Molecular profiling and survival in oncogene-addicted resected stage IIIAN2 non-small cell lung cancer (NSCLC): A study from the Lung ART IFCT 0503 trial.

Abstract

8026 Background: Molecular profiling is standard-of-care in metastatic NSCLC and increasingly important in earlier stages as personalized approaches arise. The role of adjuvant radiotherapy (ART) in oncogene-addicted, fully-resected stage IIIAN2 NSCLC remains undefined. Methods: The LungART trial (NCT00410683) randomized 501 patients (pts) with resected stage IIIAN2 NSCLC (AJCC 7th ed.) to ART or observation. No disease-free survival (DFS) benefit was found for ART. For consenting pts, a tumor block was collected. A histological central review was performed in all cases. Molecular profiling was conducted by Whole transcriptome sequencing (WTS; mRNA capture with Agilent exome lit and Illumina NovaSeq 6000 S4 Reagent Kit v1.5-300 cycles paired sequencing) to identify relevant alterations, with findings treated as per standard procedures. Results: 282 pts had available samples, from which 50% received ART. 90% were current or former smokers. Baseline characteristics were well balanced (table 1). After review, 79% of pts were classified as non-squamous cell carcinoma. TP53 was the most common mutation (mut) identified (46%). Targetable mutations included KRAS p.G12C (8.8%), EGFR -sensitizing -exon 19 in-frame deletion and L858R mut- (3.5%), and BRAF p.V600 (1.4%). Non p.G12C KRAS mut were found in 28 pts, while atypical EGFR mut including exon 20 insertion, and non V600 BRAF were identified in 3.1% and 2.8% of pts, respectively. A ERBB2 exon 20 insertion mut was identified in one case. STK11 and KEAP1 mutation were identified in 5.3% and 3.5% of pts, respectively. No translocations were detected. In the STK11 mut subgroup, a significant difference in DFS (p=0.032) and OS (p=0.0043) was observed. No differences in outcomes were observed for other major molecular alterations nor between treatment arms, including TP53 (p=1.0 and 0.86 for DFS and OS, respectively). Conclusions: Our study did not found a significant outcomes difference among major oncogenic-driven alterations, probably due to population characteristics and small representation of oncogene addicted subgroups. Our findings confirm STK11 as a poor prognostic factor in resected stage IIIAN2 NSCLC. Of note, TP53 did not show any impact on survival. Further studies are needed to confirm these observations and explore its implications. Baseline characteristics. Characteristic ART N=141 Observation N=139 Age 61 (54-68) 61 (55-66) Gender  Female 44 (31%) 42 (30%)  Male 97 (69%) 97 (70%) Neoadj. ChT 22 (16%) 23 (17%) Adj. ChT 120 (85%) 120 (86%) Smoking  Current 16 (11%) 14 (10%)  Former 110 (78%) 112 (81%)  Never 15 (11%) 13 (9.4%) Major molecular alterations TP53 67 (47%) 65 (46%) KRAS p.G12C 16 (11%) 9 (6.4%) KRAS non-p.G12C 14 (9.9%) 14 (10%) EGFR sensitizing 4 (2.8%) 6 (4.3%) EGFR (others) 3 (2.1%) 6 (4.3%) STK11 6 (4.3%) 9 (6.5%) KEAP1 6 (4.3%) 4 (2.9%) BRAF p.v600 0 (0%) 3 (2.1%) BRAF non-p.V600 6 (4.2%) 3 (2.1%)