The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

Abstract

Introduction: KEAP1-NFE2L2-mutant NSCLCs are chemoradiation resistant and at high risk for local-regional failure (LRF) after concurrent chemoradiation (cCRT). To elucidate the impact of durvalumab on local-regional control, we evaluated LRF in patients with NSCLC treated with cCRT with and without durvalumab.Methods: Patients with stage III NSCLC treated with cCRT or cCRT and durvalumab who underwent tumor genomic profiling were evaluated. The incidence of LRF and outcomes of patients with and without KEAP1-NFE2L2-mutant tumors were evaluated.Results: We analyzed 120 consecutive patients (cCRT alone, n ¼ 54; cCRT and durvalumab, n ¼ 66). Patients treated with cCRT alone had significantly more LRF events compared with those treated with cCRT and durvalumab, with 12-month LRF incidence of 39% (95% confidence interval [CI]: 24%-54%) and 18% (95% CI: 8%-28%), respectively (p ¼ 0.002). Among patients treated with cCRT alone and cCRT and durvalumab, 20 patients (37%) and 18 patients (27%), respectively, had KEAP1-NFE2L2mutant tumors. In patients treated with cCRT alone, those with KEAP1-NFE2L2-mutant tumors had worse localregional control (p ¼ 0.015), and on multivariate analysis, KEAP1-NFE2L2 mutation predicted for LRF (hazard ratio ¼ 3.9, 95% CI: 1.6-9.8, p ¼ 0.003). Nevertheless, patients with and without KEAP1-NFE2L2-mutant tumors had similar LRF outcomes (p ¼ 0.541) when treated with cCRT and durvalumab, and mutational status did not predict for LRF (p ¼ 0.545). Among those with KEAP1-NFE2L2-mutant tumors, cCRT and durvalumab significantly reduced the incidence of LRF compared with cCRT alone: 12-month LRF incidence of 62% (95% CI: 40%-*Corresponding author. Disclosure: Dr. Shaverdian reports receiving research funding from Novartis. Dr. Offin reports having advisory role for PharMar, Novartis, and Targeted Oncology and receiving honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. Dr. Shepherd reports receiving honoraria from ASCO. Dr. Simone II reports receiving honoraria from Varian Medical Systems. Dr. Wu reports receiving research support from CivaTech Oncology, Inc., nonfinancial support from AlphaTau Medical, personal fees from MoreHealth, and personal fees from AstraZeneca. Dr. Hellmann reports receiving personal fees from Genentech, Mirati, Syndax, Nektar, Blueprint Medicines, and Merck; grants, personal fees, and nonfinancial support from Bristol-Myers Squibb; personal fees and nonfinancial support from AstraZeneca; and personal fees and equity from Shattuck Labs and Immunai;

Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer

“…Shaverdian et al. reported that histology and PD-L1 expression ≥ 1% were not associated with locoregional control in 66 patients with stage III NSCLC who received CCRT and consolidation durvalumab [ 8 ]. In contrast, our study showed that CCRT with consolidation durvalumab decreased DM as an initial recurrence, and was significantly associated with improved PFS among patients with squamous cell carcinoma or PD-L1 expression < 1% compared with CCRT without durvalumab, whereas LR, especially IF, remained high.…”

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab

“…41 Uniform dose escalation to all patients does not offer clinical benefit in part due to increased toxic effects at higher radiotherapy doses. 42,43 While the addition of consolidative durvalumab improves outcomes, including a reduction in LRF, 13,44,45 we still observed a 31% risk of LRF at 24 months.…”

“…8 Pathogenic alterations in the KEAP1/NFE2L2 pathway are known to confer resistance to radiation therapy, [9][10][11][12] although we have previously found that patients treated with cCRT and durvalumab with KEAP1/NFE2L2-altered tumors have an attenuated risk of local failure compared with receipt of cCRT alone. 13 In this study, we sought to reassess this finding with a larger patient cohort and longer follow-up and to increase the sensitivity of this analysis by only comparing patients with functionally significant pathogenic alterations as categorized by OncoKB. OncoKB is the first FDA-recognized tumor mutational database 14 and contains evidence-based categorizations regarding the functional significance of somatic variants and structural alterations.…”

The Landscape of Immunotherapy Resistance in NSCLC

“…Furthermore, in an exploratory analysis of the KEYNOTE-042 trial comparing single-agent pembrolizumab to chemotherapy, STK11 mutations did not appear to impact the efficacy of ICIs, while they were associated with a worse prognosis in the chemotherapy cohort ( 26 ). KEAP1 mutations are also quite common and have been associated with poor prognosis, but there is conflicting evidence regarding their interaction with immunotherapy ( 27 , 28 ). Common co-occurring mutations involving KEAP1, PBRM1, SMARCA4 , and STK11 may synergistically explain immunogenomic differences acting against immune response ( 29 ).…”