Unlocking therapeutic potential: IL-1β as a target in non-small cell lung cancer with oncogenic mutations—Prognostic and predictive insights.
Authors: Jeon Won Jin , Guo Mengni , Gavralidis Alexander , Joung Bowon , Elliott Andrew , Baca Yasmine , Reeves Mark Evan , Mirshahidi Saied , Vanderwalde Ari M. , Mirshahidi Hamid R. 
Published: June 2024

8030

Background: Preclinical studies have demonstrated heterogeneity in interleukin-1β (IL-1β) expression and its potential implications in non-small cell lung cancer(NSCLC). The phase II CANTOS trial incidentally showed reduced lung cancer incidence and mortality with the IL-1β inhibitor canakinumab. However, the phase III CANOPY-1/2 trials failed to demonstrate survival benefit when combining canakinumab with chemo/immunotherapy. The impact of IL-1β inhibition in NSCLC with actionable mutations remains unknown. This study aims to evaluate the prognostic and predictive role of IL-1β in NSCLC and its potential as a target for combination therapy. Methods: 34,960 NSCLC tumors underwent next-gen sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were stratified by IL-1β transcriptional expression quartiles (Q1: low expression and Q4: high expression). Quartiles were established within each subpopulation. Significance was calculated using chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (p < 0.05). Overall survival (OS) from either time of tissue collection to last contact or time on treatment (TOT) was estimated from insurance claims data using the Cox proportional hazards model to calculate hazard ratio (HR) and log-rank tests to calculate p-values. Results: In the entire cohort, low IL-1β expressors showed improved OS compared to high expressors (20.0 months (m) vs 17.3 m, HR 0.88, 95%CI 0.88-0.95, p < 0.0001). For NSCLC without driver mutations, IL-1β expression did not correlate with OS difference. IL-1β expression was positively associated with TP-53 mutations (Q4 76% vs Q1 57%), high TMB (Q4 44% vs Q1 37%) and PD-L1+ expression by IHC (Q4 67% vs Q1 44%), while negatively associated with mutations in KRAS(Q4 24% vs Q1 31%) , EGFR(Q4 8% vs Q1 14%) , ERBB2 (Q4 1% vs Q1 2%) , BRAF (Q4 4% vs Q1 5%) ,and STK11 (Q4 10% vs Q1 18%) (p < 0.05). In EGFR-mutant NSCLC, Q1 showed superior OS than Q4 (34.6 m vs 25.1 m, HR 0.79, 95% CI 0.68-0.92, p = 0.002). This survival benefit was amplified in adenocarcinoma (Q1 41.2 m vs Q4 27.1 m, HR 0.74, 95% CI 0.63-0.87, p < 0.001). For ALK fusion-positive NSCLC, low expressors demonstrated improved OS (Q1 63.4 m vs Q4 27.0 m, HR 0.53, 95% CI 0.37-0.76, p < 0.001). In KRAS-mutant adenocarcinoma, high expressors showed improved immune-checkpoint inhibitor (ICI) TOT (Q4 6.4 m vs Q1 5.4 m, HR 0.85, 95% CI 0.74-0.98, p = 0.026); however, this did not correlate with improved OS. Conclusions: Our study shows promising prognostic value of IL-1β expression in NSCLC, associating low expression with improved OS across NSCLC subtypes. IL-1β expression is closely linked to key driver mutations in NSCLC and may have predictive value for ICIs. The findings suggest the potential benefit of targeting IL-1β in high IL-1β expressing NSCLC with driver mutations.