Lotan Y, Luu M, Liu M
… +15 more, Tikhonekov S, Kobayashi T, Ahdoot M, Kim HL, Porten S, Peers G, Kita Y, Daskivich T, Murakami K, Sakatani T, Pagano I, Zheng Y, Zhang Z, Furuya H, Rosser CJ
Clin Cancer Res
· 2026 Jul · PMID 42391037
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BACKGROUND: More than 50% of patients with non-muscle invasive bladder cancer (NMIBC) experience recurrence, requiring lifelong surveillance with repeated cystoscopy. Given the invasive nature and cost of cystoscopy, acc...BACKGROUND: More than 50% of patients with non-muscle invasive bladder cancer (NMIBC) experience recurrence, requiring lifelong surveillance with repeated cystoscopy. Given the invasive nature and cost of cystoscopy, accurate non-invasive tools are needed to support risk-adapted monitoring. We evaluated the ability of Oncuria-Monitor to detect recurrent bladder cancer (BC) during surveillance. METHODS: Between February 2017 and August 2020, six medical centers in the United States and Japan prospectively enrolled 300 patients with a history of BC, generating 1,248 serial urine samples. Participants were divided into training and validation cohorts. At each surveillance visit over two years, urine samples were analyzed in a blinded manner using Oncuria-Monitor and BladderChek™, alongside urine cytology. Test performance was compared with cystoscopy and histopathology-confirmed recurrence. RESULTS: Recurrent BC was identified in 31% (93/300) of participants, with 143 total recurrences during follow-up, including 90 tumors in the validation cohort. In the validation cohort, Oncuria-Monitor achieved a sensitivity of 85.6% (95% CI: 78.1-92.2%) and negative predictive value (NPV) of 93.0% (95% CI: 89.2-96.4%). In comparison, BladderChek™ demonstrated a sensitivity of 20.0% and NPV of 88.0%, while urine cytology showed a sensitivity of 36.9% and NPV of 91.6%. The number needed to evaluate to detect one recurrence was 3 for both cystoscopy and Oncuria-Monitor, compared with 15 for BladderChek™ and 8 for cytology. CONCLUSIONS: In this prospective study, Oncuria-Monitor demonstrated clinically actionable performance, enabling a rule-out strategy that could safely reduce cystoscopy in approximately 25% of surveillance visits. These findings support a paradigm shift toward biomarker-guided, risk-adapted surveillance in BC.
Gal-Mark N, Grunwald A, Gahramanov V
… +14 more, Hameiri-Grossman M, Shinderman-Maman E, Gaash D, Shichrur K, Mordoukh J, Oniashvili N, Chausky Barzakh E, Sever A, Amar S, Ash S, Birger Y, Izraeli S, Ebenstein Y, Berko ER
Clin Cancer Res
· 2026 Jul · PMID 42384765
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PURPOSE: Liquid biopsy monitoring in pediatric solid tumors is limited by low mutational burden and lack of trackable genomic drivers. We sought to develop a mutation-agnostic, methylation-based liquid biopsy framework e...PURPOSE: Liquid biopsy monitoring in pediatric solid tumors is limited by low mutational burden and lack of trackable genomic drivers. We sought to develop a mutation-agnostic, methylation-based liquid biopsy framework enabling universal molecular surveillance of high-risk neuroblastoma. EXPERIMENTAL DESIGN: Using whole-genome Oxford Nanopore Technologies sequencing of high-risk neuroblastoma tumors, we compared tumor-derived methylation profiles to a comprehensive atlas of normal human cell types and identified 72 neuroblastoma-specific differentially methylated regions (meNBLs) that were reliably detectable in cfDNA. Marker robustness and specificity were validated using independent neuroblastoma methylation datasets and assessed against methylation profiles from other cancer types. We established neuroblastoma as a distinct methylation entity within the reference atlas by integrating a panel of 25 meNBLs, enabling quantitative estimation of tumor-derived cfDNA. Assay performance was evaluated across diagnostic, remission, relapse, and healthy control samples and compared with mutation- and copy number-based approaches. RESULTS: Neuroblastoma-derived cfDNA was consistently detected at diagnosis and relapse, but was absent in healthy controls and during confirmed remission. Methylation-based deconvolution demonstrated high specificity, with no detectable background signal in controls, and improved performance relative to copy number-based tumor fraction estimation. Longitudinal profiling enabled early molecular detection of relapse and reliable disease monitoring. CONCLUSIONS: We establish a robust, mutation-independent methylation-based liquid biopsy strategy for neuroblastoma that enables accurate, quantitative disease monitoring across all high-risk patients including those lacking trackable genomic alterations. This approach supports clinical translation of methylation-based cfDNA deconvolution as a broadly applicable platform for pediatric precision oncology.
