases. HER2CLIMB [NCT02614794] included patients who had progressive brain metastases, and that's why the level of evidence is higher with tucatinib. [We have data on] efficacy in patients with brain metastases with intracranial [confirmed ORR of 47.3%], so you have direct evidence that tucatinib does work in patients with brain metastases.⁶

In terms of T-DXd, ¾ these are not randomized data per se—but with single-arm studies, you do see an [intracranial] ORR of 73% in the TUXEDO-1 trial [NCT04752059].⁷ In another trial [DEBBRAH; NCT04420598], it was [44%], so it does have activity in the brain, which was surprising.⁸ It was not expected that ADCs would have activity in patients with [active] brain metastases, but maybe you have an impaired blood-brain barrier, which allows these ADCs to cross, or maybe the payload crosses, but it does work in that setting. Similarly, with sacituzumab govitecan, it does have activity in patients with brain metastases.

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