(AD) KRAS P.G12 Mutated Advanced Non-Small Cell Lung Cancer: Characteristics and Outcomes from a Danish Nationwide Retrospective Observational Study

Publication Number: 636

Background: Treatment targeting the KRAS p.G12C (G12C) mutation was approved by both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the past year as second line of treatment (LOT2) for advanced non-small-cell lung cancer (aNSCLC). However, the treatment-eligible G12C mutant NSCLC population, has not been well characterized, nor have its outcomes with current treatment approach.

Objectives: To characterize a nationwide real-world G12C mutant NSCLC population and to estimate its overall survival (OS).

Methods: Adult aNSCLC patients diagnosed between January 1st, 2018 and October 31st, 2020 were identified using the Danish Lung Cancer Register, which contains data on all Danish lung cancer patients since 2003. Additional information was gathered from the following registers: the Danish National Patient Register, the Danish Pathology Register and the Danish Civil Registration System. The study period was from January 1, 2018, to March 31, 2021, providing a follow-up time ≥ 6 months from NSCLC-diagnosis for all included patients. The primary outcome was OS from diagnosis. Secondary outcomes included a characterization of the study population including KRAS mutation status, demographics, clinical characteristics, tumor characteristics, treatment history (LOT, type of therapy), and genetic co-mutation profile, as well as time-to-next-treatment (TTNT) and OS from LOT1 and LOT2.

Results: We identified 6,058 patients with aNSCLC, and 36.5% (n=2,214) were tested for a KRAS mutation prior to LOT1. Among those KRAS tested, 40.5% (n=896) were KRAS mutated, 9.3 % (n=206) were G12C mutated (G12C) and 39.0% (n=864) were KRAS/EGFR/ALK wild type (Triple WT). G12C were more likely than Triple WT to be female (70%, n=144 vs 47%, n=405), smokers (87%, n=179 vs 81%, n=700), and have a high PD-L1 expression ≥50%. (48%, n=99 vs 35%, n=305). Co-mutation with EGFR was present in 11% of G12C. OS from diagnosis was similar for G12C and Triple WT (7.2 months [95% CI 6.1-10.1] vs 7.6 [95% CI 6.8-8.8]), but OS was longer for G12C than Triple WT from LOT1 (16.9 months [95% CI 9.5-NE] vs. 11.7 months [95% CI 10.2-13.9]) and LOT2 (16.2 months [95% CI 6.6-NE] vs. 9.7 months [95% CI 7.8-12.5]). For G12C receiving systemic treatment, those with high expression (≥50%) of PD-L1 (28.1 months, 95% CI 14-NE) had a longer OS compared to those with PD-L1 expression < 1% (9.9 months, 95% CI 6.9-NE) and 1%-49% (18 months, 95% CI 6.4-NE).

Conclusions: G12C had a longer OS from LOT 1 and LOT2 compared to Triple WT in this real-world study on aNSCLC patients diagnosed after the implementation of the current treatment regimens incl. immunotherapy. The longer OS may be explained by a higher PD-L1 expression and consequently more frequent immunotherapy treatment in patients with G12C mutant aNSCLC.