Sato J, Katsuya Y, Koyama T
… +12 more, Shimizu T, Tanoue Y, Yamamoto M, Tozaki H, Takahara E, Shoji S, Mizutani A, Morishita D, Oda RW, Miyake H, Yonemori K, Yamamoto N
Clin Cancer Res
· 2026 May · PMID 42148878
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PURPOSE: Aberrant splicing plays a significant role in cancer progression, yet targeted treatments are lacking. Rogocekib (developmental name CTX-712) is a potent oral inhibitor of CDC2-like kinase (CLK) that targets RNA...PURPOSE: Aberrant splicing plays a significant role in cancer progression, yet targeted treatments are lacking. Rogocekib (developmental name CTX-712) is a potent oral inhibitor of CDC2-like kinase (CLK) that targets RNA splicing. This Phase I study aimed to evaluate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD) profiles, preliminary efficacy, and the recommended dose (RD) of rogocekib in patients with advanced solid tumors. PATIENTS AND METHODS: The dose escalation started with an accelerated titration phase and then transitioned to a 3+3 design at doses ranging from 10 mg to 175 mg, administered twice weekly (BIW). For dose expansion,105 mg BIW, 70 mg BIW, and 105 mg once weekly (QW) were investigated. RESULTS: In total, 46 patients with solid tumors were administered rogocekib. The MTD was determined to be 140 mg BIW. DLTs were observed in 1 patient at 140 mg BIW (platelet count decreased, hypokalemia) and 1 patient at 175 mg BIW (dehydration). Common related adverse events included nausea, vomiting, and diarrhea. Two treatment related deaths were observed. PK analysis showed a dose-dependent increase in systemic exposure to rogocekib. PD analysis of two markers (THAP9-AS1 and S6K) showed target engagement of rogocekib. Partial response (PR) was observed in 6.5% of patients, all with ovarian cancer (n=3). CONCLUSIONS: Although most toxicities were manageable, two treatment related deaths were observed, underscoring the need for vigilant safety monitoring. Overall, rogocekib demonstrated evidence of target engagement in most patients with solid tumors and preliminary antitumor activity, warranting further clinical investigation.
Santin AD, Roque DM, Siegel E
… +11 more, Ettorre V, Greenman M, McNamara B, Papatla K, Kailasam A, Buza N, Clark M, Hui P, Dottino P, Ratner E, Bellone S
Clin Cancer Res
· 2026 May · PMID 42132892
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PURPOSE: Endometrial cancer (EC) patients who progress after chemotherapy/immunotherapy have limited treatment options. We evaluated the activity and safety of sacituzumab govitecan (SG), a Trop-2-directed ADC, in patien...PURPOSE: Endometrial cancer (EC) patients who progress after chemotherapy/immunotherapy have limited treatment options. We evaluated the activity and safety of sacituzumab govitecan (SG), a Trop-2-directed ADC, in patients with advanced/recurrent EC, including carcinosarcoma. PATIENTS AND METHODS: This was a phase 2, two-stage open-label investigator-initiated trial of persistent/recurrent EC patients who had progressed following >=1 prior chemotherapy. Patients received SG 10 mg/kg on days 1, 8 q3 weeks. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included clinical benefit rate (CBR=complete response [CR]+partial response [PR]+stable disease ≥ 6mo), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety. Trop-2 expression was analyzed by IHC as an H-score. RESULTS: Fifty patients were screened and 21 enrolled during stage 1; 34 patients were screened and 29 enrolled during stage 2; 84% (n=42) of patients harbored serous carcinoma, carcinosarcoma, or grade 3 endometrioid tumors. Patients received a median of 2 prior therapies (range:1-4) and 50% had failed pembrolizumab/dostarlimab. At a median follow-up (range) of 11.0 (2.9-65.5) months, ORR was 28% (95% CI,16%-42%), including CRs (4%) and PRs (24%). Median DOR (95%CI) was 9.3 (2.0-12.9) months, with 4 still responding. CBR was 52% (26/50). Median PFS and OS were 5.5 (95% CI:3.7-7.4) and 17.5 (95% CI:10.4-22.2) months, respectively. Grade 3-4 toxicity occurred in 88% with no attributable deaths. Mean H-scores did not predict response. CONCLUSIONS: SG demonstrated encouraging efficacy in a pretreated population that included biologically aggressive recurrent EC. Adverse events were consistent with the known safety profile.
