Clinical outcomes of tumor-agnostic targeting of BRAF, tumor mutation burden-high, and RET

Background: We report the BRAF p.V600E (BRAF V600E) mutations, high tumor mutational burden (TMB-H), and RET fusions frequency/outcomes with genomically matched therapies (GMTs). To raise awareness about GMTs providing data from a real-world scenario, the KISMET project was created. In this article we report the characteristics and the outcomes of patients with advanced cancer harboring three different classes of molecular alterations: BRAF V600E mutations, TMB-H, and RET fusions. Patients and methods: We retrospectively assessed the prevalence of the three aforementioned agnostic targets among 10 893 patients who underwent next-generation sequencing (NGS) from February 2020 to May 2022. We evaluated the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) for GMT versus non-GMT in the three cohorts of patients with each specific alteration. Results: BRAF V600E occurred in 6.5% (662/10 158) of patients, TMB-H in 11.2% (265/2369), and RET fusions in 0.6% (42/7105). GMT was given to 115 (72.3%) out of the 159 patients who started a new line of treatment after NGS testing: 65 of 85 with BRAF V600E mutations, 42 of 65 for TMB-H, and 8 of 9 for RET fusions. The ORR of GMT versus non-GMT was 55.6% versus 12.8% for all patients (P < 0.0001), 51% versus 17.6% for the BRAF V600E (P = 0.016), 57.6% versus 9.5% for the TMB-H (P = 0.004), and 75% versus 0% for RET fusions (P = 0.30). The mPFS for GMT versus non-GMT was 9.6 versus 3.7 months (P = 0.001), 9.2 versus 4.2 months (P = 0.08) for BRAF V600E, and 7.9 versus 3.7 months (P = 0.04) for TMB-H, respectively. For the eight patients with RET fusions who received RET inhibitors, the mPFS was 15.0 months. Conclusions: BRAF V600E, TMB-H, and RET fusion were found in a wide variety of advanced cancers. Improved oncological outcomes with tumor type-agnostic GMT support the value of integrating comprehensive NGS testing and GMT administration for the aforementioned targets.