Genomic landscape of lung cancer in India: Insights from a precision oncology perspective.

Abstract

e20080 Background: Lung cancer is the second most common cancer with a high mortality rate. Understanding its genomic landscape is crucial for identifying clinically actionable biomarkers and overcoming therapeutic challenges. This study explores the genomic profile of lung cancer patients from India. Methods: The genomic profiles of 1,266 Indian lung cancer patients in advanced stage of the disease (80% with progression in first/second/third line standard of care), were retrospectively analyzed for SNVs/InDels, CNVs, gene fusions, and immunotherapy biomarkers, including TMB, MSI, and PD-L1 expression. FFPE tumor samples were assessed using NGS-based gene panels and exome sequencing. Results: Clinically significant variants/drivers were identified in 88.7% of the patients. Predominant genomic alterations included SNVs/InDels in TP53 (47.2% of cohort), EGFR (35.7%) and KRAS (4.8%) , gene amplifications in EGFR (2.3%) , MET (0.6%) , CDK4 (0.6%) , and ERBB2 (0.5%) , and ALK--EML4, ROS1 and RET gene fusion. Recurrent mutations included 23.5% in EGFR p.Leu858Arg (12.1%), p.Glu746_Ala750del (11.4%), KRAS p.Gly12Cys (4%) and p.Gly12Asp (2.6%). 15% of EGFR activating mutations were rare category mutations; this further emphasises the clinical benefit of CGP over hotspot panels. EGFR exon 20 insertions were seen in 1.5% of the cohort and ERBB2 mutations were seen in 3.6%. Variants associated with acquired resistance to TKI therapy were identified in 9.5% of the patients, with 5.5% harboring multiple co-occurring resistance variants. Clustering co-mutations identified targetable co-occurring variants AKT1 , KRAS and PIK3CA in patients where EGFR variants were the primary driver in 35.7% of the patients. Clinically actionable genomic alterations were detected in 84% of the cohort, which included 50% patients eligible for FDA approved therapies, 2.7% eligible for off-label therapies and 31.2% were eligible for therapies in clinical trials. High TMB (>10 mut/Mb) was observed in 7.7% of patients, MSI-H in 2.4% of patients and PDL1 expression (>1%) was noted in 9.2% of patients. Conclusions: 80% of the NSCLC patients opted for broad NGS panel after failure of first/second- or third-line standard of care therapy. Our study provides insights into the genomic landscape of lung cancer in India and highlights the utility of CGP in identifying clinically significant drivers and therapeutic biomarkers with implications in prognosis and therapy response in the routine clinical practice. Mutated genes targeted by FDA approved drugs (Level 1) Mutated genes targeted by off-label therapy (Level 2) EGFR (SNV & gene amplification) (Tier 1 AMP) ALK gene fusion (Tier 1 AMP) MAP2K1 BRCA2 (Tier 1 AMP) RET gene fusion (Tier 1 AMP) BRAF (Tier 1 AMP) ROS1 gene fusion (Tier 1 AMP) BRCA1 (Tier 1 AMP) RET gene fusion (Tier 1 AMP) MET (Tier 1 AMP) FGFR3 gene fusion (Tier 2 AMP) ERBB2 (SNV & gene amplification) (Tier 1 AMP) NTRK1 gene fusion