Lawn S, Hernandez Rojas A, Wong J
… +19 more, Degefie L, Sagoe-Wagner A, Wu A, Bissessur A, Bonderud M, Wu K, Alonzo D, Das S, Chan P, Fung V, Yang L, Winters GC, Stahl K, Urosev D, Frantzen K, Moore PA, Colombo R, Barnscher SD, Rich JR
Clin Cancer Res
· 2026 Jul · PMID 42007996
·
Publisher ↗
PURPOSE: Multiple antibody-drug conjugates (ADC) are approved for the treatment of human cancers, yet there remains significant potential for design improvements through iterative learnings from nonclinical and clinical...PURPOSE: Multiple antibody-drug conjugates (ADC) are approved for the treatment of human cancers, yet there remains significant potential for design improvements through iterative learnings from nonclinical and clinical experience. ZW191 is a clinical-stage ADC bearing a novel topoisomerase I inhibitor payload and targeted to the clinically validated tumor antigen folate receptor α (FRα). EXPERIMENTAL DESIGN: The nonclinical activity and tolerability profiles of ZW191 were assessed in vitro and in vivo, focusing on properties of its antibody and payload components. RESULTS: ZW191 has a highly differentiated efficacy and tolerability profile, markedly improving on the FDA-approved FRα-targeted ADC mirvetuximab soravtansine in its activity in tumors with both high and low levels of FRα in multiple patient-derived xenograft models of ovarian cancer, endometrial cancer, non-small cell lung cancer, and triple-negative breast cancer. ZW191's novel FRα-targeting antibody demonstrates unique binding properties and is superior to multiple other clinical-stage ADC antibodies in its internalization, payload delivery, and penetration through 3D tumor spheroids. ZW191's novel payload drives strong antitumor activity in vitro, including bystander activity. Furthermore, ZW191 is effective in vivo in combination with clinically relevant standard-of-care drugs carboplatin, bevacizumab, and paclitaxel. ZW191's best-in-class tolerability profile in Good Laboratory Practice nonhuman primate toxicity studies is owing to its payload's moderate potency-an ADC feature that we show from a clinical landscape analysis allows for higher dosing in humans. CONCLUSIONS: ZW191 demonstrates favorable preclinical efficacy and tolerability. This differentiated profile is supported by initial clinical data, potentially positioning ZW191 to meaningfully improve responses and substantially widen the targetable patient population over standard-of-care treatment.
Yu K, Tidwell RS, Bathala TK
… +28 more, Sheth RA, Karki M, Chen J, Qian J, Duan F, Perelli L, Soeung M, Rao P, Siefker-Radtke AO, Daw NC, Ingram DR, Shamsutdinova D, Wani KM, Wang WL, Lazar AJ, Zhao Z, Prabhakaran S, Bota-Rabassedas N, Futreal A, Rare Tumor Initiative Team, Patient Mosaic Team, Yang L, Lin C, Genovese G, Gao J, Wang L, Tannir NM, Msaouel P
Clin Cancer Res
· 2026 May · PMID 42007903
·
Publisher ↗
PURPOSE: SMARCB1-deficient renal medullary carcinoma (RMC) is an aggressive kidney cancer lacking mechanism-directed therapies. We conducted a single-center, single-arm, phase II study (NCT03587662) testing the proteasom...PURPOSE: SMARCB1-deficient renal medullary carcinoma (RMC) is an aggressive kidney cancer lacking mechanism-directed therapies. We conducted a single-center, single-arm, phase II study (NCT03587662) testing the proteasome inhibitor ixazomib combined with gemcitabine and doxorubicin. PATIENTS AND METHODS: Ixazomib 5.5 mg, gemcitabine 756 mg/m2, and doxorubicin 42 mg/m2 were given every 2 weeks for up to 13 cycles, followed by ixazomib plus gemcitabine maintenance. Coprimary endpoints were objective response rate (ORR) and 28-week disease-control rate (DCR) versus historic gemcitabine plus doxorubicin. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty patients (median age 34.5 years old, 90% Black) were treated. The posterior ORR was 36% [95% credible interval (CrI), 21%-54%] with a 91.4% probability of exceeding historic doublet therapy. However, the 28-week DCR was 17% (95% CrI, 6%-31%), crossing the predefined futility boundary. Median PFS and OS were 3.5 and 7.4 months, respectively. Grade ≥3 toxicities were predominantly hematologic (thrombocytopenia 20%, leukopenia 17%) and manageable, with no treatment-related deaths. Single-cell and bulk multi-omics from 11 patients revealed that immune-inflamed tumors enriched for T cells and plasmacytoid/conventional dendritic cells correlated with response, whereas stromal-myeloid niches and proliferative or neuroendocrine-squamous plastic epithelial states associated with resistance. Resistant tumors upregulated unfolded protein response, proteostasis maintenance, and NF-κB pathways. CONCLUSIONS: Addition of ixazomib to gemcitabine plus doxorubicin modestly increased radiographic response but did not extend disease control in an all-comer biomarker-unstratified RMC cohort. The integrated correlatives nominate mechanisms and biomarkers to guide future mechanism-directed trials in RMC.