Nikanjam M, Pérez-Granado J, Gramling MW
… +2 more, Larvol B, Kurzrock R
Clin Cancer Res
· 2026 Jun · PMID 42378036
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Claudin 18.2 (CLDN18.2) is exclusively expressed on gastric mucosal cell tight junctions with minimal expression in other healthy adult tissues. Prior studies assessed expression by immunohistochemistry, mainly membrane...Claudin 18.2 (CLDN18.2) is exclusively expressed on gastric mucosal cell tight junctions with minimal expression in other healthy adult tissues. Prior studies assessed expression by immunohistochemistry, mainly membrane staining. The FDA CLDN18.2 threshold for zolbetuximab approval is ≥75% moderate to strong staining. Higher level expression has been seen in a number of cancers including (but not limited to) gastric, gastroesophageal junction (GEJ), pancreatic, and ovarian cancers. CLDN18.2 expression can change with treatment and can exhibit heterogeneity between tumor sites. Zolbetuximab is a recently FDA-approved anti-CLDN18.2 monoclonal antibody for first-line therapy of gastric/GEJ cancers in combination with chemotherapy based on the improvement in outcomes demonstrated in the biomarker selected populations of the SPOTLIGHT and GLOW trials. Given limited single-agent responses rates to zolbetuximab, a number of other CLDN18.2-directed therapies, including antibody-drug conjugates, CAR-T cells, and bispecific antibodies, are under exploration in clinical trials. Despite expression of CLDN18.2 on the gastric mucosa, these therapies have overall been tolerable in clinical trials, albeit with the use of aggressive anti-emetic regimens. Herein, we summarize CLDN18.2 expression in cancer along with clinical trials of zolbetuximab and other CLDN18.2-directed therapies. Given the variability in CLDN18.2 expression within and between tumor types, biomarker-driven approaches will be critical for patient selection in clinical trials and therapeutic approaches.
Sridalla K, Machhi JK, Vitello DJ
… +15 more, Chibucos A, Cox M, Wells A, Horowitz A, Rengaraju V, Shen C, Romero N, Temosihue I, Janczewski LM, Abad J, Dawravoo K, Bentrem D, Jennings LJ, Zhang Q, Chawla A
Clin Cancer Res
· 2026 Jun · PMID 42377115
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PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) carries high mortality despite multimodal therapy, and improved biomarkers are needed to guide perioperative care. This study evaluated the prognostic significance of KRAS...PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) carries high mortality despite multimodal therapy, and improved biomarkers are needed to guide perioperative care. This study evaluated the prognostic significance of KRAS-mutant circulating tumor DNA (ctDNA) detected by next-generation sequencing (NGS) and digital droplet PCR (ddPCR) in localized PDAC. EXPERIMENTAL DESIGN: In this prospective cohort study (2020-2024), patients with localized PDAC undergoing neoadjuvant chemotherapy (NAC) were enrolled across multiple sites within Northwestern Medicine. Blood samples for ctDNA were assessed at diagnosis, post-NAC, and post-resection using tumor-agnostic NGS and ddPCR targeting KRAS G12D/V/R mutations. Overall survival (OS) was assessed using Kaplan-Meier analysis. RESULTS: The cohort included 106 patients. At diagnosis, KRAS ctDNA was detected in 17.2% (17/99) by NGS and 64.9% (63/97) by ddPCR. Detection by both platforms was associated with shorter OS, with the higher-sensitivity ddPCR assay providing greater prognostic discrimination by identifying additional patients with poor outcomes not captured by NGS (NGS median OS 11.2 vs 30.5 months, p<0.001; ddPCR median OS 24.7 vs 70.9 months, p=0.004). Stratified by detection method, median OS was shortest in patients with ctDNA detected by both NGS and ddPCR (10.9 months), longest in those not detected by either platform (40.7 months), and intermediate in patients detected only by ddPCR (26.9 months; p<0.001). CONCLUSIONS: In localized PDAC, KRAS-mutant ctDNA detected by NGS or ddPCR was associated with worse survival. ddPCR identified additional patients missed by NGS. Integrating ddPCR with NGS ctDNA measures may improve perioperative risk stratification, though validation is needed before clinical implementation.
