Efficacy of immunotherapy in first-line treatment for non-small cell lung cancer with HER2 mutation: Results from LC-SCRUM-Asia.
Authors: Kato Yuki , Udagawa Hibiki , Matsumoto Shingo , Izumi Hiroki , Ohe Yuichiro , Kato Terufumi , Nishino Kazumi , Miyamoto Shingo , Kawashima Yosuke , Chikamori Kenichi , Shingyoji Masato , Sato Yuki , Hara Satoshi , Toyozawa Ryo , Azuma Koichi , Sakai Tetsuya , Zenke Yoshitaka , Umemura Shigeki , Yoh Kiyotaka , Goto Koichi 
Published: June 2024

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Background: HER2 mutations occur in 2–4% of non-small cell lung cancer (NSCLC) patients. Previous studies with small cohorts have showed poor clinical outcomes in HER2-mutant NSCLC patients treated with immune checkpoint inhibitors (ICIs). However, in these previous studies, ICIs had not been used as the first line treatment in advanced NSCLC. Thus, the clinical outcomes in HER2-mutant NSCLC patients treated with ICIs in the first line treatment are still unclear. Methods: Using a large-scale clinical-genomic database of LC-SCRUM-Asia, the clinical-genomic characteristics and therapeutic outcomes of NSCLC patients harboring HER2 mutations were investigated. Tumor mutation burden (TMB) in tumors with HER2 mutations was compared to tumors with EGFR mutations or ALK fusions. Results: From March 2015 to June 2023, 15,251 NSCLC patients enrolled in LC-SCRUM-Asia. HER2 mutations were detected in 402 patients (2.6%). The most common subtype of HER2 mutations was exon 20 in-frame insertions (Ex20ins) (79%), followed by tyrosine kinase domain other than Ex20ins (10%), extracellular domain (7%) and transmembrane domain (3%). The most common Ex20ins was Y772_A775dupYVMA (66%), followed by G776delinsVC (14%), G778_P780dupGSP (7%). A total of 268 patients had received platinum-based chemotherapy with ICI (Chemo-ICI, n = 95) or without ICI (Chemo-alone, n = 173) until October 2022. The median follow-up periods were 18.5 and 19.9 months in the patients received Chemo-ICI and Chemo-alone, respectively. The patients received Chemo-ICI showed a significantly longer progression-free survival (PFS) compared to those received Chemo-alone (median 8.5 vs 6.3 months, HR [95%CI]: 0.66 [0.50–0.88], p < 0.005). In multivariate analysis, the addition of ICI to platinum-based chemotherapy was an independent better prognostic factor for PFS. There was no significant difference in the overall survival between the patients received Chemo-ICI and Chemo-alone (median 31.1 vs 23.3 months, HR [95%CI]: 0.80 [0.57 – 1.12]). The overall response rates were 34.7% and 35.3% in the patients received Chemo-ICI and Chemo-alone, respectively. Tumors with HER2 mutations showed a higher TMB (median 4.22 mut/Mb) and a higher percentage of TMB≥10 mut/Mb (12.3%) compared to tumors with EGFR mutations (median 2.54 mut/Mb and 1.0%, respectively) or ALK fusions (median 2.52 mut/Mb and 0.8%, respectively). The subtype of HER2 mutations showed no significant difference in the clinical outcomes of Chemo-ICI and Chemo-alone. Conclusions: Our large cohort demonstrated that the addition of ICI to platinum-based chemotherapy as first line treatment may improve PFS in NSCLC patients with HER2 mutations. Relatively high TMB may contribute to prolongation of PFS with ICI.