Molecularly matched therapies identified by comprehensive genomic profiling before the first-line setting to provide alternative treatment outcomes in patients with solid tumors: 1-year follow-up of the prospective FIRST-Dx study.
Authors: Hayashi Ryuji , Matsubara Junichi , Mukai Kumi , Yoshioka Masahiro , Kage Hidenori , Oda Katsutoshi , Ikeda Sadakatsu , Ebi Hiromichi , Muro Kei , Kajiura Shinya , Ashida Reiko , Kitano Masayuki , Muto Manabu 
Published: June 2024

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Background: Comprehensive genomic profiling (CGP) test by next-generation sequencing has been reimbursed in Japan since 2019. However, only 9.4% of patients (pts) had received molecularly-matched treatment because CGP test in Japan is only indicated after standard of care (SoC). To determine the clinical utility of a CGP test (FoundationOne CDx) in the first-line setting for pts with advanced solid tumors, we previously reported the results of the FIRST-Dx study, in which the molecular tumor board identified molecular-based recommended therapy (MBRT) for 61% of pts (105/172) (Matsubara J, et al. JAMA Netw Open 2023). In this 1-year follow-up of the FIRST-Dx study, we investigated the clinical benefits provided by the upfront CGP test. Methods: The FIRST-Dx study was a multi-institutional, prospective study in 6 hospitals in Japan. Chemotherapy-naïve adult pts with advanced solid tumor (GI, Lung, Breast, GYN, Melanoma) and ECOG performance status of 0-1 were enrolled. This follow-up study was planned for 3 years and an interim analysis was prespecified at 1 year after the final patient enrollment in the FIRST-Dx study. Primary endpoint was overall survival (OS). Secondary endpoints were the proportion of pts who received MBRT, overall response rate, progression-free survival (PFS), and a PFS ratio (PFS on MBRT/PFS on prior therapy). Results: Data from 172 pts with a median follow-up of 15.1 months were available. Median OS was not reached (95% CI: 18.4 months to not reached). Thirty-nine pts (22.7%) had received MBRT. The total number of pts treated with MBRT were 21 in 1st-line, 20 in 2nd-line, 4 in 3rd-line, and 1 in 4th-line, respectively. Overall response rate was 56.3% [95% CI: 29.9-80.2%] in 1st-line MBRT group vs 42.3% [95% CI: 33.9-51.1%] in 1st-line SoC (N=137), and 26.3% [95% CI: 9.1-51.2%] in 2nd-line MBRT group vs 17.1% [95% CI: 9.7-27.0%] in 2nd-line SoC (N=82), respectively. Median PFS was 12.9 months [95% CI: 7.4 months to not reached] in 1st-line MBRT group vs 11.3 months [95% CI: 8.6-14.1 months] in 1st-line SoC, and 6.9 months [95% CI: 2.8 months to not reached] in 2nd-line MBRT group vs 5.7 months [95% CI: 3.7-7.4 months] in 2nd-line SoC, respectively. Regarding the PFS ratio of 2nd-line MBRT (N=15) (PFS on MBRT in 2nd-line/PFS on 1st-line therapy), median PFS ratio was 1.0 (range: 0.1-14.6) and 4 pts (27%) had the PFS ratio of >1.3, indicating that MBRT might be effective in changing the clinical outcome (Von Hoff DD, et al. J Clin Oncol 2010). Conclusions: We showed that MBRT identified by CGP test before the first-line setting provides better treatment outcomes than SoC in pts with solid tumors early in their disease course. Our data suggested that the timing of CGP test in Japan for pts with advanced solid tumors should be indicated before starting SoC. Clinical trial information: jRCT1050220041 .