First-line tislelizumab plus chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in advanced squamous non-small-cell lung cancer (sq-NSCLC) at the interim analysis of the phase III RATIONALE-307 trial. We present the final analysis of this trial. Patients with treatment-naive, stage IIIB/IV, sq-NSCLC were randomized (1 : 1: 1) to 21-day cycles of i.v.: tislelizumab plus paclitaxel and carboplatin (arm A); tislelizumab plus nab-paclitaxel and carboplatin (arm B); or paclitaxel and carboplatin (arm C). The primary endpoint was independent review committee-assessed PFS; overall survival was a secondary endpoint. In total, 360 patients were randomized; 355 received treatment. At the final analysis (median study follow-up: 16.7 months), tislelizumab plus chemotherapy had a manageable safety profile, consistent with that at the interim analysis. Improvement in PFS was maintained for arms A and B versus C {hazard ratio (HR) 0.45 [95% confidence interval (CI) 0.33-0.62] and 0.43 (95% CI 0.31-0.60), respectively}. Overall survival HRs for arms A and B versus C were 0.68 (95% CI 0.46-1.01) and 0.75 (95% CI 0.50-1.12), respectively. The RATIONALE-307 final analysis demonstrated superior clinical benefit with addition of tislelizumab to chemotherapy, and a manageable safety profile, as first-line treatment of advanced sq-NSCLC.

Aberrant expression of claudin18.2 (CLDN18.2) has frequently been observed in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, making it a promising therapeutic target for this aggressive cancer. While a monoclonal antibody targeting CLDN18.2 has been approved for G/GEJ adenocarcinoma, antibody–drug conjugates (ADCs) have also emerged as therapeutic modalities. IBI343 is an ADC consisting of a fully humanized anti-CLDN18.2 monoclonal antibody conjugated to exatecan via site-specific glycol conjugation and a cleavable linker with a drug-to-antibody ratio of 4. Here we present the results from a phase 1 dose escalation and dose expansion study of the IBI343 ADC. A total of 127 patients were enrolled and dosed (19 in the escalation phase and 108 in the expansion phase). Dose-limiting toxicities occurred in two of six participants at a dose of 10 mg kg⁻¹, including one with myelosuppression (grade 4) and one with both neutropenia (grade 4) and febrile neutropenia (grade 3). Minimal gastrointestinal adverse events (grade ≥3) were observed and no interstitial lung disease was reported. The recommended phase 2 dose of IBI343 was determined to be 6 mg kg⁻¹ every 3 weeks with a confirmed objective response rate of 29% and median progression-free survival of 5.5 months in CLDN18.2-high (2+/3+ ≥ 75%) G/GEJ adenocarcinoma. IBI343 was well tolerated, with a manageable safety profile and promising efficacy in G/GEJ adenocarcinoma. Further research is required to understand optimal sequencing, and biomarker-informed combination therapy, in G/GEJ tumors given the development of multiple therapies targeting CLDN18.2 in addition to human epidermal growth factor receptor 2 and programmed cell death 1 ligand 1. ClinicalTrials.gov registration: NCT05458219.

Research on patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed on immunotherapy remains limited. BL-B01D1 is a first-in-class antibody–drug conjugate consisting of an EGFR–HER3 bispecific antibody bound to a topoisomerase I inhibitor (Ed-04) payload via a cleavable linker. Here, we present safety and efficacy data from a phase 1 study of BL-B01D1, in 82 patients previously treated for ESCC. The primary endpoint was the recommended phase 2 dose. Administered doses were 2.0 (n = 22) and 2.5 (n = 60) mg kg⁻¹ D1D8 infusion every 3 weeks (Q3W). The confirmed objective response rate (cORR) was 29.3% (24 of 82) in all patients and 32.9% (24 of 73) among evaluable patients. For patients dosed at 2.5 mg kg⁻¹, cORR was 39.6% (21 of 53) and disease control rate was 79.2% (42 of 53). In the 2.0 mg kg⁻¹ group, cORR was 15.0% (3 of 20), and the disease control rate was 50.0% (10 of 20). The phase 2 dose was established at 2.5 mg kg⁻¹ D1D8 Q3W. The incidence of G3 treatment-related adverse events at 2.5 mg kg⁻¹ was 63.3%; most common adverse events were anemia (28.3%), leukopenia and thrombocytopenia (18.3%, each), and neutropenia (16.7%). Two cases of ≥G3 interstitial lung disease were observed. Overall, BL-B01D1 demonstrated promising efficacy and manageable safety in patients with metastatic ESCC. A further phase 3 clinical trial has already been initiated. ClinicalTrials.gov registration: NCT05262491.

Visceral fat is considered the genuine and harmful white adipose tissue (WAT) that is associated to development of metabolic disorders, cardiovascular disease, and cancer. Here, we present a new concept to turn the harmful visceral fat into a beneficial energy consumption depot, which is beneficial for improvement of metabolic dysfunctions in obese mice. We show that low temperature–dependent browning of visceral fat caused decreased adipose weight, total body weight, and body mass index, despite increased food intake. In high-fat diet–fed mice, low temperature exposure improved browning of visceral fat, global metabolism via nonshivering thermogenesis, insulin sensitivity, and hepatic steatosis. Genome-wide expression profiling showed upregulation of WAT browning–related genes including Cidea and Dio2 . Conversely, Prdm16 was unchanged in healthy mice or was downregulated in obese mice. Surgical removal of visceral fat and genetic knockdown of UCP1 in epididymal fat largely ablated low temperature–increased global thermogenesis and resulted in the death of most mice. Thus, browning of visceral fat may be a compensatory heating mechanism that could provide a novel therapeutic strategy for treating visceral fat–associated obesity and diabetes.

MiRNAs are small single-stranded non-coding RNAs. MiRNA contributes to the transcriptional and post-transcriptional regulation of mRNA in different cell types, including mRNA transcription inhibition and mRNA decay and phenotypes via the effect of several essential oncogenic processes and tumor microenvironment. MiR-101 is a highly conserved miRNA that was found to alter the expression in various human cancers. MiR-101 has been reported to have tumor oncogenic and suppressive effects to regulate tumorigenesis and tumor progression. In this review, we summarize the new findings about the roles of miR-101 in cancers and the underlying mechanisms of targeting genes degradation and microenvironment regulation, which will improve biological understanding and design of novel therapeutics.

PURPOSE: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022 ) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non–small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertion mutations (exon20ins). METHODS: Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)–assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR). RESULTS: Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance ( P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%). CONCLUSION: Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.