Chae HD, Shrestha U, Das M
… +20 more, Vasanawala MS, Behl D, Davar D, Srinivas S, Colevas AD, Sunwoo JB, Del Mar N, Pierini M, Guillen M, Garcia J, Omidvari N, Gupta N, Cabrera H, Blecha J, Cherry SR, VanBrocklin H, Flavell RR, Moslehi J, Seo Y, Levi J
Clin Cancer Res
· 2026 May · PMID 42126592
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PURPOSE: Advances in cancer therapy have improved survival but increased the risk of treatment-related cardiotoxicity, which remains difficult to detect early with existing biomarkers. [¹⁸F]F-AraG is a PET tracer that ta...PURPOSE: Advances in cancer therapy have improved survival but increased the risk of treatment-related cardiotoxicity, which remains difficult to detect early with existing biomarkers. [¹⁸F]F-AraG is a PET tracer that targets cells with active mitochondrial biogenesis, including cardiomyocytes and activated T cells, and may enable concurrent assessment of cardiac involvement and therapy-associated immune activity. This study evaluated whether [¹⁸F]F-AraG PET can serve as an early imaging biomarker of cardiac effects across different cancer therapies. METHODS: Twenty-six healthy subjects underwent [¹⁸F]F-AraG PET to establish baseline myocardial uptake. Seven patients with stage III melanoma and ten with advanced non-small cell lung cancer were imaged before and after immunotherapy. Myocardial uptake (SUVmax, SUVmean, SUVtotal) was quantified in the left (LV) and right (RV) ventricles, with LV regional uptake analyzed using a 17-segment model. Myocardial uptake was examined in relation to abnormal cardiac status in a subset of patients with available electrocardiogram (ECG) data. Associations between cardiac uptake, mitochondrial content, and PGC-1α expression were evaluated. RESULTS: Healthy myocardium demonstrated consistent and spatially uniform [¹⁸F]F-AraG uptake across age and sex, with higher uptake in the LV than RV. Conventional therapy was associated with increased global myocardial uptake, whereas immunotherapy was associated with additional heterogeneous and focal myocardial uptake. Altered myocardial uptake patterns were observed in patients with ECG abnormalities. CONCLUSIONS: [¹⁸F]F-AraG PET detects therapy-associated changes in myocardial tracer uptake following cancer treatment. These findings support its potential utility as a noninvasive imaging approach for early evaluation of cardiac effects in patients receiving cancer therapies.
Clin Cancer Res
· 2026 May · PMID 42126573
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Dual PD-1/CTLA-4 inhibition improves outcomes in several cancers but remains limited by toxicity. A recent article reports the first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody, demonstrating d...Dual PD-1/CTLA-4 inhibition improves outcomes in several cancers but remains limited by toxicity. A recent article reports the first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody, demonstrating durable responses, but dose-dependent immune-related adverse events were also observed. This commentary examines whether the bispecific format meaningfully improves the therapeutic index and considers priorities for the next phase of development.
Hua C, Wu Z, Wang X
… +4 more, Liu H, Li B, Zheng Y, Lin X
Clin Cancer Res
· 2026 May · PMID 42126547
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PURPOSE: Extracranial arteriovenous malformation (AVM) is a rare and debilitating condition with significant morbidity. Clinical trial evidence for targeted therapies remains limited. We evaluated the efficacy and safety...PURPOSE: Extracranial arteriovenous malformation (AVM) is a rare and debilitating condition with significant morbidity. Clinical trial evidence for targeted therapies remains limited. We evaluated the efficacy and safety of luvometinib, a MEK1/2 inhibitor, in adults with complicated AVM that were inoperable, unsuitable for intervention, relapsed after surgery, or failed previous treatment. PATIENTS AND METHODS: This single-arm phase 2 study enrolled adults with inoperable or relapsed extracranial AVMs. Patients received luvometinib 8 mg once daily in 28-day cycles. Primary endpoint was objective response rate (ORR; patients with ≥20% reduction in lesion range) by digital subtraction angiography (DSA). Secondary endpoints included ORR (patients with ≥20% reduction in volume) by MRI, lesion clearance, improvement in arterial flow and impedance, clinical symptoms, and safety. RESULTS: We enrolled 20 patients; 18 (90%) had stage III AVM (median follow-up duration 14·6 months). ORR by DSA was 64·3% (lesion reduction ≥20%; 95% CI 35·1-87·2); 35·7% achieved major partial response (lesion reduction >50%). ORR by MRI was 61·1% (95% CI 35·7-82·7). Fourteen (77·8%) and 15 (83·3%) patients had improvements in arterial velocity and impedance, respectively; 12 (66·7%) had improvements in clinical symptoms. Response was achieved in RAS-MARK-mutated, EPHB4-mutated, or mutation-undetected patients, but not RASA1-mutated patients. Nineteen (95%) patients experienced treatment-emergent adverse events, mostly grade 1-2; 5 (25%) had grade ≥3. No deaths reported. CONCLUSIONS: In the first clinical trial of targeted therapy in adults with inoperable or relapsed extracranial AVMs, luvometinib demonstrated promising efficacy and tolerability, supporting its further development for the treatment of AVMs.