Lindsay HB, Billups CA, Kocak M
… +23 more, Alban TJ, Young Poussaint T, Wong P, Chan TA, Kovacic B, Makarov V, Juric I, Diaz-Montero CM, Srivastava R, Pavicic P, Parthasarathy P, Lenzen A, MacDonald TJ, Pollack IF, Vinitsky A, Robison NJ, Baxter P, Hwang EI, Leggas M, Khalil DN, Fangusaro J, Onar-Thomas A, Dunkel IJ
Clin Cancer Res
· 2026 Jun · PMID 42377093
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PURPOSE: The PBTC-051 study is the first pediatric evaluation of a CD40 agonist and assessed the safety, pharmacokinetics, and preliminary efficacy of sotigalimab in children and young adults with recurrent or progressiv...PURPOSE: The PBTC-051 study is the first pediatric evaluation of a CD40 agonist and assessed the safety, pharmacokinetics, and preliminary efficacy of sotigalimab in children and young adults with recurrent or progressive malignant central nervous system (CNS) tumors (stratum 1) and post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) (stratum 2). PATIENTS AND METHODS: This prospective phase 1 study conducted by the Pediatric Brain Tumor Consortium evaluated sotigalimab using a 3+3 design for dose escalation. Immune pharmacodynamics were assessed with RNA transcript analysis, T cell receptor sequencing, and cytokine profiling. RESULTS: 31 eligible patients were enrolled (stratum 1: 20, stratum 2: 11). The stratum 1 recommended phase 2 dose was 0.6 mg/kg every 3 weeks; the stratum 2 maximum tolerated dose was 0.3 mg/kg every 3 weeks. Five patients had dose-limiting toxicities. No patients had an objective response. For stratum 1, 6-month and 12-month progression-free survivals (PFS) were 13.3% (standard error [SE], 8.1%) and 6.7% (SE, 6.2%), respectively; for stratum 2, 6-month PFS and overall survival were 31.2% (SE, 14.8%) and 44.4% (SE, 16.6%), respectively. At all dose levels, the maximum serum concentration was reached at the end of infusion; no drug accumulation was detected. More than 40% of patients developed anti-drug antibodies. Signaling pathways associated with activated antigen presenting cells and T cells were enriched in patients with higher PFS, while increased loss of heterozygosity was noted in patients with lower PFS. CONCLUSIONS: Sotigalimab was well-tolerated in pediatric patients with recurrent or progressive CNS tumors and post-radiation pre-progression DIPG.
Heumann TR, Lu J, Wang H
… +25 more, Phelps M, Zhu Q, Anders R, Mitchell S, Leatherman J, Abbott N, Kim K, Imhof T, Xie Z, Partey A, Li D, Kunk PR, Iyer RV, Dayyani F, Kankeu LA, Kalyan A, Gbolahan OB, Javle MM, Davis SL, Florou V, Spencer K, Sharon E, Yarchoan M, Lesinski GB, Azad NS
Clin Cancer Res
· 2026 Jun · PMID 42377085
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PURPOSE: The addition of MEK inhibition to PD-L1 blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer (BTC). While MEK inhibitors may increase tumor cell immunogenicity, they c...PURPOSE: The addition of MEK inhibition to PD-L1 blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer (BTC). While MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance anti-tumor immunity in this combination. PATIENTS AND METHODS: We conducted a randomized, phase 2 trial evaluating atezolizumab (840mg IV days 1,15) in combination with the CD27 co-stimulatory mAb (CDX-1127/varlilumab [3mg/kg IV days 1, 15]), with/without the addition of a MEK inhibitor (cobimetinib [60mg oral daily days 1-21, off 22-28]) in unresectable BTC following at least 1 metastatic therapy. Overall response rate (ORR) and PFS were co-primary endpoints. Treatment-related changs in CD8+ tumor infiltrating lymphocytes (TIL) was the primary correlative outcome. RESULTS: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled (n=29[CAV],n=28[AV]. A majority (67%) had intrahepatic cholangiocarcinoma and 32% were immunotherapy-experienced. Both regimens were well-tolerated without new safety signals. Objective responses were rare (0%[CAV],3.8%[AV]). Median PFS was 2.40(CAV) and 1.84(AV) months (HR 0.67,95%CI[0.38,1.18]). Among immunotherapy-experienced patients, mPFS was 3.62(CAV) and 1.84(AV) months (HR 0.54,95%CI:[0.18-1.62]). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. CONCLUSIONS: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe but neither meaningfully improved outcomes in BTC treated in the later lines. Correlative tissue studies validated preclinical work that MEK inhibition increases CD8+TILs.
