Colorectal cancer is a devastating disease that affects millions of people worldwide. Colorectal cancer is the third most frequent malignancy in both men and women in the United States (US). It is also the third most frequent reason for cancer-related death. Although advancements in treatment have enhanced outcomes for many patients, there remains a subset of patients with HER2-expressing metastatic colorectal cancer. These patients have limited treatment options. However, a glimmer of hope has arisen with the introduction of trastuzumab deruxtecan .
HER2: an emerging target in colorectal cancer
Human epidermal growth factor receptor 2 (HER2), is a protein that is essential for cell growth and division. Several malignancies, including breast, gastric, and colorectal cancer, have been linked to its overexpression. This pathway was successfully targeted in cancers like breast and gastric cancer and research is being done to see if it may also be used to treat colorectal cancer.
HER2 amplification or overexpression is present in about 2-5% of individuals with metastatic colorectal cancer and has been linked to poor prognosis and limited treatment options. The 5-year survival rate for patients with metastatic colorectal cancer is still low, despite improvements in the treatment approach. Additionally, preclinical findings support the use of anti-HER2 targeted therapy and suggest that it may be useful in the management of HER2-positive metastatic colorectal cancer .
What is trastuzumab deruxtecan?
Trastuzumab deruxtecan (T-DXd) signifies a revolutionary approach to targeting HER2-positive cancers. It is an antibody-drug conjugate that combines the specificity of trastuzumab, an anti-HER2 antibody, with deruxtecan, a topoisomerase I inhibitor payload, via a tetrapeptide-based cleavable linker. Lysosomal enzymes, which are overexpressed in tumor cells, break the linker after it has been internalized, releasing the cytotoxic payload, an exatecan derivative. A bystander effect on cells nearby HER2-expressing tumor cells is also obtained since it is permeable to the cell membrane. Thus, this unique combination allows for the targeted delivery of chemotherapy directly to HER2-positive cancer cells, minimizing damage to healthy cells and potentially improving treatment efficacy .
The clinical evidence
T-DXd is already approved in several nations for the treatment of patients with metastatic HER2-positive breast and gastric cancer. The effectiveness and safety of T-DXd have been investigated in clinical trials, including a study involving patients with metastatic colorectal cancer expressing HER2. Preliminary findings from these trials have shown promising outcomes, presenting new hope for patients who previously had limited treatment options.
Outcomes of the DESTINY-CRC02 trial demonstrated that, after two or more prior therapies, patients with metastatic colorectal cancer that was HER2-positive and responsive to T-DXd showed significant and long-lasting anticancer activity. Responses were seen in several subgroups as well as in individuals who had previously received HER2-targeted therapy. The safety profile was in line with other data, and interstitial lung disease/pneumonitis is still a significant risk that necessitates close monitoring and prompt treatment (DESTINY-CRC02; NCT04744831). These promising findings encourage further research into T-DXd in patients with metastatic colorectal cancer who are HER2-positive as well as the evaluation of T-DXd in earlier lines of therapy .
The future of trastuzumab deruxtecan
The encouraging results of T-DXd in HER2-expressing metastatic colorectal cancer have laid a solid foundation for further research and development. Ongoing studies are focused on exploring the efficacy of T-DXd in combination with other treatments and investigating its potential benefits in earlier stages of the disease. Additionally, efforts are being made to identify predictive biomarkers that can help identify patients most likely to benefit from this therapy, facilitating personalized treatment decisions and improving outcomes .
A phase I/II clinical trial is determining the efficacy and safety of AZD5305 (a PARP inhibitor), alone, or in combination with anti-cancer drugs like T-DXd in patients with advanced solid tumors like colorectal cancer (ClinicalTrials.gov Identifier: NCT04644068) .
Another phase II trial investigating the efficacy and safety of T-DXd for the treatment of unresectable and/or metastatic colorectal cancer harboring specific HER2 activating mutations. The target population of this trial is patients who have advanced disease after receiving prior treatment or who have no appropriate alternative treatments, including approved second-line therapies (ClinicalTrials.gov Identifier: NCT04639219) .
T-DXd represents a notable development in the management of HER2-expressing metastatic colorectal cancer. For patients with advanced disease, this innovative therapy offers new hope with its targeted approach and promising outcomes. T-DXd has the potential to transform the field of colorectal cancer treatment as more research is conducted and data is gathered, giving people battling this difficult disease a better future.
1. Greally, M. et al. 'HER2: An emerging target in colorectal cancer'. Current Problems in Cancer. (2018) 42(6), 560–571. DOI: 10.1016/j.currproblcancer.2018.07.001.
2. Yoshino, T. et al. 'Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer'. Nat Commun. (2023) 14(1), 3332. DOI: 10.1038/s41467-023-38032-4.
3. 'Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies - Full Text View - ClinicalTrials.gov' [https://classic.clinicaltrials.gov/ct2/show/NCT04644068].
4. 'A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations - Full Text View - ClinicalTrials.gov' [https://classic.clinicaltrials.gov/ct2/show/NCT04639219].