As reported in The Lancet Oncology by Kanwal Raghav, MD, and colleagues, the phase II DESTINY-CRC02 trial has identified the preferred dosage of single-agent fam-trastuzumab deruxtecan-nxki (T-DXd) in patients with HER2-positive advanced colorectal cancer.

Kanwal Raghav, MD

Study Details

In the international study, with enrollment taking place between March 2021 and March 2022, patients with or without a RAS mutation were randomly assigned to receive T-DXd at 5.4 mg/kg (n = 40) or 6.4 mg/kg (n = 40) every 3 weeks; an additional 42 patients were then added to the 5.4-mg/kg group. In total, 51% of patients in the 5.4-mg/kg group and 60% in the 6.4-mg/kg group were Asian. The primary endpoint of the trial was confirmed objective response rate on blinded independent central review.

Responses

Median follow-up was 8.9 months in the 5.4-mg/kg group and 10.3 months in the 6.4-mg/kg group. Objective responses (all partial) were observed in 31 (37.8%, 95% confidence interval [CI] = 27.3%–49.2%) of 82 patients in the 5.4-mg/kg group and 11 (27.5%, 95% CI = 14.6%–43.9%) of 40 in the 6.4-mg/kg group. Median response duration was 5.5 months (95% CI = 4.2–8.1 months) in the 5.4-mg/kg group and 5.5 months (95% CI = 3.7 months to not evaluable) in the 6.4-mg/kg group.

In the 5.4-mg/kg group, objective responses were observed in 4 (28.6%, 95% CI = 8.4%–58.1%) of 14 patients with a RAS mutation, 27 (39.7%, 95% CI = 28.0%–52.3%) of 68 with wild-type RAS, 7 (41.2%, 95% CI = 18.4%–67.1%) of 17 who had received prior anti-HER2 treatment, and 24 (36.9%, 95% CI = 25.3%–49.8%) of 65 who had not received prior anti-HER2 treatment.

Adverse Events

Grade ≥3 treatment-related adverse events occurred in 41% of patients in the 5.4-mg/kg group and 49% of those in the 6.4-mg/kg group; the most common were decreased neutrophils (in 16%), anemia (in 7%), nausea (in 7%), and decreased white blood cells (in 6%) in the 5.4 mg/kg group, and decreased neutrophils (in 26%), anemia (in 21%), decreased platelets (in 10%), and decreased white blood cells (in 10%) in the 6.4-mg/kg group. Drug-related serious adverse events occurred in 13% of the 5.4-mg/kg group, most commonly nausea (in 4%), and 15% of the 6.4-mg/kg group, most commonly fatigue, neutropenia, and thrombocytopenia (in 5% each). Treatment-related death occurred in one patient in the 5.4-mg/kg group, due to hepatic failure. Drug-related interstitial lung disease or pneumonitis occurred in 8% vs 13% of patients, respectively.

The investigators concluded, “The promising antitumor activity and favorable safety profile support [T-DXd at] 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.”

Dr. Raghav, of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Daiichi Sankyo and AstraZeneca. For full disclosures of the study authors, visit thelancet.com.