tbuckley/cabot-search huggingface dataset:
REZILIENT2: Phase 2 study of zipalertinib in patients with advanced non-small cell lung cancer (NSCLC) with exon 20 insertions (ex20ins) and other uncommon epidermal growth factor receptor (<i>EGFR</i>) mutations.
Authors: Helena Alexandra Yu, Benjamin Besse, Makoto Nishio, Ying Cheng, Li Wei, Volker Wacheck, John Heymach
Journal: Journal of Clinical Oncology (2024)

TPS8670 Background: Patients with NSCLC harboring uncommon EGFR mutations, including ex20ins, have limited treatment options. Zipalertinib (CLN-081/TAS6417) is an oral tyrosine kinase inhibitor of EGFR with broad activity against EGFRmutations (including ex20ins) and increased selectivity for ex20ins versus wild-type EGFR. Zipalertinib has shown preclinical activity against a wide spectrum of EGFR ex20ins mutations and other uncommon EGFR mutations. In a phase 1/2a study (REZILIENT1), encouraging antitumor activity and an acceptable safety profile were observed in heavily pretreated patients with EGFRex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation from the U.S. Food and Drug Administration. The aim of REZILIENT2 is to evaluate the efficacy and safety of zipalertinib in patients with NSCLC harboring EGFRex20ins and other uncommon single or compound EGFR mutations, including patients with brain metastases and leptomeningeal disease (LMD). Methods: In this global, phase 2b, open-label, multicohort study (NCT05967689), adult patients with locally advanced or metastatic NSCLC will be assigned to one of four cohorts depending on prior treatment and type of EGFR mutation: A) patients with EGFR ex20ins mutations who have progressed on or after first-line platinum-based chemotherapy and prior therapy targeting ex20ins (administered together or separately) for advanced disease; B) patients with EGFR ex20ins mutations who have not received prior treatment for advanced disease; C) patients with ex20ins or other uncommon single or compound EGFR mutations and active central nervous system metastases (including LMD) who may or may not have received prior treatment for advanced disease; and D) patients harboring other uncommon non-ex20ins single or compound EGFR mutations who have progressed on or after standard systemic therapy. Patients will receive zipalertinib at a starting dose of 100 mg orally twice daily, which will continue on a 21-day cycle until progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumours, version 1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (cohort C), safety and tolerability, and pharmacokinetics. Estimated enrollment is 40 patients per cohort (total 160), with potential expansion to ~100 patients per cohort if predefined threshold criteria of efficacy are met. Enrollment began in July 2023. Clinical trial information: NCT05967689 .
Krascendo-170 Lung: A phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated <i>KRAS G12C+</i>advanced non-small cell lung cancer (NSCLC).
Authors: Ferdinandos Skoulidis, Kristof Cuppens, Adrian G. Sacher, Vamsidhar Velcheti, Dae Ho Lee, Mark T. Lin, Tharu M. Fernando, Shuai Li, Denise Bradley, Martina Zarak Crnkovic, Michael Mathisen
Journal: Journal of Clinical Oncology (2024)

TPS8651 Background: The KRAS G12C mutation, present in ~12% of NSCLC patients, drives oncogenic signaling and cancer formation and is associated with poor prognosis. The current first-line treatment for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) ± chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumor activity. We hypothesize that divarasib + CPI ± CT may improve outcomes for patients with KRAS G12C+ NSCLC. Methods: Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumor cell expression ≥1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumor cell expression level (Cohort B). Patients must be ≥18 years old with untreated unresectable/metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRASG12C mutation, and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumor assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterize pharmacokinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Enrollment into the combination dose finding stage of Cohort A has been completed without dose-limiting toxicities and enrollment into the dose expansion stage is continuing. Clinical trial information: NCT05789082 . [Table: see text]
SWOG S2302, PRAGMATICA-LUNG: A prospective randomized study of ramucirumab plus pembrolizumab (PR) versus standard of care (SOC) for participants previously treated with immunotherapy for stage IV or recurrent non-small cell lung cancer.
Authors: Karen L. Reckamp, Mary Weber Redman, Konstantin H. Dragnev, Wade Thomas Iams, Brian S. Henick, Jieling Miao, Michael Leo LeBlanc, Daniel R. Carrizosa, Roy S. Herbst, Charles D. Blanke, Jhanelle E. Gray
Journal: Journal of Clinical Oncology (2024)