Wang H, Wang K, Zheng X
… +6 more, Dong D, Zhu X, Sui X, Teng H, Xing B, Wang W
Clin Cancer Res
· 2026 Jun · PMID 42377073
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PURPOSE: Given the underexplored combination of immune checkpoint inhibitors, tyrosine kinase inhibitors (TKIs), and radiotherapy in locally advanced, unresectable hepatocellular carcinoma (HCC), this study aimed to eval...PURPOSE: Given the underexplored combination of immune checkpoint inhibitors, tyrosine kinase inhibitors (TKIs), and radiotherapy in locally advanced, unresectable hepatocellular carcinoma (HCC), this study aimed to evaluate camrelizumab (a PD-1 inhibitor), apatinib (a TKI), and intensity-modulated radiotherapy (IMRT) for this setting and identify potential biomarkers. PARTICIPANTS AND METHODS: This single-arm phase 2 trial enrolled locally advanced, unresectable HCC patients who were systemic treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received IMRT (50-60 Gy) to all lesions plus camrelizumab (200 mg intravenously every 3 weeks) and apatinib (250 mg orally once daily) for up to 2 years. Primary endpoint was progression-free survival (PFS); secondary endpoints included response, overall survival (OS), and safety. RESULTS: Between October, 2020, and November, 2024, 44 patients were enrolled. 40 patients (90.9%) had BCLC stage C disease, including macrovascular invasion in 36 (81.8%) and lymph node spread in 11 (25.0%) cases. Objective response rate was 84.1%. The median PFS was 13.8 months and median OS was not reached. The 24-month PFS rate was 38.1% and OS rate was 70.2%, respectively. Grade 3-4 treatment-related adverse events occurred in 36 patients (81.8%), the most common being thrombocytopenia (36.4%) and hypertension (29.5%). No treatment-related deaths were observed. TP53 mutation in circulating tumor DNA was associated with worse clinical outcomes. CONCLUSION: Camrelizumab and apatinib with radiotherapy demonstrated encouraging efficacy with manageable toxicity in locally advanced, unresectable HCC, warranting randomized trials validation.
Cowzer D, Walch H, Atri P
… +24 more, Shah F, Huq R, Thummalapalli R, Nagib F, Varghese A, Khalil DN, Park W, Rousseau B, Cercek A, Erinjeri J, Yeh R, Do RK, Basturk O, Shia J, Chakravarty D, Berger MF, Schultz N, Gonen M, O'Reilly EM, Jarnagin W, Abou-Alfa GK, Solit DB, Chatila WK, Harding JJ
Clin Cancer Res
· 2026 Jun · PMID 42360806
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PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer (BTC); however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require furt...PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer (BTC); however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. EXPERIMENTAL DESIGN: We analyzed a prospectively maintained cohort of 1254 patients with histologically confirmed BTC who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. RESULTS: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2- and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. CONCLUSIONS: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted next-generation sequencing of BTC and affirms the use of precision medicine in patients with these diseases. Characterization of genomic heterogeneity and therapeutic resistance has the potential to inform ongoing drug development efforts for BTC.
Medina S, Tokuyama N, Putcha V
… +16 more, Pathak T, Fu P, Thomas H, Subhash VV, Yip S, Lin HM, Horvath LG, Kench JG, Zhang A, Stockler MR, Joshua AM, Azad A, Oakes SR, Davis ID, Sweeney CJ, Madabhushi A
Clin Cancer Res
· 2026 Jun · PMID 42360803
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PURPOSE: The ENZAMET trial established that enzalutamide added to androgen deprivation therapy (ADT) improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), but treatment response is heter...PURPOSE: The ENZAMET trial established that enzalutamide added to androgen deprivation therapy (ADT) improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), but treatment response is heterogeneous. We tested whether the Artificial Intelligence Pathology Image Classifier (APIC), previously developed and locked in CHAARTED, predicts overall survival benefit from enzalutamide in ENZAMET. EXPERIMENTAL DESIGN: This biomarker study applied APIC to digitized hematoxylin and eosin specimens from ENZAMET (ANZUP 1304, NCT02446405). ENZAMET randomized participants with mHSPC to ADT plus enzalutamide or non-steroidal antiandrogen (NSAA), with early concurrent docetaxel permitted. APIC was applied without modification or retraining. The prespecified primary analysis evaluated the treatment-by-APIC interaction for OS using Cox models adjusted for standard clinical factors. Prespecified sensitivity analysis excluded participants receiving early concurrent docetaxel. RESULTS: Among 1125 participants, 492 with digitized tissue (median follow-up 68.8 months) were eligible. APIC classified 316 (64.0%) as APIC-negative and 176 (36.0%) as APIC-positive. APIC significantly modified enzalutamide benefit (interaction p=0.014). APIC-negative disease showed improved survival with enzalutamide versus NSAA (HR=0.50, 95%CI:0.35-0.73; 60-month OS 76.5% vs 58.3%), while APIC-positive showed limited evidence of benefit (HR=1.04, 95%CI:0.67-1.62; 60-month OS 55.6% vs 58.8%). In low-volume disease, enzalutamide improved survival in APIC-negative (HR=0.31, 95%CI:0.16-0.62) but not APIC-positive (HR=1.04, 95%CI:0.53-2.06; interaction p=0.015). For non-docetaxel-treated participants, enzalutamide benefit was greater in APIC-negative (HR=0.40; 60-month OS 82.0% vs 61.0%) than APIC-positive (HR=0.79; 60-month OS 62.8% vs 57.6%). CONCLUSIONS: The presence of APIC negative disease identified participants with a major improvement in OS with addition of enzalutamide to ADT compared with addition of NSAA.
