Second-Line Trastuzumab Deruxtecan Treatment and Side-Effect Management

Initial Presentation, Workup, and Treatment

A 49-year-old female reports left breast pain to her primary care physician. A mammogram and ultrasound lead to a biopsy, which shows grade 3 invasive ductal carcinoma. No receptors were preformed, and the patient undergoes lumpectomy and sentinel node biopsy 2 weeks later, which reveals a grade 3, 1.4-cm invasive ductal carcinoma, ER+/PR+/HER2-. Oncotype DX testing is completed with a recurrence score of 20. No chemotherapy is recommended, and the patient completes radiation. She starts ovarian suppression with leuprolide and anastrozole. One year later, she undergoes bilateral salpingo-oophorectomy and stops the leuprolide, continuing the anastrozole alone.

Metastasis Presentation and Treatment

Five years after diagnosis, at age 54, while still on anastrozole, the patient develops abdominal pain. Imaging reveals innumerable hypoechoic liver masses. Labs reveal elevated aspartate aminotransferase (AST) and alanine transaminase (ALT); total bilirubin is normal. The brain MRI is negative, except for a single calvarial metastasis. She undergoes a CT-guided liver biopsy, which shows ER+/PR-/HER2+ (immunohistochemistry 3+, no FISH (fluorescence in situ hybridization) preformed).

Due to her transaminitis, instead of starting docetaxel, the patient is started on weekly low-dose paclitaxel with trastuzumab and pertuzumab. Her transaminitis quickly resolves over the first 3 weekly cycles, and she eventually increases to full-dose paclitaxel.

After 12 weeks, she undergoes a restaging CT, which reveals interval substantial decrease in the size and conspicuity of the extensive hepatic metastatic disease, with many of the prior lesions now difficult to visualize.

Due to poor tolerance and neutropenia, the paclitaxel is stopped. The patient continues trastuzumab and pertuzumab and starts fulvestrant. Restaging scans continue to show stable disease in the liver for several years, until, at age 58, a CT reveals multiple new hypodense lesions in hepatic segments 3, 6, and 7. Labs at this time show worsening transaminitis and an elevated total bilirubin of 3.0 mg/dL. 

Based on recent data from the DESTINY-Breast03 trial,¹ she is started on trastuzumab deruxtecan (T-DXd). Due to her elevated liver function tests, she begins with 4.4 mg/kg (as opposed to the full dose of 5.4 mg/kg). A CT 6 weeks later reveals interval resolution of hepatic lesions. Her AST and ALT are normalized, and her total bilirubin is lower at 1.9 mg/dL.

Adverse Event Management

The patient continues treatment and increases to full-dose T-DXd (5.4 mg/kg). Three weeks later, she reports increased nausea, but no vomiting, despite her premedication with ondansetron, dexamethasone, and fosaprepitant. She is taking ondansetron 8 mg twice daily with good effect but often wakes in the morning nauseated. Her oncologist recommends taking lorazepam at bedtime to prevent nausea upon waking. After 5 days, she reports the nausea is still present and she is now vomiting. She is prescribed olanzapine 2.5 mg at bedtime.

One day before her next T-DXd treatment, the patient undergoes a CT, which reveals continued resolution of the liver metastases and new ground glass opacities (GGOs) in the right upper lobe. Labs reveal normal AST and ALT and a further decrease in her total bilirubin, now 0.9 mg/dL. She reports her nausea is much better controlled with the addition of olanzapine at bedtime. She denies shortness of breath and cough. Due to the new GGOs and absence of other symptoms, the oncologist decides to hold T-DXd treatment due to possible grade 1 interstitial lung disease (ILD). She is started on prednisone 0.5 mg/kg PO with breakfast daily. With her weight of 62 kg, she begins with 30 mg daily.

Two weeks later, the patient undergoes a CT chest scan without contrast, which shows that her GGOs are resolved. Her prednisone dose is decreased to 20 mg daily. One week later, she reports feeling well with the break from chemotherapy. She reports some difficulty sleeping but has continued to take the olanzapine at night as needed. Her AST, ALT, and total bilirubin remain normal. She resumes T-DXd at the previous dose of 5.4 mg/kg, and the prednisone is slowly tapered over 4 weeks.

Discussion

Results from the DESTINY-Breast03 trial showed improved progression-free and overall survival among patients with HER2+ metastatic breast cancer receiving second-line T-DXd compared with trastuzumab emtansine (T-DM1).¹ When starting a patient on T-DXd, it is important to closely monitor those with moderate hepatic impairment (defined as total bilirubin >1.5 to 3.0 times ULN (upper limit of normal) and any AST).² In the case of this patient, due to her worsening transaminitis and elevated total bilirubin (3.0 mg/dL), she was started on a lower dose of T-DXd as a precaution, which was increased once her AST and ALT normalized and total bilirubin lowered.

In clinical trials of T-DXd, nausea and vomiting were two of the most reported adverse events,^1,3 and T-DXd has been classified as moderately emetogenic.⁴ According to treatment guidelines, this patient was pretreated with a 5-HT₃ receptor antagonist, dexamethasone, and neurokinin-1 receptor antagonist.⁴ Because the nausea persisted, she was also prescribed olanzapine.

ILD/pneumonitis is another known side effect of T-DXd. In the DESTINY-Breast01 and 03 trials, 13.6% and 10.5% of patients, respectively, experienced this adverse event.^1,3 Most cases were grade 1 or 2, and four patients (2.2%) in DESTINY-Breast01 who had ILD died as a result. ILD is managed based on the grade at presentation.⁴ In the case of this patient, she was asymptomatic but new GGOs were found on a chest CT, so T-DXd was held and prednisone was initiated. Because the ILD resolved after less than 28 days, this patient was able to resume T-DXd treatment with no dose adjustments and the prednisone dose tapered. If the ILD had resolved after 28 days, she would have required a T-DXd dose reduction. And if she was experiencing symptomatic grade 2 ILD, T-DXd would have been permanently discontinued.

References

1. Cortés J, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. Engl J Med. 2022;386:1143-1154.
2. Enhertu (fam-trastuzumab deruxtecan-nxki) prescribing information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf
3. Modi S, et al. Trastuzumab deruxtecan in previously treated her2-positive breast cancer. N Engl J Med. 2020;382:610-621.
4. Rugo HS, et al. Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open. 2022;7:100553.