Optimal Trastuzumab Deruxtecan Dose for Patients With HER2-Positive Advanced Colorectal Cancer

Primary Results From the Phase 2 DESTINY-CRC02 Trial 

According to results from the phase 2 DESTINY-CRC02 trial, 5.4 mg/kg of trastuzumab deruxtecan is preferable to 6.4 mg/kg among patients with HER2-positive metastatic colorectal cancer (mCRC). 

“Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type, and BRAF wild-type metastatic colorectal cancer [however] dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted,” stated Kanwal Raghav, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors.

In this multicenter study, researchers enrolled patients with unresectable, recurrent, or metastatic HER2-positive and RAS wild-type or mutant CRC who had received prior chemotherapy and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, 40 patients were randomized on a 1-to-1 basis to receive either 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan intravenously every 21 days. Patients were stratified based on performance status, HER2 status, and RAS status. In stage 2, an additional 42 patients were assigned to receive only 5.4 mg/kg. The primary end point was confirmed objective response rate (ORR), assessed via blinded independent central review in all patients. Safety was assessed in all patients who received at least 1 dose of the study drug. 

At a median follow-up of 8.9 months in the 5.4 mg/kg arm and 10.3 months in the 6.4 mg/kg arm, the confirmed ORR was 37.8% and 27.5%, respectively. Grade ≥3 treatment-emergent adverse events were experienced by 41% of patients in the 5.4 mg/kg arm and 49% of patients in the 6.4 mg/kg arm. The most frequent events included neutrophil count decrease, anemia, nausea, white blood cell count decrease, and platelet count decrease. Drug-related serious adverse events were reported by 13% of patients in the 5.4 mg/kg arm and 15% of patients in the 6.4 mg/kg arm, most frequently including nausea, fatigue, neutropenia, and thrombocytopenia. One treatment related death occurred in the 5.4 mg/kg arm due to hepatic failure. Adjudicated drug-related interstitial lung disease or pneumonitis events were reported by 8% of patients in the 5.4 mg/kg arm (grades 1/2) and 13% of patients in the 6.4 mg/kg arm (4 grade 1/2; 1 grade 5). 

“The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5.4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both,” concluded Dr Raghav et al. 

Source:

Raghav K, Siena S, Takashima A, et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): Primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol. Published online August 5, 2024. doi: 10.1016/S1470-2045(24)00380-2