Genomic Profiling Identifies 3 NSCLC Subtypes Predictive of Adjuvant Therapy Outcomes

Next-generation sequencing (NGS) may help predict response to adjuvant therapy in patients with epidermal growth factor receptor (EGFR)-mutant stage 2 and 3 non–small cell lung cancer (NSCLC). Findings were published in Nature Communications.

After curative surgery for stage 2A-3B resected NSCLC, cisplatin-based adjuvant chemotherapy serves as the current gold standard for treatment. However, 5-year survival rates remain unsatisfactory for these populations, noted the researchers, with alarming levels of grade 3 toxicity observed in more than 60% of the patients.

In findings of the phase 3 ADJUVANT study, adjuvant gefitinib exhibited significant prolonged disease-free survival (DFS) in patients with EGFR-mutant stage 2–3A NSCLC compared with chemotherapy with vinorelbine and cisplatin (VP). Moreover, positive findings were also shown in the SELECT, EVAN, and ADAURA trials regarding the use of tyrosine kinase inhibitors (TKIs) in these patient populations.

“However, approximately 19% to 40% of TKI-treated patients still relapse after these trials, suggesting the inadequacy of EGFR-sensitizing mutants alone as a biomarker for adjuvant treatment selection,” the researchers said.

Noting the necessity for further biomarker assessment, they performed comprehensive genomic profiling (or, NGS) of 171 tumor tissues from patients with EGFR-mutant NSCLC from the ADJUVANT trial.

They searched for important comutations and key predictive biomarkers for adjuvant treatment, and then they integrated discovered biomarkers into a robust predictive score, known as the  Multiple-gene Index to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into subgroups with distinct survival benefits under either adjuvant gefitinib or chemotherapy for precision care.

Of the tumor tissues examined, 5 predictive biomarkers were identified by NGS (TP53 exon 4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). After integrating them into the MINERVA score, 3 subgroups with relative DFS and overall survival benefits from either adjuvant gefitinib or chemotherapy were identified (highly TKI-preferable [n = 60], TKI-preferable [n = 87], and chemotherapy-preferable [n = 24] groups).

The 3 subgroups demonstrated distinct treatment responses and underlying molecular profiles:

• The highly TKI-preferable group expressed significant superiority with adjuvant gefitinib (HR, 0.21; 95% CI, 0.10-0.44) and was enriched with copy number gains of NKX2-1, CDK4, and MYC, and TP53 exon 4/5 missense mutations
• The TKI-preferable group showed improved DFS among the precategorized and intention-to-treat populations (HR, 0.61; 95% CI, 0.35-1.07); this subgroup was characterized by the absence of most predictive biomarkers, except for sporadic coexistence of NKX2-1 and RB1 alterations
• A small subset of patients from the chemotherapy-preferable group, despite having EGFR-positive tumors, showed greater response and enhanced DFS (HR, 3.06; 95% CI 0.99-9.53) under VP treatment, and harbored RB1 alterations
  

“This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance toward future personalized adjuvant therapy,” concluded the researchers.

Reference

Liu SY, Bao H, Wang Q, et al. Genomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes. Nat Commun. Published online November 8, 2021. doi:10.1038/s41467-021-26806-7