RET-AREAL: A multi-center, real-world data analysis on the efficacy of pralsetinib in acquired RET fusion after resistance to EGFR/ALK-TKIs.

Pralsetinib demonstrated impressive improvement of survival in non-small cell lung cancer (NSCLC) patients harbored de novo RET fusion. However, the efficacy in patients with acquired RET fusion after resistance to EGFR/ALK-TKIs has only been reported on a case-by-case basis, and the strategy for overcoming the acquired RET fusion has not been fully investigated. This multicenter, real-world analysis enrolled 32 patients with unresectable NSCLC harbored acquired RET fusion after resistance to EGFR/ALK-TKIs in 23 centers across China from July 1st, 2018 to Nov 23rd, 2022. Epidemiological, clinical, genetic, and treatment data were collected. The primary outcome was time to treatment failure (TTF). Secondary outcomes were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and toxicity. In real-world context, patients underwent pralsetinib-based treatment had a higher proportion of central nervous system metastasis. EGFR 19del was the predominant mutation type (62.5 %) prior to acquired RET fusion. CCDC6 was the commonest RET fusion partner (40.6 %). "Clonal RET fusion" (c-RET) and "subclonal RET fusion" (s-RET) were defined according to the RET fusion allele frequency. Patients with c-RET had higher proportions of undetected EGFR mutation and KIF5B-RET fusion. First-line pralsetinib-based therapy had notably superior median TTF when compared to their counterparts (8.03 versus 4.30 months, P = 0.016). Notably, patients with c-RET had a better prognosis than those with s-RET (median TTF: NR versus 5.67 months, P = 0.037, median OS: NR versus 9.83 months, P = 0.047). In conclusion, pralsetinib-based therapy may be a potential strategy to overcome acquired RET fusion after resistance to EGFR/ALK-TKIs.