Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): Subgroup analysis from TROPION-Lung02.
8617 Background: Dato-DXd is an antibody-drug conjugate (ADC) composed of an anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. We report updated findings from TROPION-Lung02 (NCT04526691) evaluating Dato-DXd plus pembro with or without Pt-CT as 1L therapy for aNSCLC. Methods: Patients (Pts) received Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with Pt-CT (triplet; cisplatin 75 mg/m2 or carboplatin AUC 5) Q3W across 6 cohorts. Pts in the expansion stage were primarily treatment (tx)-naïve. PD-L1 expression was evaluated by tumor proportion score (TPS < 50% or ≥50%) using immunohistochemistry (22C3 assay). The primary objectives were safety and tolerability, with efficacy a secondary objective. Results: 96 pts were treated with doublet (n = 42) or triplet (n = 54) therapy in the 1L setting. At data cutoff (Oct 31, 2023), 45% and 20% of pts receiving doublet or triplet tx were ongoing. Median age was 66 years in both subgroups. Median treatment durations were 6.6 and 5.8 months. Across doublet and triplet tx, the most common any-grade (Gr) treatment-emergent adverse events (TEAEs) were stomatitis (57%, 33%) and nausea (40%, 46%), mainly Gr 1–2. Gr ≥3 TEAEs were seen in 57% and 76% of pts; serious TEAEs in 38% and 44%. TEAEs associated with Dato-DXd discontinuation occurred in 29% and 39% of pts receiving doublet or triplet tx. TEAEs associated with death were seen in 2% and 9%, none considered related to study drug. Efficacy outcomes, including ORR and preliminary PFS, in the 1L setting overall and by PD-L1 status are summarized in the Table. Conclusions: As 1L therapy for aNSCLC, Dato-DXd plus pembro with or without Pt-CT continues to demonstrate durable antitumor activity. Efficacy was observed regardless of PD-L1 expression. Tolerability of the combinations was as expected based on known profiles of the individual agents, with no new safety signals observed. To date, this is the largest dataset reported for any ADC combined with an anti-PD-1/L1 agent in the 1L setting for aNSCLC. Clinical trial information: NCT04526691 . [Table: see text]
International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors
Abstract Background Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology‐based topics spanning the field. Methods In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence‐Based Review with Recommendations, Evidence‐Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses format, and completed sections underwent a thorough and iterative consensus‐building process. The final document underwent rigorous synthesis and review prior to publication. Results The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology‐based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. Conclusion As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.
TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC).
9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable tetrapeptide-based cleavable linker. Dato-DXd had encouraging efficacy and manageable safety in heavily pretreated aNSCLC. Dato-DXd + immunotherapy yielded greater preclinical activity than either agent alone. Methods: TROPION-Lung02 (NCT04526691) is a phase 1b, global, dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) + pembro 200 mg ± Pt-CT (cisplatin 75 mg/m2 or carboplatin AUC 5) every 21 days across 6 cohorts. Pts in escalation may have received ≤2 prior lines of therapy for aNSCLC. Pts in expansion were primarily treatment (tx) naive (pts receiving Dato-DXd + pembro may have ≤1 prior Pt-based tx). The primary objective is to assess safety and tolerability, including dose-limiting toxicities (DLTs). Secondary objectives include evaluation of efficacy, pharmacokinetics, and immunogenicity. Results: As of the Oct 31, 2022, data cutoff (DCO), 120 pts were treated. All cohorts met DLT criteria to move to escalation. Median age was 65 years. PD-L1 expression was <1%, 1%-49%, and ≥50% in 40%, 33%, and 26% of pts, respectively. Median tx duration was 4.6 mo, with 55% receiving tx at DCO. The most frequent any-grade (gr) tx-emergent adverse events (TEAEs) were nausea (45%) and stomatitis (45%). Gr ≥3 TEAEs occurred in 61% of pts; most frequent were neutrophil count decreased (8%) and amylase increased (8%). TEAEs that were serious, associated with discontinuation, or associated with death occurred in 31%, 24% (16% associated with Dato-DXd), and 6% of pts, respectively. Dose reductions due to TEAEs associated with Dato-DXd occurred in 17%. Drug-related interstitial lung disease occurred in 12 pts (10%; 9 gr 1/2; 3 gr 3). The objective response rate (ORR) with 1L Dato-DXd + pembro doublet and Dato-DXd + pembro + Pt-CT triplet tx was 60% (95% CI, 36%-81%; 12 [2 unconfirmed]/20) and 55% (95% CI, 39%-70%; 23 [5 unconfirmed]/42), respectively. The ORR for any line of therapy was 38% (95% CI, 25%-54%; 18 [2 unconfirmed]/47) with doublet and 47% (95% CI, 34%-60%; 28 [5 unconfirmed]/60) with triplet tx. In both subsets, the disease control rate was 85% and median duration of response was not reached. Responses were observed in all 3 PD-L1 expression level subgroups. Although immature, median progression-free survival (95% CI) was 10.8 (8.3-15.2) and 7.8 mo (5.5-NE) with doublet and triplet tx, respectively. Conclusions: Dato-DXd + pembro ± Pt-CT demonstrated tolerable safety with notable 1L activity in this first and largest dataset with an ADC + immunotherapy ± Pt-CT in aNSCLC pts. Clinical trial information: NCT04526691 .
Comparison of synchronization between left bundle branch and his bundle pacing in atrial fibrillation patients: An intra‐patient‐controlled study
AbstractBackgroundHis bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique.ObjectiveTo evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF).MethodsConsecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation.ResultsBoth HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5 vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3 vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2 vs. 3.1 ± 12.7 ms, p < .01; Ts‐LV‐RV, 37.9 ± 10.7 vs. 18.5 ± 10.8 ms, p < .001).ConclusionsAlthough LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Human papillomavirus (HPV)–related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors’ files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions ofMYB,NFIB, andMYBL1was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested forMYB,MYBL1, orNFIBgene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.
Sequence analysis of EBV immediate-early gene BZLF1 and BRLF1 in lymphomas