First-in-human phase I/II study of BYS10 in patients (pts) with locally advanced or metastatic RET-altered solid tumors: Preliminary dose escalation results.

Abstract

8601 Background: RET alterations occur in non-small cell lung cancer (NSCLC, 2%), thyroid cancer (TC, 10%–20%) and a range of tumor types (<1%). RET inhibitors substantially improved the clinical outcomes of pts with RET-altered solid tumors. BYS10 is a highly potent and RET-specific inhibitor that overcomes RET V804 and G810 mutations, and exhibits high selectivity for RET over KDR. This study is to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of BYS10 in Chinese pts with RET-altered solid tumors. Methods: In phase Ⅰ, following an accelerated titration and BOIN design, eligible pts were treated with BYS10 at 25 to 600 mg daily dose. Primary endpoints included safety, tolerability, MTD and DLTs. Secondary endpoints included PK and preliminary antitumor activity. Results: As of 10 July, 2024, a total of 51 pts were enrolled in dose escalation cohorts at 25/50 mg QD (n = 1/1) and 50/100/200/250/300 mg BID (n = 3/12/12/9/13). The MTD was not reached. Treatment related adverse events (TRAEs) occurred in all subjects, the most common TRAE were elevated AST (64.7%), elevated ALT (58.8%), elevated TBIL (45.1%), decreased WBCs (43.1%), decreased NEUT (33.3%), hyperuricaemia (31.4%), hypertension (29.4%), hypoalbuminemia (25.5%), Elevated SCr (23.5%) and headaches (23.5%). Grade 3 to 4 TRAEs >5% included elevated AST (25.5%), elevated ALT (13.7%) and hypertension (9.8%) reported at 100 to 300 mg BID doses. Serious adverse events were recorded in 7 pts. Exposure of BYS10 increased in a dose-dependent manner from 25 to 600 mg. In 40 evaluable pts, the confirmed overall response rate (ORR) and disease control rate (DCR) by independent review committee per RECIST v1.1 were 62.5% and 85%, In pts with RET-fusion NSCLC (n=30), RET-fusion thyroid cancer (TC, n=6) and RET-mutant medullary thyroid cancer (MTC, n=4), the ORR/DCR were 60%/80%, 83.3%/100% and 50%/100%, respectively. Intracranial antitumor activity was observed by investigators in 4 pts with at least 1 measurable intracranial lesion (one intracranial complete response). The ORR/DCR by IRC in 200 mg and 300 mg BID cohorts were 66.7%/100% and 75%/91.7%, respectively. Conclusions: BYS10 was well tolerated and showed dose-dependent exposure. Preliminary antitumor activity was observed in pts with RET-altered NSCLC, TC and MTC. The study is still ongoing. Clinical trial information: ChiCTR2400085264 .