Therapeutic and prognostic impacts of specific gene alterations for squamous cell lung cancer: A result of nationwide genome screening in Japan (LC-SCRUM-Japan).

Abstract

9060 Background: Various gene alterations occur during the development of squamous cell lung cancer (SqLC), but specific gene alterations for SqLC and their clinical significance remain unknown. Methods: In a nationwide genome screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer patients for genetic alterations using a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, and have established a large-scale clinico-genomic database. Results: Since February 2013 to December 2018, a total of 6692 lung cancer patients (686 SqLCs, 5360 non-squamous non-small cell lung cancers [Non-sq] and 646 small cell lung cancers [SCLCs]) had been enrolled in the LC-SCRUM-Japan. The success rate of the NGS assay was 91%. Of 639 SqLCs analyzed, 274 (48%) had potentially targetable gene alterations, including 77 NFE2L2 (encoding NRF2) mut, 50 PIK3CA mut, 46 FGFR1 amp, 40 EGFRmut/amp, 36 PTEN mut, 23 KRAS mut, 6 AKT1 mut, 6 MET ex14skip, 5 ALK fusions, 2 FGFR3 fusions. Among the alterations detected, NFE2L2 mut and FGFR1 amp were significantly frequent in SqLC than Non-sq or SCLC (NFE2L2, 12.1% vs. 1.0% vs. 1.3%; p < 0.001, and FGFR1, 7.2% vs. 1.1% vs. 3.4%; p < 0.001). In advanced SqLC patients who received platinum-containing chemotherapies, the median progression-free survival (mPFS) was significantly shorter in NFE2L2-mutated patients (NRF2-type) than NFE2L2/FGFR1-negative patients (nonNF-type) (3.8 [95%CI, 2.9-5.1] vs. 4.5 [95%CI, 3.8-5.4] months, p = 0.03), and similarly, the mPFS of FGFR1-amplified patients (FGFR1-type) (3.5 months [95%CI, 1.5-4.9]) tended to be shorter than that of nonNF-type (p = 0.07), although the response rates were equivalent among the three types. NRF2-type also showed shorter overall survival (OS) than nonNF-type (median OS, 10.4 [95%CI, 6.9-22.3] vs. 16.6 [95%CI, 13.6-21.7] months, p = 0.10). Therapeutic efficacy of nivolumab or pembrolizumab was not different among these types in the current follow-up data. Conclusions: Our large scale genome screening identified specific gene alterations for SqLC and the alterations were associated with a less efficacy of chemotherapy and worse prognosis, suggesting the need for the development of genotype-directed therapeutic strategy for SqLC patients.