On January 15, 2021, the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki was approved for treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal adenocarcinoma who have received a prior trastuzumab-based regimen.^1,2

Supporting Efficacy Data

Approval was supported by findings in the open-label, phase II DESTINY-Gastric01 trial (ClinicalTrials.gov identifier NCT03329690), conducted in Japan and South Korea.³ In the trial, 188 patients with locally advanced or metastatic disease who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine-, and a platinum-containing chemotherapy, were randomly assigned 2:1 to receive trastuzumab deruxtecan at 6.4 mg/kg intravenously (IV) every 3 weeks (n = 126) or the physician’s choice of irinotecan or paclitaxel monotherapy (n = 62). In total, 55 patients received irinotecan (150 mg/m² biweekly) and 7 received paclitaxel (80 mg/m² weekly for 3 weeks).

The main efficacy outcome measures were overall survival and objective response rate, as assessed by independent central review using Response Evalution Criteria in Solid Tumors version 1.1 in the intent-to-treat population. Median overall survival was 12.5 months (95% confidence interval [CI] = 9.6–14.3 months) in the trastuzumab deruxtecan group vs 8.4 months (95% CI = 6.9–10.7 months) in the irinotecan or paclitaxel group (hazard ratio [HR] = 0.59, 95% CI = 0.39–0.88, P = .0097). Confirmed objective response rate was 40.5% (95% CI = 31.8%–49.6%) vs 11.3% (95% CI = 4.7%–21.9%; P < .0001). Median duration of response was 11.3 months (95% CI = 5.6 months to not reached) vs 3.9 months (95% CI = 3.0–4.9 months). Median progression-free survival was 5.6 months (95% CI = 4.3–6.9 months) vs 3.5 months (95% CI = 2.0–4.3 months; HR = 0.47, 95% CI = 0.31–0.71).

How It Works

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. Following binding to HER2 on tumor cells, trastuzumab deruxtecan undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death.

How It Is Used

Patients with locally advanced or metastatic gastric cancer must be selected for treatment based on HER2 protein overexpression or HER2 gene amplification. HER2 status should be reassessed if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with trastuzumab deruxtecan. Trastuzumab deruxtecan must not be substituted for or with trastuzumab or ado-trastuzumab emtansine.

The recommended trastuzumab deruxtecan dose for gastric cancer is 6.4 mg/kg, administered as an IV infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. The first infusion should be given over 90 minutes; subsequent infusions can be given over 30 minutes if prior infusions are well tolerated. Infusion should be slowed or interrupted if infusion-related symptoms develop. Treatment should be permanently discontinued in cases of severe infusion reactions.

Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation. In patients with gastric cancer, the dose can be reduced to 5.4 mg/kg and then to 4.4 mg/kg, with treatment being discontinued if further dose reduction is required. The dose should not be reescalated after any dose reduction. Product labeling provides specific instructions for dose modification for and management of interstitial lung disease/pneumonitis, neutropenia, febrile neutropenia, thrombocytopenia, and left-ventricular dysfunction.

Safety Profile

In the DESTINY-Gastric01 trial, the median duration of treatment was 4.6 months (range = 0.7–22.3 months) in the trastuzumab deruxtecan group and 2.8 months (range = 0.5–13.1 months) in the irinotecan or paclitaxel group.

The most common (≥ 20%) adverse events of any grade in the trastuzumab deruxtecan group were nausea (63% vs 47% in irinotecan or paclitaxel group), decreased appetite (60% vs 45%), anemia (58% vs 31%), fatigue (55% vs 44%), diarrhea (32% vs 32%), vomiting (26% vs 8%), constipation (24% vs 23%), pyrexia (24% vs 16%), and alopecia (22% vs 15%). The most common grade 3 or 4 adverse events included anemia (38% vs 23%), decreased appetite (17% vs 13%), fatigue (9% vs 5%), nausea (5% vs 2%), and febrile neutropenia (5% vs 3%). The most common grade 3 or 4 laboratory abnormalities were deceased neutrophils (51% vs 23%), decreased hemoglobin (38% vs 23%), decreased white blood cell count (29% vs 13%), decreased lymphocytes (28% vs 12%), and decreased platelets (12% vs 5%).

Serious adverse events occurred in 44% of patients in the trastuzumab deruxtecan group. Treatment was permanently discontinued in 15%. Adverse events led to death in three patients (2.4%).

Trastuzumab deruxtecan has boxed warnings for interstitial lung disease and embryofetal toxicity. Patients should be monitored and promptly evaluated for signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Treatment should be permanently discontinued in all patients with grade ≥ 2 interstitial lung disease/pneumonitis.

Trastuzumab deruxtecan also has warnings/precautions for neutropenia and left-ventricular dysfunction. Complete blood cell counts should be monitored prior to initiation of treatment, prior to each dose, and as clinically indicated. Left-ventricular ejection fraction should be assessed prior to treatment and at regular intervals during treatment as clinically indicated. Treatment should be permanently discontinued in patients with symptomatic congestive heart failure. Patients should be advised not to breastfeed while receiving trastuzumab deruxtecan. The pregnancy status of females of reproductive potential must be verified before initiation of treatment.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. Available at www.fda.gov. Accessed February 2, 2021.

2. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use, prescribing information, Daiichi Sankyo Co, Ltd., January 2021. Available at www.accessdata.fda.gov. Accessed February 2, 2021.

3. Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020.