Equalizing prognostic disparities in stage III KRAS-mutant NSCLC: addition of durvalumab to combined chemoradiotherapy improves survival

Introduction: Stage III non-small cell lung cancer (NSCLC) is heterogeneous and identification of subgroups with differential responses is crucial to optimize treatment. Addition of durvalumab to concurrent chemoradiotherapy (cCRT) has previously been shown to improve survival outcomes. Meanwhile, subgroups harboring KRAS mutations have been shown to have worse prognosis. We investigated whether KRAS mutational status may affect survival outcomes after adjuvant durvalumab following cCRT in stage III NSCLC. Methods: In this retrospective study, we present a real-world dataset of all stage III NSCLC patients treated with cCRT with a curative intent and molecularly assessed between 2016-2021 in West Sweden. Primary study outcomes were overall survival (OS) and progression free survival (PFS). Results: We identified 145 patients receiving cCRT with a curative intent, 32% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT had a worse OS (p=0.047) and PFS (p=0.038). The finding persisted on multivariate analysis with OS (HR 1.703, 95%CI 1.074-2.702, p = 0.024) and PFS (HR 1.628, 95% CI 1.081-2.453, p = 0.020). After the addition of durvalumab to cCRT, there were no longer any significant differences between KRASWT and KRASMUT in OS or PFS. Conclusions: KRAS mutations are a negative prognostic factor after cCRT in stage III NSCLC, and the addition of durvalumab equalizes the negative impact of harboring this mutation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Swedish Research Council (2018-02318 and 2022-00971 to VIS, 2021-03138 to CW), the Swedish Cancer Society (23-3062 to VIS, 22-0612FE to CW), the Gothenburg Society of Medicine (2019; 19/889991 to EAE), Assar Gabrielsson Research Foundation (to EAE, CW, and VIS), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (to HF), Department of Oncology, Sahlgrenska University Hospital (to EAE and AH), the Swedish Society for Medical Research (2018; S18-034 to VIS), the Knut and Alice Wallenberg Foundation, and the Wallenberg Centre for Molecular and Translational Medicine (to VIS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval from the Swedish Ethical Review Authority (Dnr 2019-04771 and 2021-04987) was obtained prior to the commencement of the study. No informed consent was required due to all data presented in a de-identified form according to the Swedish Ethical Review Authority I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.