Borghaei H, Balli D, Paz-Ares LG
… +24 more, Reck M, Lu S, Ramalingam SS, Brahmer JR, John T, Carbone DP, Ciuleanu TE, Schenker M, Cobo M, Zurawski B, Pluzanski A, Lee JS, Agrawal S, Spires T, Neely J, Ip V, Eccles LJ, Chang H, Szustakowski JD, Bhatia S, Yadav A, Eddy N, Geese WJ, O'Byrne KJ
Clin Cancer Res
· 2026 Jun · PMID 42360104
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PURPOSE: To identify variables associated with early detriment on first-line dual immunotherapy from the phase III CheckMate 227 and CheckMate 9LA studies. PATIENTS AND METHODS: Adults with stage IV/recurrent non-small c...PURPOSE: To identify variables associated with early detriment on first-line dual immunotherapy from the phase III CheckMate 227 and CheckMate 9LA studies. PATIENTS AND METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC) lacking EGFR/ALK alterations were randomized to nivolumab plus ipilimumab, nivolumab (PD-L1 ≥1%) or nivolumab plus chemotherapy (PD-L1 <1%), or chemotherapy in CheckMate 227 or to nivolumab plus ipilimumab with chemotherapy or chemotherapy in CheckMate 9LA. Multivariable analyses were used to identify factors associated with rapid progression (progression or death within 3 months of randomization) from nivolumab plus ipilimumab in CheckMate 227, and univariate analyses were used to assess rapid progression from nivolumab plus ipilimumab with/without the addition of chemotherapy from CheckMate 227 and CheckMate 9LA. RESULTS: Rapid progression rates were 40% with nivolumab plus ipilimumab versus 26% with chemotherapy. High neutrophil-to-leukocyte ratio, baseline tumor mutational burden (TMB) <14 mutations per megabase, tumor PD-L1 <1%, low albumin level, and higher-than-median baseline monocytic myeloid-derived suppressor cell (M-MDSC) level were associated with rapid progression in patients treated with nivolumab plus ipilimumab. Early detriment was not observed with nivolumab plus ipilimumab with chemotherapy across subgroups from CheckMate 9LA. Long-term survival favored nivolumab plus ipilimumab-containing treatment across subgroups. CONCLUSIONS: Neutrophil-to-leukocyte ratio, TMB, tumor PD-L1 expression, albumin level, and baseline M-MDSC level were associated with rapid progression in patients with metastatic NSCLC treated with first-line nivolumab plus ipilimumab. Relative to chemotherapy, early detriment was observed with nivolumab plus ipilimumab across biomarker subgroups but not with nivolumab plus ipilimumab with chemotherapy. Long-term benefit was maintained with both regimens.
Vujanovic L, Torres-Saavedra P, Tu F
… +22 more, Uppaluri R, Yao M, Chen J, Jordan R, Geiger JL, Jujjavarapu S, Chakravarti A, Phan M, Siddiqui F, Kulkarni A, Upadhyay P, Isett BR, Sica GL, Reeder C, Bao R, Chen J, Joy M, Freeman T, Harris J, Le QT, Bauman JE, Ferris RL
Clin Cancer Res
· 2026 Jun · PMID 42347893
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PURPOSE: Patients with pathologically high-risk, HPV-negative HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). As CRT can upregulate PD-1/L1 immune checkpoints, adding pembrolizumab may reverse...PURPOSE: Patients with pathologically high-risk, HPV-negative HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). As CRT can upregulate PD-1/L1 immune checkpoints, adding pembrolizumab may reverse treatment-induced immunosuppression. NRG-HN003 was a phase I trial assessing the safety and recommended phase II schedule of adjuvant pembrolizumab with CRT. Here, we report exploratory immune and genomic correlates of disease-free survival (DFS). PATIENTS AND METHODS: Thirty-four patients received pembrolizumab with CRT. PD-L1 expression was quantified by combined positive score (CPS) and spatial localization of PD-L1+ cells was assessed by multispectral imaging of baseline tumors. Disruptive TP53 mutations were evaluated by whole-exome sequencing. Soluble serum biomarkers were evaluated by Luminex, and circulating immune subsets were profiled by spectral flow cytometry at baseline and post-treatment. RESULTS: Patients with PD-L1 CPS≥20 showed numerically lower DFS than those with CPS<20; however, higher densities of PD-L1+ stromal cells were associated with more favorable outcomes. Disruptive TP53 mutations were not a significant negative prognostic factor. Among soluble markers at baseline, elevated serum arginase-1 was associated with inferior DFS, while higher levels of GM-CSF, IL-2 and nectin-2 were associated with more favorable outcomes. In circulating immune cells, higher baseline frequencies of CD8+ granzyme K+ T cells, as well as higher post-treatment frequencies of CD8+ CD39+ and regulatory CD4+ T cells, were associated with improved DFS. Increased effector and central memory T cell populations, especially post-treatment, also showed favorable associations with DFS. CONCLUSIONS: These findings highlight multiple potential immunologic correlates of pembrolizumab with CRT in high-risk HNSCC, supporting further evaluation and validation in larger, adequately powered trials.