Strawser CH, Chakraborty B, Michaud D
… +16 more, Chang CY, Dent S, Jain V, Tolaney SM, Weinhold K, McAllister SS, Miller KE, Steadman K, Arvai S, Hocke E, Agrawal Y, Perou CM, Goel S, McDonnell DP, Guerriero JL, Sammons S
Clin Cancer Res
· 2026 May · PMID 42126533
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PURPOSE: In advanced estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine thera...PURPOSE: In advanced estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care for treatment in the first-line setting. While CDK4/6i were initially developed to induce cell cycle arrest, it is evident that CDK4/6i also have the potential to regulate the tumor immune microenvironment. Here, we characterize the baseline immune landscape and the immunomodulatory effects of abemaciclib and ET in advanced breast cancer tumors. METHODS: We used single-cell RNA-sequencing of CD45-enriched cells to investigate the impact of the CDK4/6i, abemaciclib, and ET on the transcriptome of immune cell populations in 13 matched-pair advanced and metastatic ER+/HER2- breast tumor biopsies. We tested the association of immune cell population gene signatures with survival in publicly available datasets. RESULTS: We profiled 170,798 cells from bone, breast, lymph node, and liver biopsies. We find that expression of genes associated with interferon response are downregulated in many T cell populations. Expression of genes associated with antigen presentation were upregulated in tumor-associated macrophages (TAMs) and dendritic cells following treatment. The relative proportion of TREM2+ TAMs decreases following treatment with abemaciclib and ET in late progressors and lower expression of the TREM2+ TAM signature is associated with improved overall survival in breast cancer patients. CONCLUSIONS: Our data reveal heterogeneous lymphoid and myeloid subpopulations in advanced and metastatic breast tumors that are associated with late progression on abemaciclib and ET and overall survival in breast cancer patients.
Shi F, Wang H, Yang Y
… +10 more, Ding L, Ding Y, Zhang Y, Xi M, Qu Y, Chen Z, Lu Y, Yang Y, Liu L, Yue J
Clin Cancer Res
· 2026 Jul · PMID 42126314
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PURPOSE: Evidence for radiotherapy (RT) in oligoprogressive hepatocellular carcinoma (OP-HCC) is limited. We evaluated the efficacy and safety of progression-directed RT (PDRT) alongside ongoing first-line systemic thera...PURPOSE: Evidence for radiotherapy (RT) in oligoprogressive hepatocellular carcinoma (OP-HCC) is limited. We evaluated the efficacy and safety of progression-directed RT (PDRT) alongside ongoing first-line systemic therapy (FLST) in patients with OP-HCC. PATIENTS AND METHODS: Patients who developed OP-HCC during FLST were enrolled and received PDRT with a biologically effective dose of at least 60 Gy while continuing FLST. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), toxicities, and quality of life (QoL). RESULTS: From March 2024 through May 2025, 36 patients were enrolled from 10 cancer centers. At a median follow-up time of 10.9 months, median PFS time was 7.0 months (95% confidence interval 4.9-9.7), with 3-, 6-, and 9-month PFS rates of 73.7%, 64%, and 38.8%, respectively. Type of FLST and albumin-bilirubin (ALBI) grade at oligoprogression were independently associated with PFS. Median OS and DOR times were not reached; 1-year OS rates were 86.4%, and 3-, 6-, and 9-month DOR rates were 84.6%, 79.6%, and 70.8%, respectively. ORR and DCR were 64.7% and 98.0%, respectively. QoL measures generally remained stable, except for transient increases in fatigue and pain scores 1 month after PDRT. RT-related toxicities (mostly grades 1-2) occurred in 16 patients (44.4%), including grade ≥3 events in four patients (11.1%). CONCLUSIONS: Maintaining FLST with PDRT was effective, safe, and preserved QoL, supporting its feasibility for OP-HCC. FLST type and baseline ALBI grade may provide risk stratification and prognosis for PFS.
