CLDN6-positive ovarian cancer cells exhibit remarkable plasticity influenced by microenvironmental factors and chemotherapy, providing critical insights for understanding the biology of ovarian cancer progression and optimizing CLDN6-targeting therapy.

INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors. This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously once every 2 weeks or 4 weeks in parts 1 (single-agent dose escalation; 0.001-3 mg/kg) and 2 (single-agent expansion) or once every 3 weeks in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naïve disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint. Of 160 patients assessed, 81 received monotherapy (median age, 65 years; female, 50.6%), and 79 combination therapy (median age, 64 years; female, 38%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg once every 3 weeks. Head and neck squamous cell carcinoma (n = 61) and non-small cell lung cancer (n = 25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AE) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients [monotherapy, n = 25 (grade ≥3, n = 11); combination, n = 16 (grade ≥3, n = 6)]. In all patients, the objective response rate was 8.8% [monotherapy, 3.7%; combination, 13.9% (CPI-naïve, 30%; CPI-R/R, 8.6%)]; the disease control rate was 43.1%. The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105. Tumor resistance to CPIs often develops, underscoring an unmet need. This first-in-human phase 1 trial evaluated INBRX-105-a tetravalent, PD-L1-targeted 4-1BB agonist-alone or with pembrolizumab. Unfortunately, clinical development of INBRX-105 was ended because of hepatotoxicity and limited efficacy. Novel treatment combinations with nonredundant, complementary immunotherapies are needed.

We developed a patient-derived ex vivo model to study immune cell therapy responses within the TME of RCC. Immune activation toward PD-1 blockade and VEGFRi was attenuated and depended on the immune cell state.

Some ALK-positive lung cancers show early resistance to alectinib. This study found brain metastases and elevated NLR associated with early resistance. Spatial transcriptomics and functional analysis suggested involvement of ANXA1. These results reveal clinical and molecular biomarkers that may guide treatment strategies for early resistance to alectinib.

The accelerated approval (AA) pathway expedites treatment access for patients with unmet medical needs. However, evidence on the program’s impact is lacking. This study assessed real-world clinical outcomes for AA drugs in solid tumor cancers. A nationwide electronic health record (EHR)-derived deidentified database was utilized to explore the impact of the AA pathway in patients with selected solid tumors from 2011 to 2023. Included patients received AA or non-AA products with the same indication. Outcomes were real-world progression-free survival (rwPFS) and overall survival (OS). Population-level health impacts were estimated via market share and real-world progression-free life years (rwPFLYs) and life years (LYs). Twenty-three AA indications were studied. At study completion, 83% of indications had their clinical benefit verified, whereas 17% had been withdrawn from the market. Overall, 78% of indications demonstrated significant improvements in rwPFS or OS, whereas none reported significantly worse rwPFS versus controls. In total, 44% and 48% of indications had >30% rwPFS and OS improvement, respectively. More indications with sample sizes >100 in the AA cohort demonstrated significant rwPFS gains [80% (12/15)] versus cohorts <100 [38% (3/8)]. An estimated 118,107 patients received AA drugs during their AA window, resulting in 56,399 rwPFLYs and 50,848 LYs gained. Most solid tumor AA indications were associated with improved clinical outcomes, providing substantial US population-level health gains. This EHR analysis provides insight into whether the AA pathway appropriately targets promising beneficial therapies. Expanding beyond randomized controlled trial evidence and conventional primary endpoints may be necessary to verify clinical benefit, particularly in rare tumors.Significance:This study (the first examining the real-world outcomes associated with the AA period) found improved clinical outcomes for most AA drugs studied compared with existing treatments in solid tumor cancers. The improvements observed suggest potential health improvements at the US population level and the possibility of the need to look beyond randomized controlled evidence and traditional primary endpoints to verify the clinical benefit of AA drugs for relatively rare conditions.

