2221P Precision oncology in advanced thyroid carcinomas: Impact of molecular tests on patients’ outcomes

Standard therapies (ST) for advanced thyroid carcinomas (TC) are heterogeneously available in Europe. In Italy, patients (pts) with 131I-refractory differentiated/poorly differentiated TC (DTC/PDTC) can receive lenvatinib/cabozantinib in 1st/2nd line (L), respectively. NTRK/RET/BRAF alterations are mutually exclusive. Targeted therapy (TT) is provided in 1L/2L for NTRK/RET-rearranged TC. BRAF-MEK inhibitors are given in 1L for BRAF-mutant anaplastic TC (ATC), chemotherapy if BRAF wild-type (wt). Immunotherapy (IT) has shown activity in PD-L1 ≥ 1 TC. At our Center, pts not eligible/progressing to ST are studied for actionable molecular targets (AMT). Here we explored the accessibility to novel therapies (NT) and the outcomes of pts who received NT. DTC/ATC pts candidate for systemic therapy were tested for BRAF by PCR or DNA Next Generation Sequencing (NGS); if BRAF-wt, FISH or RNA NGS were performed for RET/NTRK fusions. Eligible pts could receive NT (TT/IT) in basket clinical trials (BCT), managed access programs (MAP), off-label (OL). Disease control rate (DCR) and tolerability were annotated. Median progression-free survival (mPFS) from start of NT was estimated with Kaplan-Meier method. From 2019 to 2022, 116 pts (60% female, median age 69 years, 53% DTC, 20% PDTC, 27% ATC) received at least 1 test; 53% were ST-naïve, 47% pretreated ≥ 1L. Overall, 50 PCR, 39 FISH, 91 NGS DNA, 49 NGS RNA were performed. Histology specimens aged ≥ 5 years led to not-evaluable NGS in 33% vs 6.7% (p = .0002). AMTs were found in 70% pts (median 1/pt, range 0-3), 56.4% received NT (Table). DCR for TT/IT was 97%/86%. 27% pts reported G3 toxicities, 21.6% required TT dose reduction.Table: 2221PCases with AMTNT accessibilityDrug-Target match actionedNT performed/AMT (%)Best responsesDCR (CR+PR+SD) (%)Reasons for no treatment (%)BCTSelpercatinib-RET4/72SD, 2PR97Ongoing ST (24) Active surveillance (24) Worsening Performance Status (21) BCT not available (21) Off-label ICI not available (13) BCT not pursued due to logistics (2.6)Entrectinib-NTRK1/2PRMAPDabrafenib/trametinib-BRAF30/431CR, 22PR, 5SDAlpelisib-PIK3CA1/5SDTipifarnib-HRAS1/1PROLPD1 inhibitors-tumor mutational burden ≥ 10 mut/Mb (TMB-H)/PD-L1 CPS ≥17/201CR, 3PR, 2SD86Total44/78 (56.4)CR = complete response PR = partial response SD = stable diseaseMedian PFS (months)10.82 (95% CI 6.02-19.21) Open table in a new tab A high AMT rate (70%) has been achieved by applying our sequential molecular profiling algorithm. For specimens aged ≥ 5 years PCR should be preferred over NGS DNA to analyze BRAF gene. The majority of pts received NT in MAPs. PD-L1 test/NGS panels including TMB may further expand the therapeutic options.