Afatinib in patients (pts) with solid tumors with neuregulin 1 (NRG1) fusions: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Rodon Ahnert Jordi , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Cannon Timothy Lewis , Hobbs Evthokia , Kalemkerian Gregory Peter , Hinshaw Dominique C. , Gregory Abby , Grantham Gina N. , Halabi Susan , Schilsky Richard L. 
Published: June 2024

3131 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a small cohort of pts with advanced solid tumors with NRG1 fusions treated with afatinib are reported. Methods: Eligible pts had measurable, advanced disease, NRG1fusion, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Pts with non-small cell lung cancer (NSCLC) were eligible if they had no pathogenic mutations in ALK, BRAF, EGFR or ROS1. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 40 mg of afatinib daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response, duration of SD, and safety. This cohort was closed after 2 years before completing stage 1 enrollment (n = 10) of the Simon’s 2-stage design used in TAPUR according to a prespecified cohort closure rule. Results: 4 pts with 3 tumor types with NRG1 fusion were enrolled between February 2020 and July 2021. 1 pt had NSCLC with a CD74- NRG1 fusion and achieved a PR that lasted 24 weeks (wks). This pt was a 58-year-old White, non-Hispanic female with ECOG PS 0, 2 prior systemic therapies and progressed after 32 wks on study tx. Co-alterations included CCNE1 amplification (amp), GATA amp, TP53 R65fs*58, and an ALK G1121D variant of unknown significance. 2 pts achieved SD16+: 1 was a 47-year-old White, Hispanic female with colorectal cancer (CRC) with a MATN2- NRG1 fusion, ECOG PS 1, 3 prior systemic therapies and co-alterations in APC, DDX11, FBXW7, FGFR1 and TP53; the other pt was a 49-year-old Black, non-Hispanic male with pancreatic cancer with a NRG1 exon 2 fusion, ECOG PS 1, 5 prior systemic therapies, a comutation in ARID1A. The durations of SD for these 2 pts were 136 and 64 wks, respectively. The pt with CRC underwent resection of a remaining target lesion and is still alive off study drug at 198 wks after the baseline visit as of Dec 2023. 1 pt was a 70-year-old White, non-Hispanic female with CRC with a CD74- NRG1 fusion, ECOG PS 0, 1 prior systemic therapy, and a best response of progressive disease. This pt had comutations in ARID1A, PBRM1 and TP53and progressed at 8 wks. Median OS was 81 wks. No grade 3-5 tx-related adverse events (AE) or serious AEs were reported. Conclusions: Though a small sample size, afatinib demonstrated promising activity in pts with advanced solid tumors with NRG1 fusion, including very durable DC. Additional study in a larger group of pts is warranted to confirm the efficacy of afatinib in pts with NRG1 fusion. Clinical trial information: NCT02693535 .