Zamulko O, Nusbaum S, Osterburg A
… +14 more, Crist M, Lehn M, Monroe I, Romano A, Allen CL, Forsythe A, Riaz MK, Lemmon C, Takiar V, Pan J, Rai SN, Borchers M, El-Gamal D, Wise-Draper T
Clin Cancer Res
· 2026 Jun · PMID 42347882
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BACKGROUND: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, w...BACKGROUND: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this Phase 2 clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK cell activity. METHODS: Eligible patients were randomized 1:1 into two arms: (1) metformin ER dose escalation to 2000 mg over 14 days followed by combination with pembrolizumab 200 mg q3 weeks or (2) pembrolizumab 200 mg q3 weeks followed by combination with metformin ER 2000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated by CTCAE v5.0. The distribution, activation, and cytotoxic function of NK cells was analyzed by flow cytometry. RESULTS: Twenty-one patients were enrolled. 76% were male, 52% smokers, and median age was 64. Ten patients had oropharyngeal tumors, of which 9 were p16 positive. Eighteen patients were evaluable for response, including 4 complete and 5 partial responses for an ORR of 50% (95%CI [29,71]). Combination therapy was well tolerated with no unexpected adverse events (AEs). Five Grade 3 AEs occurred, including nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK cell maturation and cytotoxic ability. CONCLUSION: The combination of metformin and pembrolizumab was well tolerated with mild GI-associated AEs and promising activity warranting further investigation in a randomized trial.
Pelletier M, Yang J, Joshi M
… +27 more, Grauel A, Abecunas C, Altzerinakou MA, Zhou Z, Zhu X, Clark K, Li L, Bai LY, Milella M, Mercade TM, Tai WMD, Bockorny B, Grell P, Sivakumar S, Wong MK, Chee CE, Aparicio T, Prager G, Bostel G, Schiessl B, Maacke H, Dranoff G, Shaw A, Fabre C, Mataraza J, Malek S, Cremasco V
Clin Cancer Res
· 2026 Jun · PMID 42347868
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BACKGROUND: Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarc...BACKGROUND: Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human monoclonal antibody targeting TGFβ, demonstrated anti-fibrotic and immunomodulatory activity in preclinical models and early-phase trials. METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cfDNA profiling, and plasma proteomics. RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of CAF markers (ACTA2, FAP) and collagen-related signatures. Despite proof-of-mechanism, clinical efficacy was not observed: median PFS and OS were comparable or numerically worse in NIS793 arm versus control (HR for OS in NIS793+ABRA/GEM vs ABRA/GEM: 1.32; 95% CI: 0.84-2.07). Safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes post-treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763).
Repetto M, Richards AL, Chen MF
… +24 more, Selenica P, Suman S, Zhu Y, Wilhelm C, Price A, Yang SR, Wahl J, Hornby Z, Krein P, Hassig C, Chang J, Brannon R, Rosen E, Brown DN, Reis-Filho JS, Raj N, Rudin CM, Kris MG, Ventura A, Berger M, Weigelt B, Drilon A, Choudhury NJ, Donoghue MTA
Clin Cancer Res
· 2026 Jun · PMID 42340371
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PURPOSE: MYC, MYCN and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESI...PURPOSE: MYC, MYCN and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESIGN: We analyzed copy number alterations of MYC family genes and their features in over 68,000 tumor-normal paired samples from pediatric and adult patients sequenced with MSK-IMPACT and annotated with FACETS. The relationship between amplification features and MYC mRNA expression levels were evaluated in over 10,000 samples from the TCGA. RESULTS: Across MSKCC samples, MYC amplifications were most common, found in 2,949 samples compared to 310 in MYCL and 217 in MYCN. While MYCN and MYCL amplifications were predominantly focal (<10Mb, 79% and 93% respectively), MYC amplifications were frequently broader (>10Mb, 62%). While most tumor types showed similar features between broad and focal amplifications of MYC, in select cancer types we identified differing co-occurrence and mutual-exclusivity patterns with other disease specific drivers. Furthermore, while MYC amplified TCGA samples showed higher mRNA expression than wild-type ones, the focality of MYC amplification was seen to have limited influence on expression levels. CONCLUSIONS: Our results suggest that MYC-dependency likely depends on many factors including, but not limited to, total copy number of the detected amplification, lineage specific factors, concomitant presence or absence of additional oncogenic alterations, and in some cases amplification focality.