Yang DD, Abdelnaser A, Haas AJ
… +19 more, Wala J, Barney AA, Saad E, Crowdis JP, Ricker CA, Awad S, Gurel B, Park J, King MT, Nguyen PL, Choueiri TK, Einstein DJ, Balk SP, Tewari AK, de Bono JS, Salari K, Taplin ME, Wu CL, Van Allen EM
Clin Cancer Res
· 2026 May · PMID 42113020
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PURPOSE: Computational pathology has emerged as an attractive option for improving risk stratification in prostate cancer (PCa), but most approaches either lack interpretability or focus solely on tumor morphology. We ai...PURPOSE: Computational pathology has emerged as an attractive option for improving risk stratification in prostate cancer (PCa), but most approaches either lack interpretability or focus solely on tumor morphology. We aimed to identify an interpretable, immune microenvironment-derived computational pathology biomarker for PCa. PATIENT AND METHODS: We identified two cohorts (Discovery and Validation) with M0 PCa (n=490) who were treated with radical prostatectomy with H&E-stained whole-slide images (WSIs) and data on distant metastasis (DM). We identified a third cohort from TCGA with M0 PCa (n=326) with prostatectomy WSIs and bulk sequencing. Immune cells were identified from WSIs using a deep learning method (CellViT), and spatially dense immune clusters were quantified using DBSCAN. CIBERSORTx was utilized for immune cell deconvolution and TRUST4 for immune receptor repertoire reconstruction. RESULTS: Median follow-up was 12.6 (Discovery) and 8.1 years (Validation). 14% (n=37, Discovery) and 17% (n=38, Validation) had Gleason 8-10 disease. Immune cell abundance was not associated with DM. In Discovery, increased immune cluster was associated with decreased risk of DM for Gleason 8-10 (adjusted hazard ratio 0.42, 95% confidence interval 0.19-0.93) but not Gleason 6-7 (1.26, 0.77-2.05; Pint=0.020), with similar results in Validation (Gleason 8-10 0.60, 0.37-0.98; Gleason 6-7 1.19, 0.74-1.91; Pint=0.043). In Gleason 8-10 but not 6-7, high-cluster samples were enriched for CD8+ T cells, activated memory CD4+ T cells, Tregs (P≤0.037), and clonal T cell populations (P≤0.039). CONCLUSIONS: These findings propose immune spatial clustering as a novel, interpretable computational pathology biomarker and provide insight into the unique immune features of high-grade PCa.
Clark HD, Aghlara-Fotovat S, Schladenhauffen J
… +26 more, Debonis J, Amador-Molina JC, Nash A, Jain M, Newman R, Jansen L, Andreas K, Rangel K, Sims TT, Fellman B, Dansky Ullmann C, Yeku O, Bregar AJ, Blakely AM, Mathews C, Igoshin OA, Haymaker C, Oberholzer J, Rios P, Lopez D, Nasir H, Joshi I, Chakrabarti R, Veiseh O, Jazaeri AA, Westin SN
Clin Cancer Res
· 2026 May · PMID 42113012
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PURPOSE: Platinum-resistant high-grade serous ovarian carcinomas (HGSOC) are associated with poor therapeutic outcomes. While HGSOC frequently metastasizes to the intraperitoneal (IP) cavity, the success of IP cytokine t...PURPOSE: Platinum-resistant high-grade serous ovarian carcinomas (HGSOC) are associated with poor therapeutic outcomes. While HGSOC frequently metastasizes to the intraperitoneal (IP) cavity, the success of IP cytokine therapies, such as IL-2, has been hampered by local toxicity and administration difficulties. AVB-001 is a novel IL-2 delivery system consisting of encapsulated, allogeneic cells engineered for constitutive human IL-2 expression. PATIENTS AND METHODS: This is a phase I dose-escalation trial of AVB-001 for the treatment of HGSOC (NCT05538624). A single dose of AVB-001 was administered IP laparoscopically, enabling hIL-2 doses from 0.6 to 3.6 μg hIL-2/kg/day. Safety was evaluated using NCI CTCAE v5.0. Efficacy was assessed via RECIST v1.1 and iRECIST criteria. RESULTS: The trial enrolled 14 patients across four dose levels. Three patients (21.4%) experienced grade 3 treatment-related adverse events (TRAEs); no grade 4-5 TRAEs were reported. There was one DLT. There was one unconfirmed partial response, but no confirmed responses (ORR 0%). Stable disease was observed in seven patients, with a median duration of 2.57 months (range 2.03-4.23). The clinical benefit rate was 14.3% (n=2). Pharmacokinetics demonstrated dose-dependent increases in serum IL-2, peaking at 1 day post-implantation. Immunological analyses revealed sustained CD8+ and CD4+ T-cell proliferation without corresponding proliferation in regulatory T cells. Dose-dependent CTLA-4 receptor upregulation was observed on CD8+ and CD4+ T cells, whereas PD-1 and TIM-3, remained unchanged. CONCLUSIONS: In patients with HGSOC, AVB-001 is safe and effectively activates cytotoxic T cells, supporting further investigation of this locoregional immunotherapy.