Campani C, Shim JH, Bouattour M
… +26 more, Touchefeu Y, Delhoume V, Rosmorduc O, Pascale A, An J, Lee HC, Regnault H, Thabut D, Amaddeo G, Ningarhari M, Ollivier-Hourmand I, Métivier C, Ronot M, Ntandaja-Wandji L, Ozenne V, Sidali S, Marra F, Hollande C, Ganne-Carrié N, Nahon P, Peron JM, Lequoy M, Sharma R, Liver Cancer Group P, Allaire M, Nault JC
Clin Cancer Res
· 2026 Apr · PMID 42008357
·
Publisher ↗
BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) can induce long-term survival and even cancer cure in several cancers. Mixture cure models (MCMs) estimate the fraction of long-term survivors and cured patients but...BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) can induce long-term survival and even cancer cure in several cancers. Mixture cure models (MCMs) estimate the fraction of long-term survivors and cured patients but have not been applied in HCC. METHODS: We identified phase 3 randomized trials of first-line ICI in advanced HCC with mature follow-up (≥30 months) and analyzed a cohort of HCC patients treated with atezolizumab-bevacizumab. After reconstructing Kaplan-Meier curves, MCMs estimated long-term survivors' fraction (overall survival, OS) and cure fractions (progression-free survival, PFS). RESULTS: In HIMALAYA (median follow-up of 60 months), long-term survival was 12.8% (95%CI:8.5-18.6%) with durvalumab-tremelimumab versus 5.2% (95%CI:2.6-10.2%) with sorafenib; cure fraction was not assessable.In CheckMate9DW (median follow-up: 35.2 month), long-term survival was 8.7% (95%CI:0.2-81.3%) versus 4.1% (95%CI:0.1-66.1%) and cure fractions were 17.8% (95%CI:12.0-25.8%) versus 3.5% (95%CI:0.7-16.7%) for nivolumab-ipilimumab and sorafenib/lenvatinib respectively with long-term OS estimates remaining exploratory due to limited late numbers at risk.In RATIONALE-301, long-term survival was 25.2% (95%CI:19.2-32.2) with tislelizumab versus 15.4% (95%CI: 10.0-22.8) with sorafenib. IMbrave150 trial was not analyzed due to insufficient follow-up (15.6 months). Among a clinical cohort of 1581 patients treated by atezolizumab-bevacizumab (median follow-up: 34.7 months), long-term survival was 12.3% (95%CI:9.3-16.1%) and cure fraction 7.9% (95%CI:6.3-9.8%). In 1187 patients meeting IMbrave150 criteria, long-term survival reached 15.4% (95%CI:10.6-18.5%) and cure fraction 9.1% (95%CI:7.3-11.4%).ALBI score, and hepatitis C predicted long-term survival and albumin and hepatitis C predicted cure. CONCLUSION: Across trials and real-world data, ICIs combinations achieve long-term survival in 10-15% of advanced HCC patients, with cure fractions of 7-9%.
