Survival Outcomes in Early-Stage NSCLC With Rare Mutations

Photo Credit: Spectral-Design

Targeted therapies, specifically for mutations like EGFR and ALK, significantly evolved the treatment landscape for non-small cell lung cancer (NSCLC), according to research presented at the 2024 ASCO Annual Meeting. Extending these therapies to other targetable mutations in NSCLC is a growing consideration. Researchers focused on recurrence-free survival (RFS) and overall survival (OS) to establish baseline outcomes for early-stage NSCLC patients with rare but treatable mutations.

The study retrospectively analyzed stage I-III patients with NSCLC who underwent curative surgery at a single center. Tissue-based next-generation sequencing identified a range of mutations: KRAS G12C, EGFR Exon 20, ERBB2, ALK, ROS1, BRAFV600E, MET Exon 14 skipping, and RET. The researchers used Cox regression to compare baseline characteristics, adjuvant chemotherapy, mutation subtypes, and TP53 co-mutation with RFS and OS; the KRAS G12C mutation served as the reference for survival comparisons.

Of the 201 patients (mean age 66.4 years, 63% female) included in the study, 61% had stage I, 19% had stage II, and 20% had stage III NSCLC. The predominant histology was adenocarcinoma (95%), and lobectomy was the most common surgical procedure (77%). UP to 37% of patients received adjuvant chemotherapy. The distribution of mutations was as follows: KRAS G12C (43%), EGFR Exon 20 (13%), ERBB2 (11%), MET (10%), ALK (7%), ROS1 (6%), BRAF (5%), and RET (2%).

Five-year survival probabilities were 75% for stage I, 56% for stage II (HR: 2.17; P=0.038), and 55% for stage III (HR: 2.38; P=0.015). Stage was a significant predictor of RFS, with higher hazard ratios for stage II (HR: 1.90; P=0.04) and stage III (HR: 2.26; P=0.006) compared with stage I. TP53 co-mutation correlated with poorer OS (aHR: 2.50; P=0.004) and RFS (aHR: 1.70; P=0.037).

Patients with rare mutations generally had shorter RFS than those with KRAS G12C, with ERBB2 showing a significant difference (aHR: 2.26; P=0.014) and only 37% remaining relapse-free at five years. However, except for ERBB2, other mutations were associated with better OS—notably fusion mutations (aHR: 0.24; P=0.021). ERBB2 had the highest incidence of brain metastasis, with 29% at five years.

This study highlighted that although RFS is generally poorer for rare mutations, OS of other mutations, except for ERBB2, was superior to KRAS G12C mutated NSCLC. TP53 co-mutation is a significant predictor of poorer outcomes. These findings suggest that targeted treatments at relapse might improve survival, advocating for the potential use of targeted agents in the adjuvant setting.