Guo Q, Deng C, Pan X
… +19 more, Liu J, Yang G, Sun Y, Shi F, Zhao M, Wang X, Yang S, Liang X, Xu W, Ye J, Huang X, Wu J, Wang W, Guo Z, Hu R, Yu Y, Zhang Y, Lou J, Wang L
Clin Cancer Res
· 2026 May · PMID 42113010
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BACKGROUND: Low-dose computed tomography (LDCT) suffers from a high false-positive rate in the evaluation of pulmonary nodules. Circulating tumor DNA (ctDNA) methylation is a promising complementary biomarker, but its de...BACKGROUND: Low-dose computed tomography (LDCT) suffers from a high false-positive rate in the evaluation of pulmonary nodules. Circulating tumor DNA (ctDNA) methylation is a promising complementary biomarker, but its detection is hindered by the highly fragmented nature of ctDNA. METHODS: We developed SAMT-Seq (Single-Strand Amplification Methylation-Targeted Sequencing), optimized for methylation detection in fragmented ctDNA. Lung cancer-specific methylation markers were identified from in-house cohort and TCGA database and validated in paired tissue and plasma samples from 30 early-stage lung cancer patients. A panel of 30 key markers was selected using LASSO regression in a training cohort (n=239). A Gaussian process classifier was developed and validated in two independent cohorts (n=59 and n=207). RESULTS: SAMT-Seq demonstrated superior analytical sensitivity and on-target efficiency compared to a standard commercial Swift method. The 30-marker classifier yielded area under the curve (AUC) of 0.95, 0.95, and 0.92 in the Training Cohort, Validation Cohort 1 and 2, respectively. Notably, it maintained robust performance across nodule types (solid/subsolid), sizes, smoking status, and insitu carcinoma. With a predefined threshold, the model achieved specificity of 100% and 92.16% in Validation Cohort 1 and 2, respectively, suggesting its potential utility in reducing false-positive classifications. CONCLUSIONS: We developed a high-specificity ctDNA methylation classifier that serves as a practical, complementary tool for risk stratification of pulmonary nodules, with the potential to significantly reduce unnecessary invasive procedures. Ongoing prospective diagnostic validation study are evaluating its clinical performance.
Lee HM, Zheng Z, Sorokin A
… +22 more, Wong CW, Napolitano S, Chowdhury S, Kanikarla PM, Singh AK, Kochat V, Bristow CA, Srinivasan S, Peoples M, Arslan E, Alshenaifi JY, Villarreal OE, Morris VK, Shen JP, Meric-Bernstam F, Jain AK, Fowlkes NW, Anderson A, Menter DG, Saw AK, Rai K, Kopetz S
Clin Cancer Res
· 2026 May · PMID 42101296
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PURPOSE: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC), particularly in the BRAFV600E-mutated metastatic subtype, which uniquely exhibits a strong epigenetic...PURPOSE: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC), particularly in the BRAFV600E-mutated metastatic subtype, which uniquely exhibits a strong epigenetic phenotype. Building on this epigenetic vulnerability, bromodomain 2, a reader of H3K27ac-marked enhancers, was found to be synthetically lethal with BRAF + EGFR inhibition. EXPERIMENTAL DESIGN: We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive transcriptomic and chromatin profiling. RESULTS: BET plus standard MAPK inhibitors demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. This combination induced a more profound downregulation of the MAPK signaling pathway than MAPK inhibition alone. The loss of activation signal on H3K27ac-marked enhancers led to the dysregulation of core-regulatory circuitries, especially the MAPK downstream E26 transformation-specific transcription factor family and MYC. Single-nucleus RNA+ATAC sequencing distinguished differential transcriptomic and chromatin dynamics at the cell-type level. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. Conversely, an abundance of dedifferentiated cell populations emerged after MAPK or combination inhibition, suggesting therapy-induced cell-state switching and adaptation. CONCLUSION: Our work demonstrates that BET inhibition improves MAPK signaling blockade through profound epigenetic reprogramming of core transcription factor circuits. These findings provide a preclinical rationale for the evaluation of BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC (NCT06102902).
