The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRAS^WT) and KRAS^G12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRAS^G12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRAS^G12D-mutant tumors in vivo. Our findings reveal a KRAS^G12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.

Herein, we characterize the landscape and prognostic significance of the T cell receptor (TCR) repertoire of early-stage non–small cell lung cancer (NSCLC) for patients with an epidermal growth factor receptor ( EGFR ) mutation. β Chain TCR sequencing was used to characterize the TCR repertoires of paraffin-preserved pretreatment tumor and tumor-adjacent tissues from 57 and 44 patients with stage II/III NSCLC with an EGFR mutation treated with gefitinib or chemotherapy in the ADJUVANT-CTONG 1104 trial. The TCR diversity was significantly decreased in patients with an EGFR mutation, and patients with high TCR diversity had a favorable overall survival (OS). A total of 10 TCR Vβ-Jβ rearrangements were significantly associated with OS. Patients with a higher frequency of Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, Vβ24-1Jβ2-1, and Vβ29-1Jβ2-7 had significantly longer OS. Weighted combinations of the 4 TCRs were significantly associated with OS and disease-free survival (DFS) of patients, which could further stratify the high and low TCR diversity groups. Importantly, Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, and Vβ24-1Jβ2-1 had a significant relationship with gefitinib treatment, while Vβ29-1Jβ2-7 was associated with chemotherapy. Four TCR Vβ-Jβ rearrangements related to favorable OS and DFS for adjuvant gefitinib and chemotherapy in patients with an EGFR mutation with stage II/III NSCLC; this may provide a novel perspective for the adjuvant setting for resectable NSCLC.