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Journal of Clinical Oncology : Official... Oct 2023This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel...
First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.
PURPOSE
This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.
RESULTS
Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression.
CONCLUSION
Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.
Topics: Adult; Humans; Carcinoma, Non-Small-Cell Lung; Immunoconjugates; Trophoblasts; Antibodies, Monoclonal, Humanized; Lung Neoplasms; Antineoplastic Agents; Antigens, Surface
PubMed: 37327461
DOI: 10.1200/JCO.23.00059 -
Journal of Feline Medicine and Surgery Aug 2023Feline chronic gingivostomatitis (FCGS) is a debilitating disease for cats and a challenge for veterinarians and cat caregivers alike. Recent literature indicates that... (Review)
Review
PRACTICAL RELEVANCE
Feline chronic gingivostomatitis (FCGS) is a debilitating disease for cats and a challenge for veterinarians and cat caregivers alike. Recent literature indicates that the disease is immune-mediated in nature and likely associated with a chronic viral infection in patients with higher alpha diversity of their subgingival microbiome. The immune-mediated nature of FCGS includes both local as well as systemic effects, and the transcriptomic analysis of affected patients supports these findings.
TREATMENT OPTIONS
Localized therapy in the form of surgical extraction of all, or nearly all, teeth continues to be the mainstay of treatment. For cats that do not respond to surgical management, medical management, in the form of immunosuppressive or immunomodulatory therapy, remains an option. Analgesia is of fundamental importance. Immunomodulation utilizing mesenchymal stromal cell therapy provides an alternative treatment avenue for refractory patients and likely targets the chronic viral infection present in this disease. The potential for treatment stratification and use of novel systemic treatment options may be revealed as the molecular pathways involved in this disease are better described.
AIMS
This review outlines current and emerging concepts linking available science pertaining to FCGS and clinical management of the disease.
EVIDENCE BASE
The article draws on the best evidence base at this juncture and is also driven by the authors' collective experience of working on the disease for over a decade.
Topics: Cats; Animals; Stomatitis; Pain Management; Cat Diseases
PubMed: 37548475
DOI: 10.1177/1098612X231186834 -
Journal of Thoracic Oncology : Official... Sep 2023In ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses... (Randomized Controlled Trial)
Randomized Controlled Trial
Three-Year Safety, Tolerability, and Health-Related Quality of Life Outcomes of Adjuvant Osimertinib in Patients With Resected Stage IB to IIIA EGFR-Mutated NSCLC: Updated Analysis From the Phase 3 ADAURA Trial.
INTRODUCTION
In ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses of three-year safety, tolerability, and health-related quality of life (HRQoL) from ADAURA.
METHODS
Patients were randomized 1:1 to osimertinib 80 mg or placebo once daily for up to 3 years. Safety assessments were performed at baseline, week 2, week 4, week 12, and every 12 weeks until treatment completion or discontinuation, and 28 days after treatment was stopped. The SF-36 survey measured HRQoL at baseline, week 12, week 24, and every 24 weeks until recurrence, treatment completion or discontinuation. Data cutoff: April 11, 2022.
RESULTS
Safety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0-38) versus 25.1 (0-39) months. Most adverse events (AEs) were first reported within 12 months of starting treatment (osimertinib 97%, placebo 86%). AEs leading to dose reduction, interruption or discontinuation were reported in 12%, 27% and 13% respectively of patients with osimertinib; 1%, 13% and 3% with placebo. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption; interstitial lung disease was the most common leading to osimertinib discontinuation (per protocol). There were no differences in time to deterioration for SF-36 physical, mental component summaries between osimertinib and placebo.
CONCLUSIONS
No new safety signals were reported and HRQoL was maintained with 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB to IIIA EGFR-mutated NSCLC.
Topics: Humans; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Quality of Life
PubMed: 37236398
DOI: 10.1016/j.jtho.2023.05.015 -
Emerging Microbes & Infections Dec 20235-Methylcytosine (mC) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes...
5-Methylcytosine (mC) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical mC methyltransferase, negatively regulates type I interferon responses during various viral infections, including SARS-CoV-2. NSUN2 specifically mediates mC methylation of mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 enhanced type I interferon and downstream ISGs during various viral infection . And , the antiviral innate response is more dramatically enhanced in mice than in mice. The highly mC methylated cytosines in mRNA were identified, and their mutation enhanced cellular mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), or Zika virus (ZIKV) resulted in a reduction of endogenous NSUN2 levels. Especially, SARS-CoV-2 infection (WT strain and BA.1 omicron variant) also decreased endogenous levels of NSUN2 in COVID-19 patients and K18-hACE2 KI mice, further increasing type I interferon and downstream ISGs. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of mRNA, while endogenous NSUN2 levels decrease during SARS-CoV-2 and various viral infections to boost antiviral responses for effective elimination of viruses.
Topics: Animals; Mice; Interferon Type I; Interferon-beta; Methylation; Zika Virus Infection; Zika Virus; COVID-19; Mice, Knockout; SARS-CoV-2; Virus Diseases; Antiviral Agents; Immunity, Innate; Interferon Regulatory Factor-3
PubMed: 36748584
DOI: 10.1080/22221751.2023.2178238 -
Science Advances Sep 2023Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode...
Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.
Topics: Animals; Mice; Immunity, Innate; Antiviral Agents; Endoplasmic Reticulum; Mice, Knockout; Mitochondria; Interferon Type I; Micropeptides
PubMed: 37656786
DOI: 10.1126/sciadv.adg7053