Pakvisal N, Wongkongkathep P, Bunrasmee W
… +39 more, Sodsai P, Siriluksana J, Boonnak N, Sangcharoen T, Trakarnsanga B, Sukprakun S, Wantanasiri P, Chotirosniramit K, Phanichkrivalkosil M, Nanthawong S, Chanchaem P, Mankhong S, Kumpunya S, Supabphol S, Sirijun N, Kongtragulsub K, Pearngam P, Somparn P, Payne DM, Zhao B, Praphanphoj V, Pornputtapong N, Sriswasdi S, Wichadakul D, Uttamapinan S, Angspatt P, Wongchanapat P, Teeyapun N, Luangdilok S, Sitthideatphaiboon P, Susiriwatananont T, Zungsontiporn N, Parinyanitikul N, Tanasanvimon S, Vinayanuwattikun C, Salazar A, Hirankarn N, Sriuranpong V, Pisitkun T
Clin Cancer Res
· 2026 May · PMID 42095629
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PURPOSE: To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors. PATIENTS AND METHODS: In this Phase I tria...PURPOSE: To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors. PATIENTS AND METHODS: In this Phase I trial, 12 patients with advanced melanoma (n=9) or renal cell carcinoma (n=3) who lacked access to further reimbursed standard therapies at enrollment received intramuscular neoantigen SLP vaccines with poly-ICLC. Each vaccine contained ~20 predicted neoantigen peptides. Adverse events were monitored throughout vaccination and follow-up. Immune profiling was performed at baseline and predefined post-vaccination time points. RESULTS: Intramuscular neoantigen vaccination was well tolerated, with only grade 1-2 local pain or fever and no immune-mediated toxicities. All participants developed de novo T-cell responses, which were detectable as early as one week post-vaccination in most patients. On average, 53% of peptides per patient were immunogenic, inducing both CD8⁺ and CD4⁺ neoantigen-specific responses. Patients previously treated with immune checkpoint inhibitors (ICIs) had higher baseline immunity but achieved comparable post-vaccination responses to ICI-naïve patients. IFN-γ-dominant CD8⁺ and TNF-α-dominant CD4⁺ responses were observed, along with increased effector memory differentiation. Two patients with higher CD8⁺ TEMRA proportions were the longest survivors. Tumor biopsies revealed enhanced CD8⁺ infiltration, and epitope spreading occurred in two evaluable cases. Analysis of 239 peptides showed greater immunogenicity for dual MHC I/II-binding, cysteine-containing, and in-frame indel- or low-VAF- derived mutations, while proline substitutions reduced responses. CONCLUSIONS: Intramuscular neoantigen SLP vaccination with poly-ICLC is safe and induces rapid, mutation-specific T-cell immunity with robust CD8⁺ effector responses. These findings support intramuscular administration as a promising strategy for peptide-based cancer vaccines.
Swiecicki PL, Hanna GJ, Geiger JL
… +16 more, Fujisawa T, Haigentz M, Honma Y, Bruce JY, Tanaka K, Muro K, Bhateja P, Kaplan J, Liu S, Gorla S, Wozniak M, Dillon R, Hamed S, Meng C, Chaney MF, Rosenberg AJ
Clin Cancer Res
· 2026 May · PMID 42084607
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PURPOSE: To assess safety and efficacy of enfortumab vedotin (EV) and pembrolizumab as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). PATIENTS AND METHODS: In this ope...PURPOSE: To assess safety and efficacy of enfortumab vedotin (EV) and pembrolizumab as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). PATIENTS AND METHODS: In this open-label, multicohort, phase 2 study (NCT04225117), the R/M HNSCC cohort (cohort 9) received EV (1.25 mg/kg IV) on days 1, 8 and pembrolizumab (200 mg IV) on day 1 in 21-day cycles. Eligible patients had R/M HNSCC, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1, and no prior systemic therapy in R/M setting. Primary endpoint was investigator-assessed confirmed objective response rate (cORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: The primary analysis included 41 patients. Of these, 39.0% had PD-L1 CPS 1-19 and 61.0% had CPS ≥20. Median (IQR) nectin-4 expression H-score was 185.0 (110.0-255.0). In patients with oropharyngeal squamous cell carcinoma (n=14), 78.6% had p16-positive disease. Median follow-up for OS was 11.0 months. Sixteen patients achieved a response and cORR was 39.0% (95% CI: 24.2-55.5). Complete response rate was 9.8%. DOR was not estimable, and estimated 6-month DOR rate was 81.7% (95% CI: 42.0-95.4). Median PFS was 5.1 months (95% CI: 3.5-NE). Grade 3 treatment-related adverse events were reported in 41.5% of patients; most commonly, maculopapular rash (7.3%). CONCLUSION: EV with pembrolizumab demonstrated promising clinical activity as first-line treatment in patients with PD-L1 CPS ≥1 R/M HNSCC. Safety results reinforced the manageable tolerability profile of EV with pembrolizumab.
