Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity — DARWIN1  

Non-small Cell Lung Cancer Clinical Trial

Official title: Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

Status Completed

Clinical Trial Summary

To assess if targeting activating EGFR and HER2 mutations in Non-Small Cell Lung Cancer (NSCLC) is more effective when these mutations are truncal dominant mutations (≥50%), as opposed to non-dominant (≥5 to <50%) or low frequency mutations (<5%). This trial will be available to patients registered to the TRACERx study (NCT01888601), or non-TRACERx patients who have two archival tissue/DNA samples who are willing to have a biopsy of their relapsed disease.

Clinical Trial Description

Increasing evidence suggests that clonal dominance of the drug target should be considered when stratifying therapeutics in solid tumours. It is likely that intratumour heterogeneity and cancer subclonal diversity may contribute to the high failure rate of oncology drugs relative to other medical specialties where drugs are applied to stable somatic genomes rather than unstable genomes found in cancer populations. In addition, increasing evidence in NSCLC and other solid tumours suggests that the selection of resistant subclones during the disease course is responsible for the acquisition of drug resistance and therapeutic failure. Finally, spatial separation of cancer subclones within the same tumour is likely to contribute to the difficulties associated with cancer biomarker validation. "Actionable mutations" may not be optimally actionable if they are present at one site of disease or within a minority tumour subclone. Such minority subclones are likely to contribute to intratumour heterogeneity and discordant results when interpreting multiple biopsies from the same tumour. Our work in NSCLC, renal cancers and glioblastomas is demonstrating that such subclones, carrying potentially targetable events, may be spatially separated within the same tumour or between primary and metastatic sites. This has been demonstrated in the context of EGFR somatic mutations that may be heterogeneous in up to 25-30% of patients, present at one site of disease but not another. The impact of such actionable driver heterogeneity on treatment response, drug resistance and outcome is currently unclear and is the subject of investigation within this protocol; DARWIN1 will assess the impact of EGFR activating mutation and HER2 mutation heterogeneity on progression free survival outcomes in advanced NSCLC treated with the EGFR tyrosine kinase inhibitor, afatinib. ;

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non-small Cell Lung Cancer

• NCT number: NCT02183883
• Study type: Interventional
• Source: University College, London
• Status: Completed
• Phase: Phase 2
• Start date: December 16, 2016
• Completion date: March 22, 2023