TPS8657 Background: Most patients (pts) with advanced non-small cell lung cancer (NSCLC) will receive treatment with immunotherapy and develop tumor resistance. Several trials investigating combination therapy have not shown benefit over chemotherapy. Additional therapeutic options are needed. Complex clinical trials increase barriers to enrollment. Pragmatic trial designs may overcome challenges with accrual and representativeness in the appropriate setting. S1800A was a randomized phase II trial within Lung-MAP that showed a statistically significant improvement in overall survival (OS) with PR versus SOC for pts with advanced NSCLC who had tumor progression on prior chemotherapy and immunotherapy (JCO 2023). As a follow-on, we designed a pragmatic, randomized, registration intent trial to validate OS results and enhance representative accrual reflecting real-world practice. Methods: S2302 is a registration-intent randomized trial for pts who previously received PD-(L)1 inhibitor therapy for at least 84 days and platinum-based therapy, stratified by immediate prior line of therapy including PD-(L)1 inhibition (yes/no) and PS (0/1 v. 2). Pts are randomized to PR or investigator’s choice SOC (recommended to be based on NCCN guidelines). The primary objective is to compare OS between the arms. The only secondary objective is to summarize serious and unexpected high-grade (Grade 3-4) treatment-related adverse events and all Grade 5 adverse events. The accrual goal is 700 pts based on a design with 85% power to detect a hazard ratio of 0.77, using a 1-sided 2.5% level log-rank test. Estimated accrual duration is 24 months. As of January 2024, 286 pts were randomized, and enrollment is ongoing. S2302 Pragmatica-Lung presents a novel and potentially practice-changing paradigm to conduct a study with a combination of FDA approved drugs with well-known safety profiles and limited toxicity overlap. There are no onerous radiology or specimen requirements, and SOC treatment is provided as per FDA-approved package inserts and institutional policies. The goal is to empower practicing clinicians to enroll pts they see every day by reducing the study barriers and burden of clinical trial participation. The resulting pts enrolled will be more representative than other registration-intent trials. This approach allows the trial to reach more patients and holds the potential to better inform the field across a more representative set of pts with broader impact. Clinical trial information: NCT05633602 .
A phase 2 study of EIK1001, a Toll-like receptor 7/8 (TLR7/8) agonist, in combination with pembrolizumab and chemotherapy in patients with stage 4 non-small cell lung cancer.
Authors: Dan Costin, Kevin Chen, Richard J. Gralla, Brage Garofalo, Meihua Wang, Etah Kurland
Journal: Journal of Clinical Oncology (2024)

TPS8667 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response. Significant advances for the treatment of non-small cell lung cancer (NSCLC) have been made using the ICI pembrolizumab in combination with chemotherapy, which confers significant clinical benefit relative to chemotherapy and placebo. Not all patients benefit, however, and some become refractory. As a result, there remains a critical unmet need to develop therapies for the treatment of NSCLC. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study EIK1001-005 is a multicenter, Phase 2, open-label study of EIK1001 in combination with pembrolizumab and chemotherapy – carboplatin plus either pemetrexed or paclitaxel – in participants (pts) with histologically confirmed Stage 4 nonsquamous or squamous NSCLC, respectively. This study includes a safety run-in period for pts enrolled in each NSCLC cohort. If &lt; 2 dose-limiting toxicities occur, an expansion phase for each NSCLC cohort will be conducted at the target dose to evaluate the tolerability and efficacy of EIK1001 (QW) in combination with pembrolizumab and chemotherapy (administered Q3W per label). Key eligibility criteria include pts ≥ 18 years of age with a life expectancy of at least 3 months, histologically or cytologically confirmed Stage 4 NSCLC (nonsquamous or squamous) without prior therapy for advanced NSCLC, confirmation that mutation-directed therapy is not indicated as first-line, and at least 1 measurable lesion at Baseline according to RECIST 1.1. The primary objective of this study is to determine the safety and tolerability of EIK1001 in combination with pembrolizumab and chemotherapy. The secondary objectives are evaluation of antitumor activity by objective response rate (ORR; defined as the proportion of pts who have a confirmed complete response [CR] or partial response [PR] per RECIST 1.1) and duration of response (DOR) by RECIST 1.1. Other exploratory objectives include evaluation of anti-tumor activity (ORR/DOR) by immune-related RECIST 1.1, overall survival, progression-free survival, investigation of the relationship between treatment with EIK1001 in combination with pembrolizumab/chemotherapy and biomarkers predictive of response, and the pharmacokinetic parameters of EIK1001. This study opened on 29 Jan 2024. Clinical trial information: NCT06246110 .
Spiderweb‐Shaped Iron‐Coordinated Polymeric Network as the Novel Coating on Microneedles for Transdermal Drug Delivery Against Infectious Wounds
Authors: Xinwei Fu, Tao Zhang, Chuanlan Xia, Shan Du, Bo Wang, Zhensen Pan, Yunlong Yu, Peng Xue, Bin Wang, Yuejun Kang
Journal: Advanced Healthcare Materials (2024)