Lacouture ME, Pan A, Maier T
… +16 more, Chen A, Dranitsaris G, Shah NJ, Dang C, Gajria D, Gordon A, Iyengar N, Razavi P, Robson M, Rosen E, Wong S, Harris U, Ketosugbo K, Bravo C, Jain M, Markova A
Clin Cancer Res
· 2026 May · PMID 42084605
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PURPOSE: Eosinophil-related cutaneous adverse events (ercAEs) are common following systemic cancer therapies and often impact health-related quality of life (HRQoL). Here we investigate the efficacy and safety of benrali...PURPOSE: Eosinophil-related cutaneous adverse events (ercAEs) are common following systemic cancer therapies and often impact health-related quality of life (HRQoL). Here we investigate the efficacy and safety of benralizumab for ercAEs following systemic cancer therapies. PATIENTS AND METHODS: This single-arm, single-center, open-label, phase 2 trial (NCT04552288) in patients with cancer and systemic therapy-associated ercAEs, was performed from September 2020 to October 2023. Benralizumab 30 mg was administered subcutaneously in the approved dosing of q4w (x3), followed by q8w (x3). The primary endpoint was clinical response (reduction in ercAEs to CTCAE grade ≤1 by Week 4). Secondary endpoints included, HRQoL, rash body surface area (rash-BSA), eosinophil levels, and AEs. RESULTS: At baseline (N = 47), ercAEs were related to PI3K inhibitors in 47%, checkpoint inhibitors in 21%, tyrosine kinase inhibitors in 9%, and antibody-drug conjugates in 9%; ercAEs were grade 2 and 3 in 49% and 51% of patients, respectively. Of the 42 patients evaluable for the primary endpoint, 76% patients (n = 32/42) responded to treatment by Week 4; median ercAE grade decreased from 2 to 1 (P < .0001). Patients exhibited improved HRQoL, reduced mean rash-BSA, and decreased peripheral eosinophils. All patients with ercAEs following alpelisib (n = 18) or enfortumab vedotin (n = 4) responded by Week 4 (both P < .05). Most AEs were mild to moderate and likely unrelated to benralizumab. CONCLUSIONS: Benralizumab demonstrated favorable efficacy and safety against grade 2/3 ercAEs following systemic cancer therapies. Further investigation in larger placebo-controlled trials is warranted.
Hashmi A, Linford J, Chauhan PS
… +24 more, Parikh K, Pillai M, Guittar J, Ben-Shachar R, Patel J, Nimeiri H, Bergsagel M, Semenkovich NP, Park SS, Olivier KR, Owen D, Routman DM, Lee KN, Sherry AD, Mansfield AS, Morgensztern D, Govindan R, Robinson CG, Bergom C, Waqar SN, Samson PP, Pellini B, Vlacich GR, Chaudhuri AA
Clin Cancer Res
· 2026 Apr · PMID 42059900
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PURPOSE: Circulating tumor fraction estimate (ctFE) is a machine learning-derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre- and early on-treatment ctFE could robustly risk-strati...PURPOSE: Circulating tumor fraction estimate (ctFE) is a machine learning-derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre- and early on-treatment ctFE could robustly risk-stratify patients with locally advanced and oligometastatic non-small cell lung cancer (NSCLC) treated with radiotherapy. EXPERIMENTAL DESIGN: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB-III NSCLC received MR-guided hypofractionated chemoradiation (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (day 10-14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: locally advanced NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with radiotherapy (OM-RW; n = 309). RESULTS: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), markedly outperforming Max VAF and ctFE detectability. Baseline ctFE was prognostic for OS (HR 5.93, p = 0.005) and PFS (HR 11.08, p < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both p < 0.001). Early ctFE dynamics defined three molecular response groups with striking OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; p < 0.001). ctFE remained associated with survival in both validation cohorts. CONCLUSIONS: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in locally advanced and oligometastatic NSCLC treated with radiotherapy, supporting its use as a practical biomarker for precision treatment adaptation.
Serrano C, Elliott A, Gómez-Peregrina D
… +14 more, Evans MG, George S, von Mehren M, Maki RG, Boikos SA, Charlson JA, Dhir A, Florou V, Mahadevan D, Oberley MJ, Sledge GW, Tinoco G, Riedel RF, Trent JC
Clin Cancer Res
· 2026 Apr · PMID 42059893
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PURPOSE: Gastrointestinal stromal tumor (GIST) is a genomically-driven neoplasm with a genetic profile that determines the clinical course of the disease. However, currently available molecular data is limited due to the...PURPOSE: Gastrointestinal stromal tumor (GIST) is a genomically-driven neoplasm with a genetic profile that determines the clinical course of the disease. However, currently available molecular data is limited due to the rarity of the disease and does not fully capture GIST clinical and biological heterogeneity. EXPERIMENTAL DESIGN: To gain deeper insight into the molecular landscape of GIST, we performed a comprehensive multi-omic analysis (targeted panel, whole exome sequencing, whole transcriptomics) in a large real-world, multicenter cohort including 1,427 cases. Pathological review was undertaken in KIT/PDGFRA-wild type cases. Molecular findings were correlated with clinical data and insurance claims outcomes. RESULTS: There is a complex spectrum of multi-layered genetic events that converge in three GIST molecular subgroups: KIT-mutant, PDGFRA-mutant, and KIT/PDGFRA-wild-type. These alterations can only be captured using next-generation sequencing technologies, and are associated with clinical features, biological aggressiveness, and patient outcomes. Mutations in alternative genes, whether actionable or not, are seldom present and unlikely to contribute to tumor progression. By contrast, the cooperative effect of novel somatic copy number alterations may be required for GIST evolution and progression, in addition to the core set of events involved in the current cytogenetic model of tumorigenesis. CONCLUSIONS: This molecular landscape provides a broader molecular understanding of GIST and supports a widespread use of genetic profiling for patients' clinical management.
