Comparing Dose Administrations of Trastuzumab Deruxtecan for mCRC in DESTINY-CRC02

Trastuzumab deruxtecan has provided encouraging activity in patients with treatment-refractory HER2+ RAS and BRAF wild-type metastatic colorectal cancer, and has shown promising efficacy in patients with HER2+ mCRC as part of the phase 2 DESTINY-CRC02 study.

As the beneficial effects of this treatment warrant further investigation into dose optimization and antitumor activity, Kanwal Raghav, MD, and colleagues have evaluated the effects of 2 different doses of the treatment in patients with pretreated HER-2 positive, RAS wild-type or mutant metastatic colorectal cancer.

DESTINY-CRC02 study was a multicenter, randomized study that examined patients with RAS wild-type or mutant mCRC in two stages. Stage 1 randomized patients to receive 5.4 mg/kg or 6.4 mg/kg trastuzumab deruxtecan intravenously every 21 days. In stage 2, patients were assigned to receive 5.4 mg/kg only.

All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had undergone previous chemotherapy in addition to anti-EGFR, anti-VEGF, or anti-PD-L1 therapy. The primary endpoint was objective response rate (ORR), and safety was assessed in all patients who received at least 1 dose of the drug.

Patients were screened between March 2021 and March 2022, with 122 enrolled in the study. Stage 1 administered trastuzumab deruxtecan 5.4 mg/kg to 40 patients, and 6.4 mg/kg to another 40 patients. Stage 2 was comprised of an additional 42 patients. The median duration of follow-up was 8.9 months (IQR 6.7-10.5) in the 5.4 mg/kg group and 10.3 months (5.9-12.7) in the 6.4 mg/kg group.

In the 5.4 mg/kg group, the objective response rate was 37.8% (31/82 [95% CI 27.3-49.2]) and 27.5% (11/40 [14.6-43.9]) in the 6.4 mg/kg group.

Treatment-related adverse events (TRAEs) of grade 3 or higher occurred in 34 (41%) patients in the 5.4 mg/kg group, and in 19 (49%) patients in the 6.4 mg/kg group, and included decreased neutrophils, anemia, nausea, and neutropenia.

Serious TRAEs occurred in 11 (13%) patients in the 5.4 mg/kg group, and in 6 (15%) patients in the 6.4 mg/kg group. Drug-related hepatic failure resulting in death occurred in one (1%) patient in the 5.4 mg/kg group. Adjudicated drug-related interstitial lung disease or pneumonitis events occurred in 7 (8%) patients in the 5.4 mg/kg group (all grade 1 or 2) and in 5 (13%) patients in the 6.4 mg/kg group (4 grade 1 or 2; 1 grade 5).

The results of this additional research demonstrate a promising safety profile and encouraging antitumor activity for trastuzumab deruxtecan 5.4 mg/kg as a single-agent dose for patients with pretreated HER2+ mCRC with RAS mutations or previous anti-HER2 therapy.