Li Z, Izadmehr S, Hoffman-Censits J
… +23 more, Maughan B, Mayer T, Tan A, Brody R, Xie H, Nie K, Kelly G, Ioannou G, Cabal R, Tuballes K, Guo R, Figueiredo I, Del Valle DM, Mehrazin R, Yu M, Zhao Q, Kim-Schulze S, Sfakianos JP, Gupta S, Hahn NM, Gonzalez-Kozlova E, Gnjatic S, Galsky MD
Clin Cancer Res
· 2026 Apr · PMID 42001507
·
Publisher ↗
Purpose Oxaliplatin has demonstrated the ability to sensitize tumors to immune checkpoint blockade through its immunomodulatory properties in model systems of cancer. This randomized trial aimed to evaluate gemcitabine/o...Purpose Oxaliplatin has demonstrated the ability to sensitize tumors to immune checkpoint blockade through its immunomodulatory properties in model systems of cancer. This randomized trial aimed to evaluate gemcitabine/oxaliplatin and gemcitabine/carboplatin, each combined with nivolumab, in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. Patients and Methods Cisplatin-ineligible patients with mUC were randomized 1:1 to gemcitabine/carboplatin plus nivolumab or gemcitabine/oxaliplatin plus nivolumab for up to 6 cycles, followed by nivolumab monotherapy. A pick-the-winner design was employed with objective response rate (ORR) as the primary endpoint. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory analyses evaluated plasma protein analytes, circulating immune cell populations, and circulating tumor cells. Results Forty-nine patients were enrolled (carboplatin arm, N = 25; oxaliplatin arm, N = 24). The ORR was 69.6% (95% confidence interval [CI] 0.48-0.87) for the carboplatin arm and 33.3% (95% CI 0.15-0.57) for the oxaliplatin arm. Median OS was 24.74 months and 16.43 months for the carboplatin group and oxaliplatin arms, respectively (hazard ratio 1.99, 95% CI 0.94-4.22; p = 0.07). Exploratory biomarker analyses revealed sustained adaptive immune activation in the carboplatin arm and features suggestive of tumor-promoting inflammation in the oxaliplatin arm. Conclusions Oxaliplatin-based chemo-immunotherapy, versus carboplatin-based chemo-immunotherapy, did not yield a higher response rate, challenging assumptions based on preclinical data.
Canzoniero JV, Rabizadeh D, Ziakas I
… +22 more, Wehr J, Balan A, Jamali A, Landon BV, Sivapalan L, Scott S, Pereira G, Lam VK, Hann CL, Lovly CM, Tao J, Forde PM, Murray JC, Sausen M, Meijer GA, Vink GR, Fijneman RJA, MEDOCC Group, Velculescu VE, Phallen J, Scharpf RB, Anagnostou V
Clin Cancer Res
· 2026 May · PMID 42001480
·
Full text
PURPOSE: Targeted next-generation sequencing (NGS) of cell-free DNA (cfDNA) enables comprehensive molecular profiling and can guide the selection of genotype-targeted therapies. However, the detection of variants derived...PURPOSE: Targeted next-generation sequencing (NGS) of cell-free DNA (cfDNA) enables comprehensive molecular profiling and can guide the selection of genotype-targeted therapies. However, the detection of variants derived from clonal hematopoiesis (CH) is a significant confounder in liquid biopsies. EXPERIMENTAL DESIGN: Using a training cohort of 426 variants identified in cfDNA NGS from 225 patients with stage I to IV solid tumors, we developed plasma Clonal Hematopoiesis ORigin Detection (plasmaCHORD), a machine learning model that includes fragment-, variant-, and patient-level features to distinguish between tumor and CH origin for each variant detected by liquid biopsies. Model performance was assessed by comparison with the reference origin for each plasma variant determined from matched white blood cell and tumor NGS. Following the locking of the model parameters, we applied plasmaCHORD to an independent validation cohort of 1,418 plasma variants detected in 114 patients with metastatic cancers, as well as to cfDNA NGS from patients enrolled in a prospective clinical trial (NCT05585684). RESULTS: plasmaCHORD predicted tumor origin versus CH origin in the training set with high accuracy (AUC = 0.94). In the independent validation cohort, the locked model maintained similar overall accuracy (AUC = 0.9) and demonstrated significant improvement in accuracy for clinically significant genes. When applied to clinically challenging cases in the context of a precision oncology clinical trial, plasmaCHORD precisely determined variant origin, preventing mismatches with genotype-targeted therapies. CONCLUSIONS: plasmaCHORD, a multifeature machine learning model, can significantly enhance the ability to identify bona fide tumor variants in routine plasma-only NGS, addressing a critical need for implementing liquid biopsy-guided therapy by minimizing misinterpretation caused by CH.
