Optimal Dose of ADC Drug Shows Improved Efficacy in HER2-Positive Colorectal Cancer

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Optimal Dose of ADC Drug Shows Improved Efficacy in HER2-Positive Colorectal Cancer: Findings from The Lancet Oncology

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Optimal Dose of ADC Drug Shows Improved Efficacy in HER2-Positive Colorectal Cancer: Findings from The Lancet Oncology

HER2-positive metastatic colorectal cancer, predominantly found in patients with wild-type RAS and BRAF genes, is often associated with poor prognosis, brain metastasis, and resistance to anti-EGFR therapies.

Trastuzumab deruxtecan (T-Dxd) is a next-generation antibody-drug conjugate (ADC) that targets HER2 and has shown promising anti-tumor activity in patients with refractory HER2-positive, wild-type RAS and BRAF metastatic colorectal cancer. However, the optimal dosing for trastuzumab deruxtecan had not been determined—until now.

Recently, The Lancet Oncology published the results of the DESTINY-CRC02 study, which identified a more effective and safer dose of trastuzumab deruxtecan at 5.4 mg/kg for patients with HER2-positive, wild-type or mutant RAS metastatic colorectal cancer who had previously received standard chemotherapy.

The objective response rate at this dose was 37.8%, demonstrating significant anti-tumor activity while maintaining a favorable safety profile.

In recent years, ADC therapies have gained traction in cancer treatment, with HER2 being a particularly popular target. Below, we summarize the current clinical progress of ADC drugs targeting HER2.

The DESTINY-CRC02 trial was a multicenter, randomized, two-stage, phase 2 clinical study conducted across 53 countries. A total of 122 patients aged 18 and older, diagnosed with unresectable, recurrent, or metastatic HER2-positive, wild-type or mutant RAS colorectal cancer, were enrolled. All patients met the following criteria: an ECOG performance status of 0-1, and previous treatment with chemotherapy, anti-EGFR, anti-VEGF, or anti-PD-1 therapies.

In the first phase, 80 patients were randomized to receive either 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan every 21 days. In the second phase, an additional 42 patients received the 5.4 mg/kg dose without a fixed treatment cycle. Dose adjustments were allowed, with patients initially on 6.4 mg/kg being reduced to 5.4 mg/kg or 4.4 mg/kg if necessary, and those on 5.4 mg/kg being reduced to 4.4 mg/kg or 3.2 mg/kg if needed. If a patient could not tolerate the lowest dose, they were withdrawn from the study.

The median follow-up periods for the 5.4 mg/kg and 6.4 mg/kg groups were 8.9 and 10.3 months, respectively. Independent blind reviews confirmed that the objective response rate was 37.8% (31 out of 82) for the 5.4 mg/kg group and 27.5% (11 out of 40) for the 6.4 mg/kg group, with both groups showing partial responses. The median overall survival was 13.4 months for the 5.4 mg/kg group, while data for the 6.4 mg/kg group is still being collected (9.9 months–NA).

The article noted that a previous DESTINY-CRC01 study had observed a 45.3% objective response rate with a 6.4 mg/kg dose, compared to 27.5% in the current study. The reasons for this discrepancy are unclear, as the baseline characteristics of patients were similar. However, researchers suggest several factors that might explain the differences: small sample sizes in both studies, DESTINY-CRC01 only included wild-type RAS tumors, and a higher percentage of patients with an ECOG score of 1 (indicating poorer physical function) received the 6.4 mg/kg dose in the DESTINY-CRC02 study.

In terms of safety, 41% of patients in the 5.4 mg/kg group and 49% in the 6.4 mg/kg group experienced grade 3 or higher adverse events, primarily including decreased neutrophil counts, anemia, nausea, and leukopenia. The safety profile observed in this study was consistent with known risks of trastuzumab deruxtecan, with the 5.4 mg/kg dose leading to fewer severe adverse events, serious adverse events, and dose reductions than the 6.4 mg/kg dose. Most adverse events were mild, and the study’s design allowed for dose adjustments or temporary treatment interruptions to maximize patient safety and treatment outcomes.

In conclusion, this study demonstrated that trastuzumab deruxtecan exhibits clinically meaningful anti-tumor activity in HER2-positive metastatic colorectal cancer, with a generally manageable safety profile. The results suggest that a 5.4 mg/kg dose of trastuzumab deruxtecan may be more widely applicable, particularly for patients with wild-type or mutant RAS HER2-positive metastatic colorectal cancer who have limited benefit from standard treatments, and those who have previously received HER2-targeted therapies. This supports the use of the 5.4 mg/kg dose as a preferred option for monotherapy in these patients.

As ADC therapies continue to evolve, they have shown great promise in enhancing cancer treatment by combining monoclonal antibodies with potent cytotoxic drugs. HER2 remains a key target in this field, with 11 HER2-targeted ADC therapies currently in phase 1 to 3 clinical trials globally. These innovative ADCs are also being explored in a broader range of HER2-expressing or HER2 gene-aberrant solid tumors.

Optimal Dose of ADC Drug Shows Improved Efficacy in HER2-Positive Colorectal Cancer: Findings from The Lancet Oncology

(source:internet, reference only)

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