The level of genomic alterations in genes associated with the oncogenesis of specific solid tumor types is being investigated in patients that have demonstrated an exceptional response to currently approved targeted therapies, researchers announced at the International Congress on Targeted Anticancer Therapies (TAT) in Paris, France, which is organized by the European Society for Medical Oncology (ESMO).

Olivia Le Saux of the Department of Medical Oncology, Hospices Civils de Lyon in Lyon, France and colleagues are conducting the multicenter, prospective EXPRESS Study (NCT02701907), which investigates the level of genomic alterations in cancer-associated genes in patients demonstrating an exceptional response to standard treatment for several types of advanced solid cancers.

Dr. Le Saux noted that the majority of targeted therapies have been granted approval for the treatment of cancer based upon clinical studies that were carried out in genetically unselected patients. However, in this overall population, exceptional responses are observed in small subsets of patients (10%).

The study is investigating whether exceptional responses may be associated with patients having low levels of genomic alterations in genes that have been identified as being causally implicated in cancer. Patients with low levels of genomic alteration have been defined as having less than the 5^th quantile of genomic alterations to be expected for each specific tumor type.

The investigators defined an exceptional response according to the NCI definition, which is based upon three criteria that include the achievement of a complete or partial response lasting 6 or more months, and is not expected to occur in more than 10% of the patients receiving the specific drug for tumors affecting the specific organ.

Patients demonstrating exceptional responses will be reviewed monthly by the Response Confirmation Committee comprising the study coordinators and at least one expert of each organ-specific tumour.

The EXPRESS Study is continuing to recruit adult patients who have demonstrated an exceptional or unexpected response to a currently approved antineoplastic targeted therapy for advanced melanoma or solid cancers, including breast, lung, colorectal, ovarian, and kidney cancers.

The study will test the null hypothesis H0: π=0.05 against the one-sided alternative hypothesis π>0.05 per each tumor type in six cohorts with a sample size of a minimum 44 patients, which is necessary to achieve 80% power at π=15 with a one-sided level 5% test.

Recruitment is ongoing in this study, which has a proposed completion date of August 2019.

Patients showing an exceptional response to treatment for all 6 solid tumor types have already been enrolled

Of the 150 patients screened in 31 French centers, 52 patients were enrolled as of February 2018. Twenty-four patients had breast cancer, 15 patients had kidney carcinoma, 5 had melanoma, 4 had lung cancer, 3 had colorectal cancer, and 1 patient had ovarian cancer.

All patients had shown an exceptional response to a currently approved targeted therapy, including the 5 most frequently used drugs: sunitinib, everolimus, bevacizumab, trastuzumab, and pazopanib.

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor approved for patients with renal cell carcinoma, everolimus inhibits the mammalian target of rapamycin (mTOR) and has been approved for treatment of breast cancer, neuroendocrine, and other tumors, and trastuzumab is used in the treatment of HER2-overexpressing breast cancer and metastatic stomach cancer. Both bevacizumab and pazopanib block angiogenesis by binding the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors. Pazopanib has been approved for renal cell carcinoma and soft-tissue sarcoma and the recombinant humanized monoclonal IgG1 antibody, bevacizumab, has been approved for several indications, including colorectal cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, cervical cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer.

Any physician, oncologist based in France can contribute to the study. Cases are collected on an ongoing basis. If you treat patients who present exceptional responses to targeted therapy, please send an email to express@unicancer.fr.

The investigators concluded that identifying the molecular traits associated with exceptional response may aid the development of predictive genetic classifiers for precision medicine. They noted that this study also provides a unique opportunity to better understand cancer biology.