Abstract 4117: Clinicopathologic and molecular characterization of KRASG12D lung cancers
Authors: Luo Jia , Ricciuti Biagio , Alessi Joao V. , Wang Xinan , Vaz Victor , Pecci Federica , Nguyen Tom , Lindsay James , Sharma Bijaya , Felt Kristen D. , Rodig Scott J. , Nishino Mizuki H. , Sholl Lynette M. , Barbie David A. , Jänne Pasi A. , Awad Mark M. 
Published: June 2022

Abstract
Introduction: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRASmut non-small cell lung cancers (NSCLCs) exhibit heterogenous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never smoking status and has not been characterized in depth.
Methods: We examined characteristics of patients with advanced KRASmut NSCLC seen at a single center. RECISTv1.1 and Cox-proportional hazards models adjusting for line of therapy and performance status were used to compare outcomes to immunotherapy. Benjamini-Hochberg corrected q-values were used for genomic comparisons.
Results: Of 1,823 patients with KRASmut NSCLC, 16% (n=283) harbored KRASG12D which was mutually exclusive from other targetable alterations. Among these, the median age was 66 (range 20-92), 0.7% had squamous histology, 30% had a never/light smoking history (&lt;10 pack-years, KRASG12D,light-sm) and 43% had a high pack-year smoking history (≥30 pack-years, KRASG12D,high-sm). Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year smoking history (median 22 vs 30, p&lt;0.0001), more commonly had NKX2-1 and CDKN2A co-mutations (q&lt;0.05), and less commonly had STK11 co-mutations (q&lt;0.05). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% vs 10%, p=0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.3 v 9.9 mt/Mb, p&lt;0.0001). Compared with KRASG12D,high-sm, KRASG12D,light-sm had lower PD-L1 TPS (median 0% vs 10%, p=0.005) and TMB (median 6.1 vs 9.9 mt/Mb, p&lt;0.0001).As compared to patients with KRASnon-G12D (n=120) NSCLC and adequate baseline tissue for multiplex-immunofluorescence, KRASG12D (n=25) had fewer CD8+PD1+ T cells (median 13 vs 32 cells/mm2, p=0.04), PD1+ T cells (median 90 vs 135 cells/mm2, p=0.03), and lower proportion of PD-L1+ tumor and immune cells (median 1.2% vs 3.3%, p=0.06 and median 3.4% vs 7.5%, p=0.01, respectively).Among the subset of patients with advanced KRASmut NSCLC who received immunotherapy (n=57 with KRASG12D, n=411 with KRASnon-G12D), there was no difference in clinical outcomes to anti-PD-(L)1 monotherapy between KRASG12D and KRASnon-G12D (ORR: 18% vs 26%, p=0.3; mPFS: 2.8 vs 3.9 months, aHR 0.86 95% CI 0.60-1.25; mOS: 7.4 vs 15.1 months, aHR 0.77 95% CI 0.51-1.16). Similarly, there was no difference in clinical outcomes to chemo-immunotherapy between KRASG12D and KRASnon-G12D (ORR: 18% vs 39%, p=0.10; mPFS: 6.3 vs 7.0 months, aHR 0.79 95% CI 0.43-1.43; mOS: 14.0 vs 20.8 months, aHR 0.72 95% CI 0.38-1.35).
Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS mutated lung cancers and numerically worse outcomes to PD-(L)1 blockade-based therapies. Drug development for KRASG12D lung cancers will have to take these differences into account.
Citation Format: Jia Luo, Biagio Ricciuti, Joao V. Alessi, Xinan Wang, Victor Vaz, Federica Pecci, Tom Nguyen, James Lindsay, Bijaya Sharma, Kristen D. Felt, Scott J. Rodig, Mizuki H. Nishino, Lynette M. Sholl, David A. Barbie, Pasi A. Jänne, Mark M. Awad. Clinicopathologic and molecular characterization of KRASG12D lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4117.