Fusions involving ROS1 or NTRK1/2/3 are oncogenic drivers that occur in < 1% of solid tumors. Small molecule inhibitors of NTRK (e.g. entrectinib and larotrectinib) and ROS1 (e.g. entrectinib and crizotinib) have shown clinically meaningful responses in NTRK fusion + solid tumors and in ROS1 fusion + NSCLC. We assessed the genomic landscape in these rare tumors to test for co-occurrence of clinically relevant biomarkers that may impact response to these inhibitors.
Comprehensive genomic profiling of > 300 cancer-related genes, including tumor mutational burden (TMB) and predicted ancestry, was done at Foundation Medicine on 166,067 tumors from 75 solid tumor types, most from the US. Odds ratios for mutational co-occurrence were generated using Fisher’s exact test.
Across all solid tumors, NTRK and ROS1 fusions were statistically significantly mutually exclusive with driver alterations in KRAS, APC and PIK3CA. ROS1 fusions were also mutually exclusive with BRAF, PTEN and FBXW7. There was significant co-occurrence of NTRK fusions with alterations in 15 genes, including IGF1R, CDKN2B and CDK4. ROS1 fusions co-occurred with alterations in SMARCD1, CDKN2A/B and SETD2. No enrichment or exclusivity was seen with clinically actionable biomarkers such as EGFR, ERBB2, RET, ALK or MET. TMB was similar in NTRK and ROS1 fusion + vs – tumors. There was a higher NTRK prevalence in patients with primarily East Asian ancestry (0.46%, p = 0.015) compared to South Asian (0.37%), American (0.34%), European (0.29%) or African (0.32%) ancestry, while there was a higher prevalence of ROS1 across all tumor types in East (0.74%, p < 0.001) and South (0.78%, p = 0.001) Asian ancestry groups compared to American (0.40%), European (0.31%) or African (0.31%) ancestry.
Across tumor types, NTRK and ROS1 fusions generally did not co-occur with clinically actionable alterations (e.g. EGFR, ERBB2) or alterations that are clear oncogenes (e.g. KRAS, BRAF). ROS1 and NTRK fusions occur at a slightly higher frequency in patients of primarily Asian ancestry compared to other ancestries. Future studies will evaluate these implications on response to NTRK and ROS1 inhibitors.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche.
F. Hoffmann-La Roche.
T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. E.S. Sokol: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Foundation Medicine. S.E. Trabucco: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Foundation Medicine. J.Y. Newberg: Full / Part-time employment: Foundation Medicine. B. Simmons: Full / Part-time employment: Roche; Full / Part-time employment: Genentech. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche; Full / Part-time employment: Genentech. S.L. Maund: Full / Part-time employment: Genentech.