175MO - Investigating the clinical and immunobiological impact of Orphan Genomic Alterations (OGAs) in advanced NSCLC patients treated with immunotherapy.

Background

Orphan Genomic Alterations (OGAs), specifically KRAS not-G12C, BRAF not-V600E and PIK3CA mutations, are a common finding in patients with NSCLC treated with Immune Checkpoint Inhibitors (ICIs), but still poorly investigated. Our aim is to prove that patients harboring selected OGAs may exhibit a different outcome compared to OGAs-wild type NSCLC, underlying distinctive clinicopathological and immune-inflammatory features.

Methods

On a cohort of 125 consecutive advanced NSCLC patients receiving ICIs, the following procedures were performed: - complete DNA and RNA NGS panel (Illumina) on the diagnostic tissue sample, targeting 523 genes including the three OGAs of interest - flow cytometric analysis of relevant circulating immunophenotypes at T0 (baseline) and T1 (first disease assessment), as their delta variation (Δ% = [T1 value – T0 value / T0 value] * 100) - survival outcomes, estimated according to the Kaplan Meier method - disease response, assessed according to RECIST 1.1 criteria.

Results

In the overall population, OGAs patients were 55 (44%), with similar clinical characteristic to the OGAs-WT group. Strikingly, 65.5% of OGAs cases resulted in either CR, PR or SD >= 6 months, versus only 48.5 % of WT patients (p=0.05). Median TTF was significantly longer in OGAs compared to non-OGAs, and a tendency towards a better PFS was noted. Baseline analyses showed a trend towards higher CD3+ and CD8PD1+ T cells coupled with lower CD8ki67+ and NK bright phenotypes (p=0.05) in OGAs. At T1, significantly higher CD4ki67+ (p=0.006) and CD8ki67+, coupled with lower CD4CD25+FOXP3^high Tregs were noted in OGAs. A trend towards lower CD3+ and CD4+ lymphocytes, higher CD4PD1+ and CD8PD1+ was also noticeable in this group. Finally, a significant increase in CD8ki67+ (p=0.005) and CD4ki67+ (p=0.004) characterized OGAs patients.

Conclusions

Our analyses underlined a difference in terms of response to ICIs in OGAs patients, along with significant evidence in terms of dynamic behavior of immunophenotypic profiles. These results suggest how NSCLC patients harboring OGAs represent a peculiar subpopulation which might benefit from ICIs, thus offering a valuable treatment option in this subset of patients.

Legal entity responsible for the study

University Hospital of Parma.

Funding

AIRC - Associazione Italiana per la Ricerca sul Cancro.

Disclosure

A. Leonetti: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Takeda, Sanofi; Financial Interests, Personal, Advisory Board: Sanofi, Beigene, Novartis; Financial Interests, Personal, Writing Engagement: Roche, Ely Lilly; Financial Interests, Personal, Other, Travel Support: MSD, Novartis. M. Tiseo: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Roche, Amgen, Takeda, MSD, Merck, BMS, Pfizer, Eli-Lilly, Novartis, Janssen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Roche. All other authors have declared no conflicts of interest.