1399P - Tumor-immune microenvironment analysis of de novo and acquired KRAS-mutated non-small cell lung cancer

Background

With the emergence of novel KRAS-targeted drugs, molecular analysis of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known resistance mechanism in driver mutation-positive (DM+) NSCLC. The impact of acquired vs. de novo KRAS mutations on the tumor-immune microenvironment (TIME) is unknown.

Methods

Mutation status was assessed using next-generation sequencing (Caris Life Sciences) with paired whole-exome and whole-transcriptome sequencing (Illumina NovaSeq). KRAS-mutated (KRASmt) subgroups were defined as de novo KRASmt NSCLC (KRAS only identified driver – DN) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known drivers – ACQ). Immune pathway enrichment was assessed with single sample gene set enrichment analyses (SSGSEA). Hierarchical agglomerative clustering (HAC) was performed on expression of a panel of immune checkpoints to define immune low/medium/high clusters. Fisher’s exact, Chi-square, and Mann-Whitney U tests were used, as appropriate, to assess statistical significance and corrected for multiple hypothesis testing (q<0.05/FDR <0.25).

Results

6240 KRASmt NSCLC cases were identified - 6186 DN, 54 ACQ. A trend (p<0.05,q>0.05) toward increased expression of immune checkpoints PD-L1, TIM-3, and CD86, as well as a significant enrichment of TNFα, IFNα, IFNλ, JAK-STAT, and inflammatory response signaling pathways were observed in ACQ compared to DN. HAC analysis to delineate the immune profile associated with specific KRAS mutations revealed that the distribution of KRAS mutations was significantly different among immune clusters in the DN but not the ACQ subgroup (see table). Table: 1399P

Conclusions

Differences in the TIME were observed between DN and ACQ KRASmt NSCLC. KRAS mutation subtype frequency appeared to differ according to TIME phenotype in DN KRASmt NSCLC. The clinical and therapeutic implications of these findings warrant further investigation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Reuss: Financial Interests, Personal, Advisory Board: Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol Myers Squibb, Arcus, AbbVie; Financial Interests, Personal, Other, honoraria: AstraZeneca, Merck; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Local PI: Verastem, Nuvalent. N. Gandhi: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. P. Walker: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. J. Nieva: Financial Interests, Institutional, Research Funding: Merck, Genentech/Roche; Financial Interests, Personal, Advisory Role: Aadi Therapeutics, ANP Technologies, Bioalta, AstraZeneca, Mindmed, Sanofi, Fujirebio, Naveris, Boehringer Ingelheim, G1 Therapeutics; Financial Interests, Personal, Other: Kalivir; Financial Interests, Personal, Licencing Fees: Cansera; Financial Interests, Personal, Ownership Interest: Cansera, Epic Sciences, Indee Bio, Quantgene. J. Carlisle: Financial Interests, Institutional, Local PI: AstraZeneca, Amgen, Hutchmed. A. Desai: Financial Interests, Personal, Advisory Board: Foundation Medicine, Amgen, Sanofi. A.M. VanderWalde: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences; Financial Interests, Personal, Speaker, Consultant, Advisor: West Clinic, George Clinical, Genentech, Mirati. P.C. Ma: Financial Interests, Personal, Advisory Role: Caris Life Sciences, AstraZeneca; Financial Interests, Personal, Other, honoraria: AstraZeneca; Financial Interests, Institutional, Research Funding: AstraZeneca, Bristol Myers Squibb, AbbVie, Merck, Apollomics, OncoC4, Genmab, BeiGene, Mirati, Genentech/Roche, Elevation Oncology, Calithera Biosciences. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Novartis, Regeneron, Sanofi, Turning Point Therapeutics; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, Eisai, Gilead, Guardant Health, Merus, Takeda; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Merck; Financial Interests, Institutional, Local PI: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; Financial Interests, Institutional, Steering Committee Member, Local PI: Genentech; Non-Financial Interests, Member: ASCO, IASLC. All other authors have declared no conflicts of interest.