Abstract Introduction: Petosemtamab, a bispecific antibody targeting LGR5 (Leucine-rich repeat-containing G-protein coupled receptor 5) and EGFR, is under clinical development. Wnt-driven LGR5, a stem cell-associated marker, stabilizes EGFR by preventing lysosomal degradation, thereby promoting cancer cell survival. However, its role in lung squamous cell carcinoma (LUSC) remains unclear. This study evaluates the impact of LGR5 expression on clinical characteristics, genomic alterations, and therapeutic outcomes in LUSC. Methods: Using the LC-SCRUM-Asia clinico-genomic database, mRNA levels of LGR5, EGFR, and other genes were assessed via the AMOY Master Panel. High LGR5 was defined as above the median. Clinical, genomic characteristics, and treatment outcomes were compared between high and low LGR5 groups. Results: LGR5 expression was evaluated in 233 LUSC patients between June 2021 and February 2022. The median LGR5 expression was 0.02 FPKM (range: 0.00-5.44), and the median EGFR expression was 12.09 FPKM (range: 0.07-572.49). No correlation was observed between LGR5 and EGFR expression (Pearson r = -0.0387, P = 0.687). Clinical characteristics, including age, sex, smoking history, ECOG-PS, and clinical stage, did not differ significantly between high and low LGR5 groups. The prevalence of driver gene alterations (KRAS mutation: 6 vs. 3, EGFR mutation: 2 vs. 4, MET ex14 skipping: 2 vs. 4, ALK fusion: 3 vs. 1) also showed no significant differences (P = 0.816). Among 103 patients receiving first-line ICI with or without chemotherapy, the median PFS was 8.0 months in the high LGR5 group and 5.6 months in the low LGR5 group (HR = 0.91, 95% CI: 0.58-1.44, P = 0.570). In 90 patients treated with first-line platinum-based chemotherapy, the median PFS was 5.5 months in the high LGR5 group and 4.3 months in the low LGR5 group (HR = 0.99, 95% CI: 0.52-1.91, P = 0.985). Wnt (P-weighted Log2FC = 0.753), Hedgehog (P-weighted Log2FC = 0.877), and Notch (P-weighted Log2FC = 0.564) pathways, key regulators of stem cell function, were significantly upregulated in the high LGR5 group (all P 0.05). Conclusion: High LGR5 expression does not define a clinically or genomically distinct subgroup of LUSC; however, it is associated with a transcriptionally stemness-activated phenotype characterized by upregulation of Wnt, Hedgehog, and Notch pathways. These findings suggest that LGR5-high LUSC represents a biologically distinct subtype that may inform future development of LGR5×EGFR-targeted therapies. Citation Format: Yu Tanaka, Shuji Murakami, Kazumi Nishino, Motoko Tachihara, Ichiro Nakachi, Mayu Kawakami, Satoshi Hara, hitomi Aono, Shoichi Kuyama, Gaku Yamamoto, Eri Sugiyama, Tetsuya Sakai, Hiroki Izumi, Shigeki Umemura, HIBIKI UDAGAWA, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto. Clinical, genomic, and therapeutic outcomes of lung squamous cell carcinoma with high LGR5 expression : A study from the LC-SCRUM-Asia database abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7919.
Tanaka et al. (Fri,) studied this question.