Period2 (Per2) is a key circadian clock gene, and its deregulation contributes to tumour development, including breast cancer. However, the biological function and clinicopathological significance of Per2 in non-small cell lung cancer (NSCLC) remain unclear. The present study aimed to explore the role of Per2 and its relative clinical significance in NSCLC. To analyse Per2 expression in NSCLC specimens, reverse transcription-quantitative polymerase chain reaction was performed, and the results indicated that Per2 expression was markedly downregulated in 83.87% (26/31) of NSCLC samples compared with their adjacent matched tissues. Increased Per2 expression was associated with increased differentiation (P<0.01) and reduced lymph node metastasis (P<0.0001). Functional studies identified that enhancing Per2 expression in A549 cells by lentivirus transduction not only significantly suppressed cell growth, migration and invasion (P<0.05) but also inhibited NSCLC growth and metastasis in vivo. Animal studies and histopathological analysis identified that Per2 expression in A549 cells not only markedly increased expression of tumour anti-oncogenes Bax, P53 and P21 but also inhibited expression of pro-oncogenes vascular endothelial growth factor, CD44 and c-Myc. These results indicate that the loss of Per2 is one of the factors underlying tumourigenesis in NSCLC, and it may function as a novel molecular target for NSCLC.

Aim: To study the expression profile of NFIX, its prognostic value and the mechanism of its dysregulation in lung adenocarcinoma (LUAD). Patients & materials: A retrospective study was performed by using data from the Cancer Genome Atlas and the Human Protein Atlas. Results: High NFIX RNA expression was an independent prognostic factor of favorable overall survival (HR: 0.687, 95% CI: 0.496–0.951; p = 0.024) and recurrence-free survival (HR: 0.700, 95% CI: 0.493–0.994, p = 0.046) in LUAD, but not in lung squamous cell carcinoma. NFIX DNA hypermethylation was associated with significantly decreased NFIX expression and shorter overall survival and recurrence-free survival in LUAD. Conclusion: NFIX downregulation might independently predict poor prognosis in LUAD. DNA hypermethylation might be an important cause of the downregulation.

PURPOSE: Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non–small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2, ClinicalTrials.gov identifier: NCT04129502 ) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC. METHODS: Patients with treatment-naive EGFR ex20ins+ locally advanced/metastatic NSCLC were randomly assigned 1:1 to mobocertinib 160 mg once daily or pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by maintenance pemetrexed. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR), with planned interim analysis (IA) after approximately 70% of 227 expected PFS events. RESULTS: A total of 354 patients were randomly assigned (mobocertinib: n = 179; chemotherapy: n = 175). Baseline characteristics were balanced between arms. At IA (cutoff: April 4, 2023), the median PFS per BICR was 9.6 months in each treatment arm (hazard ratio [HR], 1.04 [95% CI, 0.77 to 1.39]; P = .803). The primary end point crossed the prespecified futility boundary (HR > 1). The confirmed objective response rate (95% CI) per BICR was 32% (26 to 40) with mobocertinib versus 30% (24 to 38) with chemotherapy; the median duration of response was 12.0 versus 8.4 months. Quality-of-life assessments indicated clinically meaningful delays in time to deterioration of lung cancer symptoms, cognitive function, and constipation with mobocertinib versus chemotherapy. Grade ≥3 adverse events in >5% of patients (mobocertinib, chemotherapy) were diarrhea (20%, 1%), anemia (6%, 10%), increased lipase (6%, 0%), and decreased neutrophil count (1%, 7%). CONCLUSION: The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.

Differently from epidermal growth factor receptor (EGFR) 19Del and L858R mutations, the panoramic description of uncommon EGFR mutations is far from mature. Our understanding of its population characteristics, treatment response, and drug resistance mechanisms needs urgent expansion and deepening. Our study enrolled 437 patients with non–small‐cell lung cancer from four clinical centers and who had uncommon EGFR mutations. The clinical characteristics of all patients and the treatment outcomes of 190 advanced patients who received pharmacotherapy were analyzed. Moreover, the acquired resistance mechanisms were explored based on 53 tissue or liquid re‐biopsy data in 45 patients. Patients with EGFR 20ins had a shorter survival time compared with patients with non‐20ins mutations. In total, 149 cases had received EGFR‐tyrosine kinase inhibitors (TKI); afatinib was significantly superior to other EGFR‐TKIs both in ORR and mPFS in all uncommon mutations and especially in the L861Q group. The most common acquired drug resistance mechanism was MET amplification, followed by EGFR T790M, which was significantly different from common EGFR mutations.

This phase Ib study was designed to assess the safety/tolerability and preliminary antitumor activity of neoadjuvant low-dose radiotherapy (LDRT) plus durvalumab and chemotherapy for potentially resectable stage III non-small-cell lung cancer (NSCLC). Eligible patients received dose-escalated radiotherapy (10 Gy in 5 fractions [cohort 1], 20 Gy in 10 fractions [cohort 2], and 30 Gy in 15 fractions [cohort 3]) according to a 3 + 3 design, with concurrent durvalumab plus standard chemotherapy for two cycles. Primary objective was safety/tolerability. Secondary objectives included major pathological response (MPR), pathological complete response (pCR), event-free survival (EFS), and exploratory biomarker analysis. Nine patients were enrolled and completed the planned neoadjuvant therapy. No dose-limiting toxicity was recorded. Grade 3-4 treatment-related adverse events were observed in three (33.3 %) patients. Seven (77.8 %) patients successfully converted to resectable cases with R0 resection. No treatment-related surgical delay or death was reported. The MPR and pCR rates were both 33.3 % % (1/3) for cohort 1, 66.7 % (2/3) and 0.0 % for cohort 2, and 100.0 % (3/3), and 66.7 % (2/3) for cohort 3. At data cutoff, the 12 month-EFS rates were 33.3 %, 66.7 %, and 100 % for three cohorts, respectively. By biomarker analysis, TMB values were higher in either pathologically or radiologically responders than in others (all p > 0.05). Neoadjuvant LDRT plus durvalumab and chemotherapy was well-tolerated in potentially resectable stage III NSCLC. The preliminary efficacy supports this combined regimen's potential, the optimal radiotherapy dosage was determined to be 30 Gy in 15 fractions, warranting further clinical investigation.