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HER2 Tx Toxicities
Managing Key Toxicities With HER2-Targeted Therapies for Breast Cancer

Released: May 31, 2023

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Key Takeaways
  • Diarrhea is very common with HER2 tyrosine kinase inhibitors (TKIs), and can generally be managed with antidiarrheals, treatment holds, and dose reductions.
  • Regularly monitor liver function tests in patients receiving HER2 TKIs, which can cause severe toxicity.
  • Closely monitor CT scans and symptoms of interstitial lung disease in patients receiving trastuzumab deruxtecan.

The treatment options for patients with HER2-positive breast cancer continue to evolve, with HER2-targeted therapies now including multiple antibody–drug conjugates (ADCs), antibodies, and tyrosine kinase inhibitors (TKIs). Unfortunately, these therapies can cause toxicities that can worsen quality of life or, if too severe, lead to permanent therapy discontinuation. In this commentary, I recommend strategies for monitoring and managing key toxicities related to HER2-targeted therapies: diarrhea, hepatotoxicity, cardiotoxicity, and interstitial lung disease (ILD).

Diarrhea
The most common toxicity with HER2 TKIs is diarrhea, which is likely related to EGFR inhibition. We see more severe diarrhea with neratinib, an irreversible pan-HER inhibitor, than with tucatinib, a selective HER2 inhibitor with a lower affinity for EGFR, or lapatinib, a reversible dual HER2 and EGFR inhibitor. In clinical trial participants, any-grade diarrhea occurred in 83% (including grade 3 events in 24%) of those treated with neratinib plus capecitabine, 66% (13% with grade 3 events) with lapatinib plus capecitabine, and 82% (13.1% with grade ≥3 events) with tucatinib plus trastuzumab/capecitabine. To put that in perspective, grade 2 diarrhea is having 4 to 6 additional bowel movements per day. Patients sometimes have trouble leaving the house with that degree of diarrhea.

Diarrhea related to tucatinib or lapatinib can be managed with antidiarrheals and, for grade 3/4 events, treatment interruptions, dose reductions, and potentially permanent discontinuation. We have 4 active dose levels for tucatinib ranging from 300 to 150 mg twice daily. Lapatinib has 3 active dose levels from 1250 to 750 mg once daily.

For neratinib, hold treatment for severe or persistent diarrhea. Discontinue for grade 4 or for grade ≥2 events after reaching the maximum dose reduction (neratinib has 4 active dose levels from 240 to 120 mg once daily). To reduce the risk of diarrhea, start patients at the lowest dose level and increase 1 dose level per week until you reach 240 mg once daily, while also administering loperamide. In the CONTROL trial, this dose-escalation approach reduced the incidence of grade ≥3 diarrhea from a historical rate of 40% to 15%.

Hepatotoxicity
Hepatotoxicity can be severe with HER2 TKIs. In clinical trial participants, grade ≥3 alanine transaminase (ALT)/ aspartate aminotransferase (AST) elevations were reported in 4.7% to 5.7% of those treated with tucatinib plus trastuzumab/capecitabine, 2% with neratinib, and <1% with lapatinib.

Monitoring is key: for tucatinib, assess ALT, AST, and bilirubin prior to starting therapy, then every 3 weeks during treatment and as clinically indicated. For neratinib, monitor monthly for the first 3 months and then every 3 months; for lapatinib, monitor every 4 to 6 weeks.

As with diarrhea, manage hepatotoxicity with dose holds and reductions. Permanently discontinue therapy in patients with grade 4 liver abnormalities.                                                               

Cardiotoxicity
Cardiotoxicity is a well-established part of the safety profile for HER2-targeted agents, with T-DM1, T-DXd, margetuximab, lapatinib, and SC pertuzumab/trastuzumab all carrying warnings for cardiomyopathy, left ventricular ejection fraction (LVEF), or heart failure. However, cardiotoxicity rates were typically <2.0% in clinical trials. HER2 TKIs generally have less cardiomyopathy than antibodies or ADCs.

Perform an echocardiogram at baseline and every 3 months, and plan to withhold treatment if you see an LVEF decline or QTc prolongation. You can resume therapy if the LVEF recovers, but therapy will need to be permanently discontinued if the decline persists.

ILD
The inflammation from ILD can cause fibrosis—a hardening of the lung interstitium that inhibits gas exchange. ILD is most common with T-DXd but can occur with T-DM1. In the DESTINY-Breast03 trial, any-grade ILD/pneumonitis occurred in 15% of patients treated with T-DXd vs 3% with T-DM1; grade 3 cases occurred in <1% with either agent.

Patients receiving trastuzumab-based therapies must be monitored for ILD and pneumonitis. I have seen ILD in my practice—it can develop and progress quickly. Follow patients with CT scans every 9 weeks initially and then every 3 months after a few cycles. If you do see an asymptomatic patient with a CT scan revealing pulmonary infiltrates, hold T-DXd immediately and start steroids. Be very quick to suspect ILD even if the patient just has a new cough or has been exposed to somebody who is sick. Get a high-resolution CT with ILD protocol and involve a pulmonologist immediately. We often use bronchoscopy to differentiate inflammation from infection.

For grade 1 ILD, hold T-DXd until resolved to <1. Give the patient prednisone at 1 mg/kg and follow up with a CT scan in 28 days. If the ILD has resolved, you can dose reduce and resume therapy. A patient with grade 2 ILD must permanently discontinue T-DXd and promptly initiate systemic steroids at 1 mg/kg of prednisone or equivalent for at least 14 days, followed by a taper over 4 weeks, and follow-up with another CT with ILD protocol to ensure the ILD is not progressing. You may need to admit the patient for further workup and management with pulmonary specialists.

We have preliminary data on resuming T-DXd after withholding for grade 1 ILD from a pooled analysis of 9 early-phase studies across multiple malignancies. Of 76 patients with grade 1 ILD, 47 resumed T-DXd as recommended and only 3 of those had a second ILD event (all grade 1). The takeaway here is that if you catch a grade 1 ILD early and treat it promptly so it resolves, you can then resume therapy with a dose reduction knowing that only a small proportion will have a second ILD event. However, if a patient has a second ILD event, they must permanently discontinue therapy.

Your Thoughts?
What challenges do you face when managing side effects of HER2-targeted therapies in patients with breast cancer? Please post a comment in the discussion box sharing your experience.