1339P - Impact of KRAS, STK11, and KEAP1 co-mutations on survival outcome and response to chemoimmunotherapy in patients with metastatic NSCLC

Background

Limited retrospective studies have shown benefit of chemo-IO in KRAS mutated metastatic NSCLC (mNSCLC), but response in the presence of STK11 or KEAP1 mutations and impact on OS remain unclear.

Methods

Pooled data from AACR GENIE database of mNSCLC patients with documented KRAS, STK11, and KEAP1 mutation status were included. Patients with stage I-III NSCLC who had adjuvant or neoadjuvant therapy before disease progression were excluded. KM curves and multivariate Cox proportional hazard regression were used to compare OS and evaluate prognostic factors.

Results

A total of 1004 patients were included - KRAS^wt/ STK11^wt/ KEAP1^wt (64.7%), KRAS^mut/ STK11^wt/ KEAP1^wt (24.1%), KRAS^mut/ STK11^mut or KEAP1 ^mut (6.5%) and KRAS^mut/ STK11^mut/ KEAP1^mut (4.7%). The median age at diagnosis was 62.6, 67, 67.7. and 65.9 years respectively for the four groups. Amongst all patients, 63.7% were females, 67.1% had de novo stage IV disease, 68% had adenocarcinoma, and 18.7% had brain metastases. Patients who had some form of therapy (N=574) included – 63.1% with chemotherapy alone, 4.9% with IO alone, and 32% with chemo-IO. The median OS for the four groups were – 44.2, 46.9, 29.3, and 10.8 months, and 3-year OS were- 59%, 57.2%, 43.2%, and 36.1%, respectively. The table below shows median and 3-year OS of chemo-IO and chemotherapy alone in each group (results for IO alone not included due to very small number). Compared to triple wild type, the presence of KRAS^mut alone (HR 1.34, 95% CI 1.06-1.67, p=0.01), KRAS^mut with either STK11^mut or KEAP1^mut (HR 1.67, 95% CI 1.18-2.35, p=0.003), and triple mutation (HR 4.08, 95% CI 2.78-5.99, p<0.001) showed worse OS.

Conclusions

STK11 and/or KEAP1 co-mutations with KRAS mutation predicted poor OS, with triple mutated group demonstrating worst OS. KRAS-only mutation or triple mutation derived greater benefit from chemo-IO compared to chemotherapy alone, although small sample size in triple mutated group may limit this conclusion.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors. Table: 1339P

Funding

Has not received any funding.

Disclosure

M. Shafique: Other, Personal, Advisory Board: Jazz Pharmaceuticals; Other, Institutional, Research Funding: Vaccinex, Pfizer, Genentech; Other, Personal, Research Funding: Daiichi Sankyo/Lilly. All other authors have declared no conflicts of interest.