Background
Phase II randomized two-stage two-arm trial. 122 patients with pretreated HER2-positive (IHC3+ or IHC2+/ISH+), RAS wild-type or mutant metastatic colorectal cancer. ECOG PS 0–1, ≥1 prior chemotherapy line. Evaluated two doses of trastuzumab deruxtecan (T-DXd) — 5.4 mg/kg and 6.4 mg/kg — to select the optimal dose for future development. Expanded population vs DESTINY-CRC01 (includes RAS-mutant and prior anti-HER2 patients).
Interventions and follow up
Arm A: T-DXd 5.4 mg/kg IV q3wk (n=82 evaluable from 2-stage design: 40 stage 1 + 42 stage 2) until disease progression or unacceptable toxicity
Arm B: T-DXd 6.4 mg/kg IV q3wk (n=40 evaluable, stage 1 only) until disease progression or unacceptable toxicity
Primary endpoint: Confirmed ORR by BICR (full analysis set by dose)
mFollow up: 8.9 months (5.4 mg/kg); 10.3 months (6.4 mg/kg)
Arm B: T-DXd 6.4 mg/kg IV q3wk (n=40 evaluable, stage 1 only) until disease progression or unacceptable toxicity
Primary endpoint: Confirmed ORR by BICR (full analysis set by dose)
mFollow up: 8.9 months (5.4 mg/kg); 10.3 months (6.4 mg/kg)
Results
ORR (5.4 mg/kg): 37.8% (31/82, 95% CI 27.3–49.2%)
ORR (6.4 mg/kg): 27.5% (11/40, 95% CI 14.6–43.9%)
DCR (5.4 mg/kg): 76.8%
mPFS (5.4 mg/kg): 5.8 months
mPFS (6.4 mg/kg): 4.4 months
ORR (6.4 mg/kg): 27.5% (11/40, 95% CI 14.6–43.9%)
DCR (5.4 mg/kg): 76.8%
mPFS (5.4 mg/kg): 5.8 months
mPFS (6.4 mg/kg): 4.4 months
Adverse events
Overall: Grade ≥3 drug-related AEs 41% (5.4 mg/kg) vs 49% (6.4 mg/kg)
Hematologic (5.4 mg/kg): Neutrophil count decreased 16%, anaemia 7%, WBC decreased 6%
GI (5.4 mg/kg): Nausea 7%
Pulmonary: Adjudicated drug-related ILD/pneumonitis 8% (5.4 mg/kg, all grade 1–2) vs 13% (6.4 mg/kg, one grade 5 death)
Deaths: One drug-related death (hepatic failure) in 5.4 mg/kg group
Hematologic (5.4 mg/kg): Neutrophil count decreased 16%, anaemia 7%, WBC decreased 6%
GI (5.4 mg/kg): Nausea 7%
Pulmonary: Adjudicated drug-related ILD/pneumonitis 8% (5.4 mg/kg, all grade 1–2) vs 13% (6.4 mg/kg, one grade 5 death)
Deaths: One drug-related death (hepatic failure) in 5.4 mg/kg group
Conclusions
T-DXd 5.4 mg/kg achieved ORR of 37.8% in HER2+ mCRC including RAS-mutant and anti-HER2-pretreated patients — with a more favorable safety profile than 6.4 mg/kg. The 5.4 mg/kg dose was established as the optimal dose for mCRC, extending the applicability of T-DXd beyond RAS wild-type patients.
Key Limitations
Key Limitations: Relatively short median follow-up (8.9 months) with no mature PFS or OS data. Non-comparative dose selection design — doses were not randomized to show superiority of one over the other (different enrollment sizes). ILD signal (8% at 5.4 mg/kg including one grade 5) requires careful monitoring; 1% grade 5 toxicity. Expanded RAS-mutant population adds breadth but makes cross-trial comparison with DESTINY-CRC01 (RAS WT only) difficult. Long-term efficacy and impact on OS not yet established.
Clinical Context
DESTINY-CRC02 established T-DXd 5.4 mg/kg as the recommended dose for HER2+ mCRC, leading to FDA approval in January 2024 for HER2-positive unresectable or metastatic CRC in patients who had received prior systemic treatment. T-DXd and tucatinib+trastuzumab (MOUNTAINEER) are now both FDA-approved for HER2+ mCRC. No direct comparison exists between the two. DESTINY-CRC02 notably includes RAS-mutant patients — a broader label than tucatinib+trastuzumab (RAS WT only).