1477P STK11 mutations predict poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status

The upfront treatment of non-oncogene addicted NSCLC relies on immunotherapy single-agent (IO) or in combination with chemotherapy (CT-IO). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact the survival outcomes. The prognostic role of STK11 mutations under upfront IO or CT-IO is still unclear. We performed an observational study of 145 patients (pts) treated with first-line IO or CT-IO for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel. The primary objective was to assess the clinical outcomes of STK11 mutated (mut) pts. Then, we performed an external validation through the public OAK/POPLAR dataset, including nsq NSCLC pts treated with single-agent IO or CT. Most pts were male (59.7%), former smokers (61.1%), with ECOG PS 0-1 (84%), and received first-line CT-IO (58.6%). 44.8% had a mutation in KRAS, 21.4% in KEAP1, 50.3% in TP53, 13.1% in SMARCA4, and 14.4% in the STK11 gene. In 14/21 pts STK11 and KRAS mutations co-occur (p=0.053). The median overall survival (OS) was 13.2 months (mo.) (95% CI, 8.6-19.6), while the median progression-free survival (PFS) was 6.5 mo. (95% CI, 4.8-8.9). The mOS was 8 mo. (95% CI, 5-16.7) for STK11 mut pts and 17.3 mo. for STK11 WT pts (95% CI, 8.9-24.4) (p=0.038). TP53 (8.3 vs 17.3), KRAS (9.2 vs 15.9), and KEAP1 (8.9 vs 15.9) mut pts evidenced a trend for dismal mOS. SMARCA4 status had no impact on mOS. STK11 mutations were detrimental to OS in the univariate (HR 1.74, p=0.041) and multivariate model (HR 1.97, p=0.025) after adjusting for sex, age, ECOG PS, treatment (IO vs CT-IO), KRAS, KEAP1, TP53, SMARCA4 status. Genomic alterations did not impact the mPFS in our cohort. Within the OAK/POPLAR dataset, STK11 mutations (60/818 pts) were significantly associated with increased death risk in the univariate (HR 2.01, p<0.001) and multivariate model (HR 1.66, p=0.001) after adjusting for age, sex, treatment (IO vs CT), KRAS, KEAP1, TP53, SMARCA4 status. STK11 aberrations hampered the mOS of nsq NSCLC pts treated with first-line IO or CT-IO. The negative prognostic impact seems to be unrelated to IO administration.