Sharma S, Mundhara N, Tekoglu E
… +12 more, Amaral A, Gu P, Luo J, Xie S, Konchou MM, Pepra-Ameyaw P, De Marzo AM, Brennen WN, Baraban EG, Lotan TL, Lack NA, Shenderov E
Clin Cancer Res
· 2026 Apr · PMID 42053993
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PURPOSE: Advanced Prostate Cancer (PCa) management suffers from therapeutic resistance due to naturally transient or AR-dependent expression of clinically actionable surface targets. We aimed to identify the most promisi...PURPOSE: Advanced Prostate Cancer (PCa) management suffers from therapeutic resistance due to naturally transient or AR-dependent expression of clinically actionable surface targets. We aimed to identify the most promising clinically relevant PCa targets using RNA and protein expression levels across the PCa continuum-hormone-sensitive, castration-resistant, neuroendocrine, and "double-negative" prostate cancer (DNPC). EXPERIMENTAL DESIGN: We performed integration of a large single-cell transcriptomics atlas (JHU-PANORAMA, ~1 million cells and 213 patients) and PDX models for systematic investigation of clinically relevant surfaceome, followed by proteomic validation on patient samples and mechanistic investigations on PCa cell lines and patient samples. RESULTS: B7-H3 was found to be the most uniformly expressed across the entire PCa continuum. JHU-PANORAMA is made available for interactive visualization as RShiny webapp. Further mitigation of therapeutic resistance is proposed through a systematic framework for bispecific antibody design, where B7-H3 demonstrated high combinatorial scores with TROP-2, NECTIN1, KLK2, and NECTIN4. B7-H3 was also shown to be negatively regulated by AR and synergistically inhibited tumor growth when combined with androgen inhibition. CONCLUSIONS: B7-H3 demonstrates low inter-patient and intra-tumoral heterogeneity with significant synergistic effects in combination with AR inhibition. These properties could uniquely place B7-H3 as a broad-spectrum therapeutic target with the potential to combine B7-H3 based therapeutics with standard ADT for synergistic effects to overcome therapeutic resistance across the PCa disease continuum.
Hahn A, Irenaeus S, Sandin LC
… +11 more, Nordström C, Wenthe J, Lövgren T, Eriksson E, Alsaqal S, Pahnke S, Sundin A, Leja Jarblad J, Gustafsson Liljefors M, Loskog A, Ullenhag GJ
Clin Cancer Res
· 2026 Apr · PMID 42053989
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PURPOSE: Patients with advanced cancer have a poor prognosis and need for novel treatments. LOAd703 is a tumor microenvironment (TME) gene engineering viral vector encoding genes targeting the CD40 and 4-1BB pathways. In...PURPOSE: Patients with advanced cancer have a poor prognosis and need for novel treatments. LOAd703 is a tumor microenvironment (TME) gene engineering viral vector encoding genes targeting the CD40 and 4-1BB pathways. In this study, tolerability (primary endpoint), response activity, and the capacity to inflame the TME were evaluated. PATIENTS AND METHODS: In an open-label, single arm phase I/IIb clinical trial (NCT03225989), maximum eight intratumoral injections of LOAd703 were administered biweekly combined with a gemcitabine-based chemotherapy regimen, either standard-of-care treatment or conditioning gemcitabine if no standard options were available. Dose escalation followed a standard 3+3 design (phase I) and, to optimize dosage, the two highest dose levels were expanded in phase II. RESULTS: Forty-one patients were enrolled with pancreatic cancer (n=29), colorectal cancer (n=5), ovarian cancer (n=4) and biliary cancer (n=3). The treatment was overall well tolerated with the most common adverse events attributed to LOAd703 being pyrexia (76%), chills (39%) and fatigue (34%), mostly grade 1-2. The overall response rate (ORR) was 0 in the LOAd703 dose cohort 5x1010 viral particles (VP), 25% in 1x1011 VP, and 12% in 5x1011 VP. All patients with an objective response had pancreatic cancer and were treated in first line (ORR 35%). The TME showed a significant upregulation of Th1 immunity biomarkers at week 13 post treatment initiation. CONCLUSIONS: TME gene engineering using LOAd703 inflamed immune cold tumors and was followed by long term stabilized disease in several patients. Further evaluation of LOAd703 together with chemotherapy and/or checkpoint inhibitors is warranted.