TARE with 90Y is widely used for liver cancer, yet its molecular determinants of response are poorly understood. Using a diverse panel of liver cancer cell lines, we identify EMT, adhesion, and stress response pathways associated with resistance. These findings highlight candidate biomarkers and molecular vulnerabilities that may guide future therapeutic strategies and patient selection.

Although pathologic stage I (pStage I) non–small cell lung cancer (NSCLC) has a good prognosis, some patients experience disease recurrence. Identification of prognostic markers for pStage I NSCLC may facilitate personalized perioperative treatment by expanding the candidates for adjuvant treatment. Patients with NSCLC with ground-glass opacity have excellent survival outcomes. Therefore, in this study, we explored prognostic biomarkers in pure solid nonsquamous NSCLC. We focused on nonsquamous NSCLC because the gene expression status is distinct from that of squamous cell carcinomas. RNA sequencing was performed on frozen tumor specimens from 33 patients with nonsquamous NSCLC with disease recurrence (recurrence group) and 33 counterparts (control group) extracted from patients without disease recurrence using propensity score matching (cohort 1). The candidate genes were further refined using an independent real-world cohort 2a (N = 125) and validated in The Cancer Genome Atlas cohort. Through the analysis of cohort 1 and cohort 2a, we found that low expression of six genes (BMP6, KCNK3, NFASC, OLFM1, PEG3, and TNXB) was associated with disease recurrence. The prognostic impact of the six genes was confirmed using The Cancer Genome Atlas lung adenocarcinoma database. Multivariable proportional hazard analysis using the cohort 2a dataset revealed that the combination of BMP6 and OLFM1 status predicted recurrence-free survival. In conclusion, we found that low BMP6/OLFM1 gene status is a potential biomarker to identify patients with high-risk pStage I pure solid nonsquamous NSCLC after pulmonary resection.Significance:The identification of subgroups with a high risk of disease recurrence among patients with NSCLC with pStage I is an important clinical issue. We explored genetic factors in patients with pStage I NSCLC with a high-risk clinical feature and identified low expression of OLFM1 and BMP6 genes as candidate biomarkers. Clinical application of these biomarkers, together with others, will open an opportunity to administer adequate adjuvant treatment for these high-risk patients.

As survival rates for lymphoid malignancies continue to improve, understanding the late effects after treatment, such as secondary myeloid neoplasms (sMN), is increasingly critical for survivorship. This large-scale population-based (SEER-Medicare) study investigated the risk factors and cumulative incidence of sMNs in patients with diagnosis of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma between 2000 and 2011, with follow-up through 2015. Patients with FL had a continuous increase in the cumulative incidence of sMNs with longer follow-up, whereas incidence of patients with multiple myeloma plateaued after 60 months. Notably, patients with DLBCL diagnosed in more recent years (2004–2007 and 2008–2011) had a higher cumulative sMN incidence compared with those diagnosed earlier (2000–2003). In the Medicare population, older age at diagnosis was associated with significant increase in sMN risk in patients with DLBCL and FL. Chemotherapy exposure or G-CSF exposure significantly increased sMN risk across all three malignancies. Chronic autoimmune conditions increased sMN risk in patients with DLBCL. These findings provide crucial insights into sMN risk factors. Chemotherapy exposure is a recognized risk factor, and comorbidities such as a history of autoimmunity and G-CSF exposures have been identified as additional mediators of sMN risk in our study.Significance:Our study reveals population-level risk factors for sMNs, including novel links to autoimmune disease and G-CSF, in addition to known causes like chemotherapy/radiation. These findings underscore the complex pathogenesis of sMNs and the need for molecular data in prospective studies to guide prevention, detection, and survivorship care.

