HER2-Directed Therapy, Trastuzumab Deruxtecan, Approved for Metastatic NSCLC

Fam-trastuzumab deruxtecan-nxki (Enhertu) has received accelerated approval from the FDA based on findings from DESTINY-Lung02 (NCT04644237). The antibody-drug conjugate has been approved for previously treated patients with HER2-mutated unresectable or metastatic non–small cell lung cancer (NSCLC).¹

Phase 2 findings showed that the overall response rate among a pre-specified patient cohort (n = 52) was 57.7% (95% CI, 43.2%-71.3%), as confirmed by blinded independent central review. Complete responses were observed in 1.9% of patients and partial responses were observed in 55.8% of patients. The median duration of response was 8.7 months (95% CI 7.1-not estimable). Further analyses on DESTINY-Lung02 trial are anticipated at upcoming medical meetings.

“The approval of trastuzumab deruxtecan in NSCLC is an important milestone for patients and the oncology community,” Bob T. Li, MD, PhD, MPH, a medical oncologist and physician-scientist at Memorial Sloan Kettering Cancer Center, said in a news release. “After 2 decades of research into the role of targeting HER2 in lung cancer, the approval of the first HER2-directed treatment option validates HER2 as an actionable target in lung cancer and marks an important step forward for treating this patient population with unmet medical needs.”

The recommended dose of trastuzumab deruxtecan is 5.4 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. For patients who require dose reduction because of adverse events (AEs), the first recommended dose reduction for NSCLC is 4.4 mg/kg, followed by 3.2 mg/kg. If a patient is unable to tolerate 3.2 mg/kg, treatment should be discontinued.²

Trastuzumab deruxtecan should not be re-escalated following a dose reduction. If a patient misses a dose or has it delayed, the dose should be administered as soon as possible. Providers should not wait until the next planned cycle, but rather adjust the schedule so to maintain a 3-week interval between doses.

According to the label, the targeted therapy is moderately emetogenic, and may induce delayed nausea and/or vomiting. Prophylactic antiemetic medications are recommended and should be administered in accordance with institutional guidelines.

Trastuzumab deruxtecan is associated with the following clinically significant AEs: interstitial lung disease (ILD)/pneumonitis, neutropenia and left ventricular dysfunction.

ILD occurred in 12% of patients with HER2-mutant NSCLC who received this agent at 5.4 mg/kg. The median onset time was 2.8 months (range, 1.2-21 months). Approximately 1% of patients died because of ILD complications.

Patients should be taught to report any cough, dyspnea, fever, or any new or worsening respiratory symptoms. Patients suspected of having ILD should be assessed via radiographic imaging. Consulting a pulmonologist may be appropriate.

For asymptomatic ILD, corticosteroid treatment may be considered, with a treatment hold until recover. In the event of grade 2 or higher ILD, systematic corticosteroid treatment should be initiated promptly, and continued for at least 14 days with a gradual taper across a minimum of 4 weeks. Patients diagnosed with symptomatic ILD must permanently discontinue trastuzumab deruxtecan.

Decreased neutrophil counts occurred in 65% of patients with NSCLC who received trastuzumab deruxtecan, of whom 16% had grade 3 or 4 severity. The median onset time was 22 days (range, 2-664 days). Approximately 1.1% of patients developed febrile neutropenia. Complete blood counts should be assessed at baseline and monitored after each dose. Depending on neutropenia severity, dose interruptions or reductions may be necessary.

Left ventricular dysfunction occurred in 3.6% of patients, of which 0.4% were grade 3. Left ventricular ejection fraction (LVEF) decreased has been observed with anti-HER2 therapies, including trastuzumab deruxtecan. LVEF should be assessed at baseline and at regular intervals throughout treatment. If LVEF drops below 40% or an absolute decrease from baseline greater than 20% is detected, the targeted therapy should be permanently discontinued. If symptomatic congestive heart failure occurs, the therapy should be discontinued.

As of August 2022, the agent has not been studied in patients with a history of clinically significant heart disease of LVEF less than 50% before treatment initiation.

Patients should also be educated about the embryo-fetal toxicity associated with the drug. Common AEs included in the trial included nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).

If not immediately used, trastuzumab deruxtecan should be protected from light and stored in a refrigerator between 36 to 46 degrees Fahrenheit. It should not be frozen. If not used after 24 hours, it should be discarded.

The reconstituted agent should be dilated in an intravenous infusion bag containing 100 mL of 5% dextrose injection, USP. It should not be diluted with sodium chloride injection, USP.

It is compatible with infusion bags composed of polyvinylchloride or polyolefin, filters used during administrations should also be composed of polyvinylchloride or polyolefin. The first infusion should be given over a 90-minute span. If well tolerated, further infusions can be given over a 30-minute span.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

References

1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. Updated August 11, 2022. Accessed August 12, 2022. https://bit.ly/3bVts9g
2. Enhertu. Prescribing information. Daiichi Sankyo Company, Ltd; 2022. Accessed August 12, 2022. https://bit.ly/3bNS18m