Chauhan PS, Pachynski RK, Maher CA
… +1 more, Chaudhuri AA
Clin Cancer Res
· 2026 Jun · PMID 41996129
·
Full text
Longitudinal plasma cell-free DNA profiling from the phase 3 Alliance A031201 trial revealed divergent resistance trajectories in metastatic castration-resistant prostate cancer. Rapid progressors harbored non-androgen r...Longitudinal plasma cell-free DNA profiling from the phase 3 Alliance A031201 trial revealed divergent resistance trajectories in metastatic castration-resistant prostate cancer. Rapid progressors harbored non-androgen receptor (AR) alterations suggesting intrinsic resistance, whereas delayed progressors showed progressive AR amplifications, structural rearrangements, and extrachromosomal DNA-associated evolution. These findings support biomarker-guided strategies targeting AR-dependent and AR-independent disease states. See related article by Valentín López et al., p. 2413.
Yoshimura S, Li Y, Inoue S
… +16 more, Meyer CT, Yang X, Du G, Hsiao YC, Li Z, Yang W, Hu J, Andersen CL, Saygin C, Karol SE, Bernt KM, Yu J, Stock W, Teachey DT, Konopleva M, Yang JJ
Clin Cancer Res
· 2026 Apr · PMID 41995729
·
Full text
PURPOSE: BH3 mimetics targeting anti-apoptotic BCL2 family proteins are promising therapeutics for T-cell acute lymphoblastic leukemia (T-ALL). However, their activity across genomic subtypes of this cancer and interacti...PURPOSE: BH3 mimetics targeting anti-apoptotic BCL2 family proteins are promising therapeutics for T-cell acute lymphoblastic leukemia (T-ALL). However, their activity across genomic subtypes of this cancer and interactions with other anti-leukemic agents remain incompletely defined. EXPERIMENTAL DESIGN: We evaluated the ex vivo sensitivity of BCL2/BCL-XL dual, BCL2-, BCL-XL-, and MCL1-selective inhibitors across 58 T-ALL patient-derived xenografts representing diverse molecular subtypes. The BCL2-BCL-XL dual inhibitor AZD4320 was further assessed in combination with selected anti-leukemic agents. Drug responses were quantified by dose-dependent induction of apoptosis and integrated with genomic and functional analyses. RESULTS: AZD4320 demonstrated subtype-specific cytotoxicity, with increased sensitivity in ETP-like T-ALL and resistance in TAL1 αβ-like T-ALL. Gene network analysis revealed subtype-dependent activation of distinct BCL2 family proteins, with AZD4320 response associated with BCL2 and MCL1 activity. Drug-drug interaction analysis using the MuSyC algorithm showed that AZD4320 synergized by potency-rather than maximal efficacy-with asparaginase and dasatinib, particularly broad interaction with asparaginase across subtypes. In vivo, AZD4320-asparaginase combination therapy conferred survival benefit. Mechanistically, asparaginase-induced asparagine depletion promoted mitochondrial dysfunction, potentiating AZD4320-mediated cytotoxicity. CONCLUSIONS: These findings highlight genomic context in shaping BH3 mimetic responses and point to rational combination of this class of drugs with anti-leukemic agents such as asparaginase.
Sinicrope FA, Sharma N, Mohiuddin M
… +6 more, Saberzadeh-Ardestani B, Graham RP, Lewis JT, Li B, Abbott CW, Boyle SM
Clin Cancer Res
· 2026 Apr · PMID 41995725
·
Full text
PURPOSE: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic dMMR CRC, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-re...PURPOSE: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic dMMR CRC, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-related biomarkers associated with clinical outcomes following anti-PD-1 therapy. METHODS: Consecutive patients with metastatic dMMR CRC (N=39) treated with anti-PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. MSI burden was quantified as the percentage of unstable microsatellite loci using MSIsensor-pro. Associations with objective response were evaluated, and progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: Higher MSI burden was associated with improved objective response (P=0.018) and survival. Dichotomized MSI level (Q2-4 vs Q1) was associated with longer PFS (HR, 0.18; 95% CI, 0.06-0.56, p=0.003) and OS (HR, 0.20; 95% CI, 0.07-0.58, p=0.003), with similar results when modeled continuously. MSI burden correlated with neoantigen clonality but not burden (R=0.53, p=0.01). Responders exhibited significantly greater T-cell receptor repertoire diversity; both T- and B- cell receptor diversity were associated with survival. Although HLA-A, -B, -C expression was not prognostic, the HLA-B*07:02 allele was associated with best overall response. In contrast, overexpression of immune exhaustion-related genes and cytotoxic T-cell and NK-cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. CONCLUSIONS: Integrated exome/transcriptome profiling with MSI quantification identified MSI burden and adaptive immune repertoire diversity as potential correlates of response and survival following ICB. These findings suggest a mechanistic link between genomic instability, antigen recognition diversity, and immunotherapy benefit.