Nguyen D, Kantarjian HM, Bidikian A
… +20 more, Manuel CM, Qiao W, Ning J, DiNardo CD, Kadia TM, Daver N, Borthakur G, Jabbour E, Yilmaz M, Maiti A, Sasaki K, Montalban-Bravo G, Chien K, Hammond D, Pierce S, Andreeff M, Ravandi F, Short NJ, Garcia-Manero G, Issa GC
Clin Cancer Res
· 2026 Jun · PMID 42329225
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PURPOSE: Outcomes in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remain discouraging despite rapid expansion of treatment paradigms over the past decade. Clinicians must often decide between conv...PURPOSE: Outcomes in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remain discouraging despite rapid expansion of treatment paradigms over the past decade. Clinicians must often decide between conventional salvage treatment regimens or enrollment on clinical trials. EXPERIMENTAL DESIGN: We retrospectively identified 657 patients with AML in second treatment salvage and compared the outcomes of those who received investigational agents (N=354) versus conventional salvage regimens (N=303). RESULTS: Conventional salvage was associated with higher response rates (CR/CRi rate: 22% vs 12%, P=0.0008) and higher early mortality rates (60-day mortality: 17% vs 7%, P=0.0002). There was no difference in rates of bridging to allogeneic stem cell transplant (7% vs 10%, P=0.2), event free survival (EFS; median: 1.5 months vs 2.0 months, P=0.9) or overall survival (OS; median: 4.1 months vs 4.5 months, P=0.8). A subgroup analysis of conventional regimens showed improved EFS (median EFS: 3.6 months vs 1.4 months, P=0.004) and a trend towards improved OS (median OS: 7.5 months vs 3.8 months, P=0.06) with the addition of venetoclax in venetoclax-naïve patients. CONCLUSION: Enrollment of R/R patients on clinical trials is a suitable alternative to conventional salvage regimens, offering novel therapeutic approaches to improve upon the historically dismal outcomes in this setting.
Pinto N, Künkele A, Albert CM
… +18 more, Taylor MR, Ullom HB, Vitanza NA, Wilson AL, Cole BL, Yeung CCS, Wright JH, Huang W, Wendler J, Seidel K, Brown C, Gustafson J, Rawlings-Rhea SD, Beebe A, Mgebroff S, Gardner RA, Jensen MC, Park JR
Clin Cancer Res
· 2026 Jun · PMID 42312971
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PURPOSE: Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 (NCT02311621) was a first-in-human clinical trial for patients with relapsed and refractory neuroblastoma using chimeric anti...PURPOSE: Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 (NCT02311621) was a first-in-human clinical trial for patients with relapsed and refractory neuroblastoma using chimeric antigen receptor (CAR) T cells targeting L1CAM, an adhesion molecule that is overexpressed in neuroblastoma with limited normal tissue expression. PATIENTS AND METHODS: This trial evaluated three different CAR constructs: a short spacer second-generation 4-1BB CAR (2GS, Arm A), a short spacer third-generation 4-1BB+CD28 CAR (3GS, Arm B) and a long spacer second-generation 4-1BB CAR (2GL, Arm C). RESULTS: Thirty-six patients were enrolled and 22 were treated (Arm A/2GS n=11, Arm B/3GS n=8 and Arm C/2GL n=3). Thirty-four of 36 patients had a CAR T cell product successfully manufactured. Cytokine release syndrome, skin rash and hyponatremia were common ≥ Grade 2 toxicities. Hyponatremia was dose-limiting in 3 patients (DL5 Arm A/2GS, DL3 Arm B/3GS and DL2 Arm C/2GL). Patterns of toxicity appeared at lower dose levels on Arm B and Arm C compared to Arm A, suggesting differential potency of the third generation and long spacer products. No objective responses were seen. Correlative analyses demonstrated CAR T cell presence in tumor and skin, with evidence of macrophage tumor infiltration. CONCLUSIONS: While feasible to manufacture in a heavily pretreated population, L1CAM may not be an appropriate target in neuroblastoma. Additional engineering strategies may be needed to prevent toxicity and provide durable anti-tumor effects.
