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Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1-51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 (ClinicalTrials.gov).

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

PURPOSE: Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set. METHODS: The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). P values were adjusted for multiple testing and considered significant at Q < 0.05 (molecular comparisons) or Q < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis. RESULTS: The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). FGFR2 fusion (15.7% in eoBTC v 5.9% in aoBTC) and NIPBL fusion (1.1% v 0%) were significantly more prevalent in eoBTC (both Q < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; Q = 0.01) and T-cell inflammation score (FC, 17.3; Q = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; Q = 0.16), whereas IFG (NES = –1.58; Q = 0.06) and inflammatory response (NES = –1.46; Q = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, P =.004. The median OS by FGFR2 fusion (with fusion v without) was 21.7 versus 15.0 months (P =.47) for eoBTC and 18.6 versus 12.2 months (P <.001) for aoBTC. CONCLUSION: We identified crucial differences including higher prevalence of FGFR2 fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the FGFR2 fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets. Multiomic analysis shows higher FGFR2 fusions and #immunotherapy marker variations in early-onset biliary cancer [ABSTRACT FROM AUTHOR]

Background: Pamiparib is a potent, selective, poly (ADP‐ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two‐stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Methods: Oral pamiparib 60 mg was administered twice daily. During the dose‐escalation stage, increasing doses of TMZ (40–120 mg once daily pulsed or 20–40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose‐expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Results: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7‐day pulsed 60 mg once daily. The most common treatment‐emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose‐escalation stage, four patients experienced dose‐limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression‐free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Conclusions: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted. [ABSTRACT FROM AUTHOR]

The rapid advancement of deepfake technology presents significant challenges in detecting highly convincing fake videos, posing risks such as misinformation, identity theft, and privacy violations. In response, this paper proposes an innovative approach to deepfake video detection by integrating features derived from ant colony optimization–particle swarm optimization (ACO-PSO) and deep learning techniques. The proposed methodology leverages ACO-PSO features and deep learning models to enhance detection accuracy and robustness. Features from ACO-PSO are extracted from the spatial and temporal characteristics of video frames, capturing subtle patterns indicative of deepfake manipulation. These features are then used to train a deep learning classifier to automatically distinguish between authentic and deepfake videos. Extensive experiments using comparative datasets demonstrate the superiority of the proposed method in terms of detection accuracy, robustness to manipulation techniques, and generalization to unseen data. The computational efficiency of the approach is also analyzed, highlighting its practical feasibility for real-time applications. The findings revealed that the proposed method achieved an accuracy of 98.91% and an F1 score of 99.12%, indicating remarkable success in deepfake detection. The integration of ACO-PSO features and deep learning enables comprehensive analysis, bolstering precision and resilience in detecting deepfake content. This approach addresses the challenges involved in facial forgery detection and contributes to safeguarding digital media integrity amid misinformation and manipulation. [ABSTRACT FROM AUTHOR]

Simple Summary: In the era of precision medicine, translational oncology seeks to identify new, targeted therapies for tumors with rare genetic mutations. Patients receiving targeted therapy are known to have better outcomes (i.e., live longer and better) compared to those receiving non-targeted therapies. In this analysis, we retrospectively analyzed 63,873 tumor tissues to better understand the rare HRAS mutation. We found that only 0.8% of tumors are HRAS mutant, and these tumors look different at the molecular level and behave differently on a clinical level. Targeted therapies for patients with HRAS mutations, such as tipifarnib, currently exist and are being tested in various tumor types. Our study seeks to add to the limited information currently known about this rare genetic mutation. Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design. [ABSTRACT FROM AUTHOR]