Abstract CT073: A first-in-human study of oral TNO155 (batoprotafib) alone and in combination with EGF816 (nazartinib) in adult patients with advanced solid tumors

Background: TNO155 (batoprotafib), a selective, allosteric, oral inhibitor of SHP2, showed anti-tumor efficacy in preclinical cancer models. SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. EGF816 (nazartinib), an EGFR inhibitor, targets specific mutations in the EGFR gene commonly found in non-small cell lung cancer (NSCLC). Here, we present results from the first-in-human study of TNO155 single agent (SA), and in combination with nazartinib, in adult patients (pts) with advanced solid tumors. Methods: CTNO155X2101 (NCT03114319) is an ongoing, dose escalation/expansion (ESC/EXP) trial consisting of two arms: A) TNO155 SA and B) TNO155 with nazartinib. Primary objective is to assess safety and identify dosing regimen(s) for future study. Secondary objectives include pharmacokinetics, pharmacodynamics, and preliminary efficacy. Arm A included pts with advanced solid tumors in ESC and pts with advanced RAS/BRAF WT solid malignancies (Group 1), KRAS G12C-mutant NSCLC (Group 2), and NRAS/BRAF WT cutaneous melanoma (Group 3) in EXP; Arm B included pts with advanced NSCLC with an EGFR TKI-sensitizing mutation. Arm B EXP required progression on osimertinib as the most recent prior therapy. Results: As of 1-Aug-2024, 227 pts were treated (Arm A: ESC; n=141; EXP; n=42; Arm B; ESC; n=29; EXP; n=15), and 224 (98.6%) pts had discontinued study treatment, mainly due to progressive disease. Arm A ESC cohorts were previously reported (Brana et al. 2021). The recommended dose for expansion (RDE) was declared as 60 mg QD 2 weeks on/1 week off (2/1). Arm B ESC pts were treated with TNO155 20-60 mg QD 2/1 with nazartinib 100-150 mg QD continuous (cont). The RDE was declared as TNO155 40 mg QD 2/1 plus nazartinib 100 mg QD cont. Dose-limiting toxicities were reported in 2 pts, both on TNO155 60 mg QD 2/1 + nazartinib 100 mg QD cont (grade 4 decreased platelet count and grade 3 diarrhea). At the corresponding RDEs, the most common adverse events (>30%), regardless of relationship, reported in Arm A pts (n=55) were peripheral edema and anemia, and in Arm B pts (n=22) were diarrhea, thrombocytopenia, peripheral edema, anemia, and increased creatine phosphokinase.Plasma concentrations on day 14 of TNO155 and nazartinib administered in combination were within the range observed when administered at the same doses as SAs. Best overall response per RECIST v1.1 in Arm A EXP was stable disease (SD) in 5/15 pts (33%) in group 1, 1/12 pts (8.3%) in group 2, and 7/15 pts (46.7%) in group 3 and in Arm B EXP was SD in 3/15 pts (20%). Median duration of SD was 4.4 months in Arm A EXP, and 5.5 months in Arm B EXP.At the RDEs a reduction in tumor DUSP6 expression of >50% from baseline was observed in 9/12 pts in Arm A, and in 2/2 pts in Arm B. Conclusions: TNO155 shows acceptable safety as a SA and with nazartinib and demonstrates evidence of MAPK pathway suppression in tumors. Citation Format: Chia-Chi Lin, Helena Yu, Dong-Wan Kim, Daniel Tan, Dae Ho Lee, Maria Jove Casulleras, N Steeghs, Fredericus Eskens, Ahmad A. Tarhini, Melissa Johnson, Irene Brana, Giuseppe Curigliano, Lillian Siu, Aitana Calvo Ferrandiz, Geoffrey Shapiro, Victor Moreno Garcia, Hironobu Minami, Martin Klumpp, Helen Evans, Thomas Hengelage, Suresh B. Lakshminarayana, John Ritz, Xin Yang, David Kodack, Christopher Straub, Pruthvi Desireddy, Susan Moody, Pilar Garrido. A first-in-human study of oral TNO155 (batoprotafib) alone and in combination with EGF816 (nazartinib) in adult patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT073.