PARP inhibitors (PARPi) have reshaped the clinical management paradigm of multiple cancers, but none more than homologous recombination–deficient high-grade serous carcinoma (HGSC) of tubo-ovarian origin. In patients with HGSC that harbor BRCA1/2-mutations, PARPi maintenance therapy after first-line chemotherapy has resulted in significantly prolonged progression-free and overall survival. However, PARPi resistance is a major clinical challenge, and subsequent therapeutic options for patients with resistant disease remain limited. Whereas mechanisms of PARPi therapy have been described, there have been few clinical studies to translate these strategies into overcoming resistance. Elevated WNT signaling and T-cell factor (TCF) transcriptional activity contribute to PARPi resistance; however, directly targeting WNT signaling is challenging due to on-target adverse events. We tested an indirect WNT inhibitor, a dual CDC-like kinase and dual-specificity tyrosine phosphorylation–regulated kinase inhibitor, SM08502 (cirtuvivint), in combination with PARPi in multiple resistant HGSC models. We determined TCF transcriptional activity and differential gene expression with splicing analysis and used multispectral IHC to interrogate the tumor microenvironment. In PARPi-resistant models, SM08502 inhibits WNT/TCF transcriptional activity, reduces cell viability, and induces DNA damage. In addition, using multiple immune-compromised and immune-intact in vivo models of PARPi-resistant disease, SM08502, in combination with olaparib, significantly reduces disease progression, remodels the tumor immune microenvironment, and extends survival. Specifically, tumors treated with the SM08502/olaparib combination exhibit reduced immune-suppressive PD-1 and PD-L1 expression. This study provides strong preclinical evidence that SM08502, in combination with PARPi, may be an effective strategy to overcome PARPi resistance.Significance:PARPi resistance is a major clinical challenge. Overcoming PARPi resistance will provide patients with therapeutic options. The study shows, in the context of resistant disease, the potential of targeting CDC-like kinase/dual-specificity tyrosine phosphorylation–regulated kinase alone and in combination with PARP inhibitors.

Purpose:Metastatic castration-resistant prostate cancer with homologous recombination (HR) deficiency (HRD) is sensitive to PARP inhibitors (PARPi). PI3K inhibitors (PI3Ki) sensitize to PARPi by disrupting HR in preclinical models. This phase Ib/II study investigated copanlisib (Copa; pan–class I PI3Ki) and rucaparib (R).Patients and Methods:Eligible patients had metastatic castration-resistant prostate cancer treated with ≥1 androgen receptor inhibitor and taxanes. Phase I followed a standard 3 + 3 dose-escalation design (rucaparib 400–600 mg orally twice a day; Copa 45–60 mg i.v. on days 1, 8, and 15). Primary goal of phase I was to establish MTD and the recommended phase II dose. The primary endpoint of phase II was PSA50 response rate.Results:Thirteen patients enrolled had a median age of 64 (55–78) years and PSA was 11.7 ng/mL (0.018–2,101). Seven patients received taxanes, and one patient received PARPi. Eight patients had HRD+ tumors [BRCA2 (four), BRCA1 (one), RAD51C (one), CDK12 (one), and FANCA (one)] and three had PTEN loss. There were two dose-limiting toxicities in dose level 1 (rucaparib 400 mg twice a day; Copa 45 mg on days 1, 8, and 15): grade 3 rash and aspartate aminotransferase/alanine aminotransferase elevation. Treatment-related adverse events ≥ grade 2 included leukopenia (54%), anemia (38%), rash (30%), fatigue (23%), and neutropenia (23%). Six patients were treated at dose level –1 without dose-limiting toxicities, which was established as the recommended phase II dose (rucaparib 400 mg twice a day + Copa 45 mg on day 1/15). Among patients with HRD+, one had confirmed partial response and three had stable disease by RECIST, including one patient treated with prior PARPi, and three patients had PSA50 responses (23%).Conclusions:Copa/R had an acceptable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.Significance:Gene alterations in the PI3K and HR pathways are common in prostate cancer. Based on preclinical studies, the inhibition of PI3K disrupts HR, and PARP blockade induces AKT activation, supporting the combination of PI3Ki and PARPi. Herein, we investigated the safety and preliminary efficacy of the PI3Ki copanlisib and the PARPi rucaparib in patients with or without alterations in HR repair pathway genes.