Abstract Coated microneedles (CMNs) are a minimally invasive platform for immediate‐release transdermal drug delivery. However, the practical applications of CMNs have been significantly hindered by the challenges associated with complex formulations, single function, and limited drug loading capacity. This study has developed a spiderweb‐shaped iron‐coordinated polymeric nanowire network (Fe‐IDA NWs). The resulting Fe‐IDA NWs are endowed with a certain viscosity due to the synergy of multiple supramolecular interactions. This allows them to replace traditional polymeric thickeners as microneedle coatings. The Fe‐IDA NWs‐coated microneedles (Fe‐IDA MNs) display rapid disintegration in the skin model, which also enables the swift diffusion of Fe‐IDA NWs and their payloads into the deeper skin layers. Additionally, Fe‐IDA MNs exhibit desirable enzymatic activity and potential antibacterial ability. Thus, Fe‐IDA MNs can enhance the therapeutic efficacy against wound infection through synergistic effects, and avoid the overly complicated formulation and the release of nontherapeutic molecules of conventional CMNs. As a proof‐of‐concept, Fe‐IDA MNs loaded with chlorin e6 showed a synergistic chemodynamic‐photodynamic antibacterial effect in a methicillin‐resistant Staphylococcus aureus‐infected wound model in mice. Collectively, this work has significant implications for the future of CMNs‐based transdermal drug delivery systems and expands the application fields of metal coordination polymer (MCP) materials.
Early detection of side effects in patients with metastatic melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [<sup>89</sup>Zr] crefmirlimab berdoxam PET.
Authors: Teresa Amaral, Manfred Kneilling, Andrea Forschner, Ulrike M. Leiter, Johannes Schwenck, Gabriele Kienzle, Brigitte Gückel, Dominik Sonanini, Gerald Reischl, Ian Wilson, Bernd J. Pichler, Christian la Fougère, Lukas Flatz
Journal: Journal of Clinical Oncology (2024)

TPS9601 Background: Immune checkpoint inhibitors (ICI) improved outcomes of patients (pts) with advanced melanoma. Nevertheless, a significant number have immune-mediated adverse event (iAE). Due to the impact on quality of life and other therapeutic options, early identification of pts with increased risk of iAE is needed. CD8 immuno-PET with [ 89 Zr] crefmirlimab berdoxam (Zr-Df-IAB22M2C) has shown to be a specific tool to visualize CD8+ T cells mediating both anti-tumor immune response and inflammatory adverse effects rendering this an innovative evaluation method in the field of immuno-oncology. Methods: Trial design: Open-label, single-arm, single center study to determine if CD8+ T-cell infiltration evaluated by immune-PET provides diagnostic gain in early detection of severe iAE. Pts with irresectable stage III/IV melanoma receiving nivolumab + ipilimumab (NIVO+IPI) may be included. Primary objective: Feasibility of early detection of iAE by semiquantitative assessment of CD8+ T-cell infiltration using immune-PET. Secondary objectives: 1) Prediction of iAE using immuno-PET for semiquantitative assessment of CD8+ T-cell infiltration; 2) Correlation between CD8+ T-cell infiltration in metastasis and lymphoid organs and response. Baseline Imaging. To assess glucose metabolism in metastases, primary and secondary lymphatic organs [ 18 F] FDG PET/CT (60 min p.i. 1.5 MBq/KG/BW) is performed on a high sensitivity PET/CT with large field of view (Siemens Vision Quadra). Immediately after PET/CT data acquisition, pts are injected with [ 89 Zr] crefmirlimab berdoxam (37 MBq ±20%) and undergo immuno-PET/CT 24 hours p.i. to detect CD8+ T-cells in metastases and lymphoid organs. NIVO+IPI is administered immediately after completion of [ 89 Zr] crefmirlimab berdoxam-PET/CT. Blood samples are taken for immune cell composition analysis, activation state, proteomic investigation (cytokine/chemokines) as well as metabolic profile. Therapy Phase Imaging: Three weeks after first ICI cycle and before second cycle, follow-up PET/CT are performed with both radiotracers [ 18 F]FDG and [ 89 Zr] crefmirlimab berdoxam following the identical protocol described above. Clinical trial information: EudraCT number - 2021-004328-13 .
A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physician’s choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).
Authors: Jason J. Luke, George Kong, Giuseppe Gullo, Caroline Robert
Journal: Journal of Clinical Oncology (2024)

