The Phase II DESTINY-CRC02 study (NCT04744831) presented at the 2023 ASCO Annual Meeting revealed that ENHERTU (Fam-trastuzumab deruxtecan-nxki) administered at a dosage of 5.4 mg/kg demonstrated higher efficacy in patients with HER2-positive mCRC compared to the 6.4 mg/kg dosage of the same treatment.
The study was conducted in two stages. In the first stage, patients were randomly assigned in a 1:1 ratio to receive either ENHERTU at a dose of 5.4 mg/kg (n = 40) or 6.4 mg/kg (n = 40) every 3 weeks. In the second stage, 42 patients were enrolled to receive the 5.4 mg/kg dose. The primary objective was to assess the confirmed objective response rate (cORR) as determined by a blinded independent central review (BICR). Secondary objectives included evaluating the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.
These findings indicate that the lower dose is the preferred and most effective treatment option for this specific group of patients. Additionally, among all patients who received a 5.4 mg/kg dosage of trastuzumab deruxtecan (n = 82), the cORR was 37.8% compared to 27.5% for those who received 6.4 mg/kg (n = 40). No complete responses were observed with either dosage. The median DoR was similar, with both the 5.4 mg/kg and 6.4 mg/kg dose levels showing a DoR of 5.5 months.
In the group receiving a dosage of 5.4 mg/kg, the disease control rate (DCR) was 86.6%, while it was 85.0% in the group receiving a dosage of 6.4 mg/kg. Among the overall cohort of patients receiving a dosage of 5.4 mg/kg, 48.8% had stable disease (SD) and 9.8% had progressive disease (PD). In the group receiving a dosage of 6.4 mg/kg, 57.5% had stable disease (SD) and 10.0% had progressive disease (PD).
The median PFS was 5.8 months in the 5.4-mg/kg cohort, and the median OS was 13.4 months. In the 6.4-mg/kg cohort, the median PFS was 5.5 months, and the median OS was NE.
Regarding safety, nearly all patients in the 5.4 mg/kg safety cohort (n = 83) and all patients in the 6.4 mg/kg safety cohort (n = 39) experienced treatment-emergent adverse effects (TEAEs), except for one patient in the 5.4 mg/kg cohort. Grade 3 or higher TEAEs were reported in 49.4% and 59.0% of patients, with 41.0% and 48.7% of these events being drug-related, respectively. The occurrence of serious TEAEs was 24.1% in the 5.4 mg/kg cohort, including 13.3% that were related to the drug, while in the 6.4 mg/kg cohort, these rates were 30.8% and 15.4%, respectively.
KOL insights
“These promising results support the use of trastuzumab deruxtecan at a dose of 5.4 mg/kg given intravenously every 3 weeks as the optimal dose as a single agent in this patient population of HER2-positive mCRC, [for disease that is either] RAS wild-type or RAS-mutant, due to its positive benefit-risk profile” –Expert Opinion.
Conclusion
There are currently no medicines approved to specifically treat HER2 overexpressing colorectal cancer, which affects approximately 2 to 5% of patients. Anti-EGFR drugs have been linked to resistance development. Studies indicate that HER2-targeted therapies, particularly dual anti-HER2 inhibition, hold promise as a strategy for treating patients with HER2-positive, RAS wild-type colorectal cancer. However, resistance can emerge, and the responses observed are not entirely satisfactory, highlighting an area that requires further attention and improvement. Positive results from the DESTINY-CRC02 study in HER2-positive colorectal cancer in the third-line settings could help in further data accumulation and confirmation of the optimal dose