Low JL, Chong WQ, Hui EP
… +11 more, Tan TZ, Lai W, Le TBU, Sooi K, Walsh RJ, Li WY, Kong LR, Lim YC, Chan ATC, Ma B, Goh BC
Clin Cancer Res
· 2026 Jun · PMID 42307653
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PURPOSE: Therapeutic options beyond platinum, gemcitabine and immunotherapy in r/m NPC remain limited. Median overall survival for R/M disease is 20 months. This study evaluated the efficacy and safety of FTD/TPI in plat...PURPOSE: Therapeutic options beyond platinum, gemcitabine and immunotherapy in r/m NPC remain limited. Median overall survival for R/M disease is 20 months. This study evaluated the efficacy and safety of FTD/TPI in platinum-resistant R/M NPC. EXPERIMENTAL DESIGN: In this single-arm, phase II study, patients received oral FTD/TPI at 35 mg/m² twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR) and safety. RESULTS: Thirty-five patients were enrolled. Median age was 56 years with a median of 2 prior lines of systemic therapy (range, 1-7). 45% had prior fluoropyrimidine. DCR at 12 weeks was 57.1% (95% CI: 39.4%-73.7%) and the ORR was 22.9% (95% CI: 10.4-40.1). DCR was comparable with and without fluoropyrimidine exposure (55.6% vs 58.8%). Median PFS was 6.5 months, and median OS was 13.1 months. Treatment-emergent adverse events were predominantly hematologic, including ≥ Grade 3 neutropenia (43%), anemia (26%), and thrombocytopenia (9%), with grade ≥3 events largely hematologic. Dose modifications were required in 60%, most commonly due to neutropenia, manageable with dose reduction. One patient discontinued treatment due to symptomatic anemia. G3-4 neutropenia was significantly associated with improved ORR (p<0.001). Exploratory plasma proteomic analyses suggested potential differences in baseline and on-treatment protein expression between responders and non-responders, warranting further validation in larger cohorts. CONCLUSION: FTD/TPI demonstrated a manageable safety profile and encouraging antitumor activity. It is a convenient oral alternative to intravenous chemotherapy.
Jimenez M, Hatton BA, Moreno-Gonzalez A
… +15 more, Iding JS, Flandes J, van der Heijden EHFM, Ng CSH, Prieto C, Teodosio C, Flores-Montero JA, Rodríguez-González M, Cedeño Diaz OM, Vos S, Lau RWH, Kaiza ME, Moore WH, Orfao A, Bruno TC
Clin Cancer Res
· 2026 Jun · PMID 42307634
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PURPOSE: This treat-and-resect clinical study evaluated a specialized form of pulsed electric field (PEF) ablation's potential to modulate antitumor immunity in early-stage non-small cell lung cancer (NSCLC). Tertiary ly...PURPOSE: This treat-and-resect clinical study evaluated a specialized form of pulsed electric field (PEF) ablation's potential to modulate antitumor immunity in early-stage non-small cell lung cancer (NSCLC). Tertiary lymphoid structures (TLS) are lymphoid aggregates that recruit immune cells into the tumor microenvironment (TME) and serve as immunity-generating neighborhoods. TLS with germinal centers (GC) have strong prognostic value in most cancers and promote tumor control and responsiveness to immune-based therapies, but no commercially available therapeutics induce their formation. The Aliya System is a proprietary electrosurgical technology that delivers microsecond electrical pulses to tissue, achieving tumor clearance while maintaining stromal architecture. PATIENTS AND METHODS: Treatment group patients received ablation immediately after diagnostic biopsy versus a biopsy-only control group. Herein we report on exploratory endpoints examining immune modulation in blood and tumor samples collected from patients in both groups. RESULTS: Histopathological assessments revealed the presence of TLS with GC in resected tumors. Tissue cytokine assessments and single-cell RNA sequencing demonstrated upregulation of cytokines capable of recruiting and organizing TLS-associated lymphocytes, including CXCL13, and significant increases in GC-related immune populations, including class-switched memory B cells and plasma cells in ablated tumors versus pre-ablation biopsies. Ablation group patients had more tumors containing TLS with GC (47%) vs. control (24%). Ablation group patients exhibited enhanced systemic immunity, with increased serum HMGB1 and circulating cytotoxic T cells. CONCLUSIONS: This specialized PEF may orchestrate multiple simultaneous changes that promote a more immunologically active TME and represent a new approach for improving immunotherapeutic regimen responses in NSCLC patients.
Clin Cancer Res
· 2026 Jun · PMID 42307267
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P-PSMA-101 is a first-in-class, stem cell memory T cell-enriched, PSMA-targeting CAR-T therapy. This cellular therapy showed notable clinical activity in two patients; however, PSA50 responses were generally modest. Whil...P-PSMA-101 is a first-in-class, stem cell memory T cell-enriched, PSMA-targeting CAR-T therapy. This cellular therapy showed notable clinical activity in two patients; however, PSA50 responses were generally modest. While severe immune effector-related toxicities were observed in some patients, a novel iCasp9 safety switch was largely effective in mitigating toxicity.
Clin Cancer Res
· 2026 Jun · PMID 42301752
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Low-dose intestinal irradiation challenges the long-standing view of the gut as a radiation-sensitive organ to avoid. Clinical and mechanistic data suggest that targeted exposure of the small intestine within a 1 to 3 Gy...Low-dose intestinal irradiation challenges the long-standing view of the gut as a radiation-sensitive organ to avoid. Clinical and mechanistic data suggest that targeted exposure of the small intestine within a 1 to 3 Gy window can remodel the microbiome and enhance systemic antitumor immunity.