Journal of Thoracic Oncology最新文献

Introduction: In the first interim analysis of the phase 3 ADRIATIC trial, consolidation durvalumab significantly improved overall survival and progression-free survival (primary endpoints) versus placebo in patients with limited-stage small-cell lung cancer (LS-SCLC) without disease progression after concurrent chemoradiotherapy (cCRT). We report the patient-reported outcomes.

Methods: Patients received durvalumab, durvalumab-tremelimumab, or placebo every 4 weeks for up to 24 months. Patient-reported global health status/quality of life (GHS/QoL), functioning, and symptoms, assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30/Questionnaire-Lung Cancer 13 (secondary endpoints), are reported for durvalumab and placebo only; the durvalumab-tremelimumab arm remained blinded at this analysis. Change from baseline (for prespecified key scales), time to deterioration (TTD), and improvement rates (all scales) were examined. A score change of ≥10 from baseline was considered a clinically meaningful deterioration/improvement. Analyses were not alpha-controlled.

Results: In both arms (durvalumab, n=264; placebo, n=266), mean score changes in prespecified key scales from baseline up to 24 months were small and not clinically meaningful. There were no between-arm differences in TTD except for arm/shoulder pain (longer with durvalumab versus placebo [median TTD: 25.7 versus 9.1 months; HR: 0.70 (95% CI: 0.51-0.94)]) and similar improvement rates between arms for most scales; a higher improvement rate for chest pain was observed with durvalumab versus placebo (odds ratio: 2.28 [95% CI: 1.08-4.95]).

Conclusions: Consolidation durvalumab following cCRT did not compromise patients' GHS/QoL, functioning, or symptoms versus placebo, further supporting this treatment regimen as the new standard of care for LS-SCLC.

Introduction: Outcomes in unresected locally advanced NSCLC (LA-NSCLC) are poor despite improvement with immunotherapy after concurrent chemoradiation (cCRT). Although KRAS is the most common mutated oncogene in NSCLC, its impact on outcomes in LA-NSCLC treated with cCRT and durvalumab remains underexplored.

Methods: We conducted a multicenter retrospective analysis of patients with stage III nonsquamous NSCLC treated with definitive cCRT followed by durvalumab. Progression-free survival (PFS) and incidence of distant metastasis and locoregional recurrence were compared by KRAS status. Of patients who underwent next-generation sequencing, we assessed the impact of co-alterations on PFS.

Results: Among 208 consecutive patients, 117 had KRAS wild-type (WT) and 91 had KRAS-mutant disease. Median PFS was shorter for those with KRAS-mutant disease compared with those with KRAS WT (16 versus 28 mo, p = 0.024). KRAS mutations were associated with worse PFS on univariable and multivariable analyses. There was an increased incidence of distant metastasis for patients with KRAS-mutant disease compared with patients with KRAS WT disease (2 y, 44% versus 34%, p = 0.042), including increased brain metastasis incidence (p = 0.007). Among KRAS-mutant tumors, co-alterations with CDKN2A or STK11 were associated with worse PFS compared with KRAS WT, whereas KRAS mutations without CDKN2A or STK11 co-alterations were not.

Conclusions: KRAS-mutant nonsquamous LA-NSCLC is associated with inferior outcomes, largely driven by increased distant and brain metastases. Tumors with concurrent CDKN2A or STK11 alterations had the poorest outcomes. These findings support the evaluation of KRAS inhibitors in this high-risk stage III population.

BRAF mutations are detected in approximately 3% to 8% of patients with NSCLC. In contrast to melanoma, in which most BRAF mutations occur at the V600 codon, only approximately 35% of BRAF-mutant NSCLC tumors harbor V600 mutations. Among the remaining cases, 60% to 70% present non-V600 mutations, primarily in exons 11 and 15. BRAF mutations are classified into three classes according to their kinase activity and their dependence on RAS activation. Compared with class I (V600), patients with class II and class III mutations are associated with poorer clinical outcomes partly due to the lack of effective targeted therapeutic strategies. Indeed, although dual BRAF and MEK inhibition has demonstrated clinical benefit in BRAF V600-mutant NSCLC, there is currently no consensus on treatment strategies for patients with class II and class III mutations. Beyond point mutations, other BRAF alterations (e.g., gene fusions, deletions, and amplifications) have been identified in treatment-naive tumors and in the context of acquired resistance to targeted therapies in other oncogene-driven NSCLC subtypes. However, the biology and clinical implications of these alterations remain poorly characterized. In this review, we provide a comprehensive overview on the biology, epidemiology, and therapeutic strategies of class II/III BRAF mutations, fusions, deletions, and amplifications in NSCLC. We highlight current challenges in the clinical management of BRAF-mutant NSCLC, emerging inhibitors, and combinatorial therapeutic strategies developed to treat non-V600E BRAF-driven cancers. Finally, we briefly discuss BRAF alterations in the context of resistance to targeted therapies in other oncogene-driven NSCLC.