TPS9604 Background: Melanoma is the 5 th most common cancer type, with ~100,000 new cases and ~8,000 deaths estimated in the US for 2024. First-line systemic treatment with immune checkpoint inhibitors improved the objective response rate (ORR) and extended progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. The combination of anti–PD-1 nivolumab (nivo) + anti–CTLA-4 ipilimumab (ipi) therapy is associated with the highest ORR and best PFS and OS in this setting. However, only about half of patients respond, and there is no standard of care for patients who progress after anti–PD-1–based therapy. VO (also referred to as RP1) is a selectively replication-competent HSV-1 oncolytic virus that expresses human GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). Preliminary data from the phase 1/2 study (IGNYTE) showed that intratumoral (IT) VO plus intravenous (IV) nivolumab (nivo) was well tolerated and had meaningful antitumor activity (ORR, 31.4%) with durable responses in patients with advanced melanoma who progressed on prior anti–PD-1 therapy. This phase 3 study will evaluate the overall survival and clinical benefit as well as the safety of VO plus nivo for patients with advanced melanoma whose disease has progressed after receiving anti–PD-1 and anti–CTLA-4 therapy (or who are not eligible for anti–CTLA-4 therapy in addition to anti–PD-1) versus physician’s choice. Methods: This is a randomized, controlled, multicenter, phase 3 clinical trial comparing VO in combination with nivo vs physician’s choice of treatment in patients with unresectable or metastatic melanoma. Key eligibility criteria include age ≥12 years, stage IIIb–IV/M1a–M1d cutaneous melanoma, confirmed disease progression on an anti–PD–1 and anti–CTLA-4 treatment (administered in combination or in sequence with anti–PD-1 last), at least 1 measurable tumor (≥1 cm), and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll if they have confirmed progression on anti–PD-1 therapy. Patients with BRAF V600 mutant melanoma must have received an anti-BRAF + anti-MEK targeted therapy prior to enrollment. Patients (N = ~400) will be randomized 1:1 to receive VO plus nivo or physician’s choice (nivo + relatlimab, anti–PD–1 monotherapy rechallenge [nivo or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). VO is given IT Q2W; nivo is administered IV at 240 mg Q2W or 480 mg Q4W starting with the 2 nd dose of VO. The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR. Additional endpoints include complete response rate, duration of response, disease control rate, and safety. Clinical trial information: NCT06264180 .
Acceptable performance of blood biomarker tests of amyloid pathology — recommendations from the Global CEO Initiative on Alzheimer’s Disease
Authors: Suzanne E. Schindler, Douglas Galasko, Ana C. Pereira, Gil D. Rabinovici, Stephen Salloway, Marc Suárez-Calvet, Ara S. Khachaturian, Michelle M. Mielke, Chi Udeh-Momoh, Joan Weiss, Richard Batrla, Sasha Bozeat, John R. Dwyer, Drew Holzapfel, Daryl Rhys Jones, James F. Murray, Katherine A. Partrick, Emily Scholler, George Vradenburg, Dylan Young, Alicia Algeciras-Schimnich, Jiri Aubrecht, Joel B. Braunstein, James Hendrix, Yan Helen Hu, Soeren Mattke, Mark Monane, David Reilly, Elizabeth Somers, Charlotte E. Teunissen, Eli Shobin, Hugo Vanderstichele, Michael W. Weiner, David Wilson, Oskar Hansson
Journal: Nature Reviews Neurology (2024)

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75–85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests — a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments. Anti-amyloid treatments for early symptomatic Alzheimer disease have greatly increased the need for biomarker confirmation of amyloid pathology and blood biomarker tests offer an accessible and scalable biomarker test. This Consensus Statement provides recommendations for the minimum acceptable performance of blood biomarker tests for clinical use.