Phase 1/2, open-label, first-in-human study of the anti-GPC3 T-cell engager SAR444200 in patients with advanced solid tumors: Updated efficacy and biomarker analysis.

2521 Background: SAR444200 is a novel NANOBODY T cell engager that simultaneously binds TCRαβ and glypican-3 (GPC3) to co-engage T cells with GPC3+ tumor cells, resulting in T cell-dependent cellular cytotoxicity. We present updated safety, efficacy, and biomarker data from the dose escalation cohort (Part 1A) of a multicenter, first-in-human, Phase 1/2 trial (NCT05450562). Methods: Patients (Pts) with GPC3+ refractory solid tumors received SAR444200 intravenously (IV) weekly with lead-in doses at dose levels (DLs) 1 (3 mg), 1A (1 mg), 2A (2.5 mg), 3A (4.5 mg), 4A (18 mg), 5A (36 mg), 6A and 7A (different lead-in doses, target dose 70 mg). Pts with ECOG PS ≤1, and ≥1 measurable lesion per RECIST 1.1, were eligible. Primary objective for Part 1A was safety. Key secondary objectives included efficacy and PK/PD. Levels of interleukin-6 (IL-6) and interferon gamma (IFNγ) were evaluated with a multiplex ECL-based assay. Study imaging was performed every 9 weeks following first infusion. Circulating tumor (ct) DNA was analyzed in blood samples using a mutational profiling NGS approach. Results: As of October 15, 2024, 33 pts (23 pts with hepatocellular carcinoma [HCC]) were treated with SAR444200 (premedicated with dexamethasone 15 mg IV or equivalent) for a median of 23 cycles (range, 1–32). Median lines of prior therapies were 3–4. Most pts (32 [97%]) experienced ≥1 AE of any Grade. Grade ≥3 TEAEs in 16 (48.5%) pts and serious TRAEs in 8 (24.2%) pts were reported. 2 Grade 3 cytokine release syndrome events were reported as DLTs at DL6A and 1 at DL7A during the lead-in dosing. Key efficacy data are summarized in Table 1. An increase in IL-6 and IFNγ (maximum of 1326 pg and 461 pg on average per DL, respectively) was observed during lead-in-doses in pts from DL1 to DL5A, supporting CRS diagnosis. Cytokine levels declined after Cycle 1. Of 18 HCC pts with baseline alpha fetoprotein (AFP) ≥20%, 5 (27%) pts showed ≥50% AFP reduction. Median time of observing any AFP decrease was 4 weeks post-treatment. Among these, 3 pts had sustained decrease over 13 cycles. Stable disease (SD) was reported in 10 (30.3%) pts including 2 who were on study drug for 12 and 22 months. Of the 18 pts with measurable ctDNA, 4 (including 3 pts at DL5 and above) had reductions in ctDNA (18%–48%) from baseline. Conclusions: SAR444200 was tolerated at the investigated DLs in pts with GPC3+ advanced solid tumors. Decrease in AFP post treatment along with SD in a subset of pts is suggestive of preliminary anti-tumor activity. Clinical trial information: NCT05450562 . Efficacy analysis. n (%) DL13 mg 2Wn=4 DL1A1 mg 2Wn=4 DL2A2.5 mg 2Wn=4 DL3A4.5 mg 2Wn=4 DL4A18 mg 3Wn=4 DL5A36 mg 3Wn=6 DL6A70 mg 3Wn=3 DL7A70 mg 3Wn = 4 All(N = 33) BORStable DiseaseProgressive disease 1 (25.0)3 (75.0) 1 (25.0)3 (75.0) 1 (25.0)3 (75.0) 1 (25.0)2 (50.0) 2 (50.0)2 (50.0) 3 (50.0)2 (33.3) 1 (33.3)1 (33.3) 02 (50.0) 10 (30.3)18 (54.5) BOR, best overall response; DL, dose level; W, weeks.

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