Abstract
Background
Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody–drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated.
Methods
Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression.
Results
Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041).
Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm.
Conclusions
In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification.
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Acknowledgements
We are grateful to GONO and ARCO Foundations, to all participating patients and their families, and to the GONO investigators from the participating Italian centres.
Funding
The study was supported by GONO and ARCO Foundations (no grant number applicable). The sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
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Study concepts: RM, CU, MMG, CC. Study design: RM, CU, MMG, MG, CC. Data acquisition: CU, MMG, MG. Quality control of the data and algorithms: CU, MMG, MG. Data analysis and interpretation: RM, CU, MMG, MG, CC. Statistical analysis: RM, MMG. Manuscript preparation: RM, MMG. Manuscript editing: CU, GF, CC. Manuscript review: all authors.
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FP: Honoraria—Amgen, Merck-Serono, Sanofi, Lilly, Bayer, Servier, Astrazeneca, MSD; Research Grants—Astrazeneca, BMS, Incyte. SL: Speakers’ Bureau—Amgen, Merck, Roche, Lilly, Bristol-Myers Squibb, Pierre-Fabre, GSK and Servier. Consulting or advisory role—Amgen, MSD, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, Research Grants—Bayer, Merck, Amgen, Roche, Lilly, Astra Zeneca Bristol-Myers Squibb. FB: Honoraria—Lilly. Travel, accommodations and expenses—Bayer, Ipsen. GM: Honoraria—Amgen, Hoffmane-La Roche, Bayer, Merk Serono, Sirtex. CC: Honoraria—Amgen, Bayer, Merck, Roche and Servier. Consulting or advisory role—Amgen, Bayer, MSD, Roche. Speakers’ Bureau—Servier. Research funding—Bayer, Merck, Servier. Travel, accommodations and expenses—Roche and Servier. The remaining authors declared no competing interests.
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All patients provided written informed consent to study procedures before enrolment. Approvals for TRIBE protocol were obtained from local ethics committees of participating sites.
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Moretto, R., Germani, M.M., Giordano, M. et al. Trop-2 and Nectin-4 immunohistochemical expression in metastatic colorectal cancer: searching for the right population for drugs’ development. Br J Cancer 128, 1391–1399 (2023). https://doi.org/10.1038/s41416-023-02180-7
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DOI: https://doi.org/10.1038/s41416-023-02180-7