Desmedt C, Nguyen HL, Richard F
… +17 more, Linn S, Metzger Fihlo O, Poncet C, Wesseling J, Aalders K, Delorenzi M, Delaloge S, Pierga JY, Brain E, Vrijaldenhoven S, Van Baelen K, Maetens M, Rutgers E, Piccart M, van 't Veer L, Viale G, Cardoso F
Clin Cancer Res
· 2026 Apr · PMID 41995722
·
Publisher ↗
BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer after invasive breast cancer of no special type (IBC-NST). This retrospective analysis of the MINDACT trial investigated tra...BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer after invasive breast cancer of no special type (IBC-NST). This retrospective analysis of the MINDACT trial investigated transcriptomic differences between estrogen receptor-positive/HER2-negative (ER+/HER2-) ILC versus ER+/HER2- IBC-NST, classic and non-classic ER+/HER2- ILC, and, recurring and non-recurring ER+/HER2- ILC in patients with a low genomic risk and either a low (cL/gL) or high clinical risk (cH/gL). PATIENTS AND METHODS: We analyzed 4261 ER+/HER2- tumors (63.7%, 464 ILC, 3798 IBC-NST) with central pathology review. Differential gene expression analysis was adjusted for age and grade, followed by gene set enrichment analysis. Adjusted regression models evaluated associations of transcriptomic profiles with disease-free (DFS) and distant recurrence-free survival (DRFS). RESULTS: An increased expression of CDH1 (E-cadherin) in IBC-NST compared to ILC was observed. ILC showed more uptake of extracellular lipid sources (LPL, CD36, LEP, LEPR), while IBC-NST favored lipid synthesis (FASN). Decreased ER-signaling, increased PI3K/Akt-signaling, and differences related to the extracellular matrix was also observed in ILC. Classic and non-classic ILC differed subtly, notably in cell cycle regulation. In ER+/HER2- ILC patients with a cL/gL risk, enrichment of apoptosis, inflammatory response, hypoxia and oncogenic signaling (PI3K/Akt, Ras, c-Myc) was associated with worse survival. In contrast, in the cH/gL group, associations between ILC transcriptomic features and survival were more subtle. CONCLUSIONS: This represents the largest transcriptomic dataset for ILC from a clinical trial with central histology review. Findings may provide insights to refine treatment and relapse risk assessment for ILC patients.
Clin Cancer Res
· 2026 Apr · PMID 41995718
·
Publisher ↗
PURPOSE: Resistance to bevacizumab (Bev) remains a major challenge in the management of glioblastoma multiforme (GBM). Our previous work indicated that BMAL1 participates in lactate metabolism in GBM and may be involved...PURPOSE: Resistance to bevacizumab (Bev) remains a major challenge in the management of glioblastoma multiforme (GBM). Our previous work indicated that BMAL1 participates in lactate metabolism in GBM and may be involved in the mechanisms underlying Bev resistance. However, the specific roles of BMAL1 and lactate in this process require further investigation. EXPERIMENTAL DESIGN: This study employed a comprehensive strategy combining in vitro GBM cell line models, patient-derived xenografts (PDX), and in vivo mouse studies. Functional assays (CCK-8, 3D spheroid invasion), molecular techniques (ChIP-qPCR, Co-IP, IP-MS), and biochemical analyses were performed to dissect the mechanism. The clinical relevance of our findings was validated in five independent GBM cohorts and through analysis of human GBM tissues. RESULTS: We identified a previously unrecognized signaling axis in which lactate promotes BMAL1 expression via H3K18la modification at its promoter. In addition, lactate induces BMAL1 protein lactylation at lysine 123, which facilitates its nuclear translocation. IP-MS further showed that lactylated BMAL1 displays a strengthened interaction with TUBA1C, a protein essential for its nuclear import. This lactylation-dependent BMAL1/TUBA1C complex subsequently enhances VEGFA transcription, thereby driving Bev resistance. Importantly, targeting this pathway either by silencing BMAL1, inhibiting lactate transporters, or introducing a lactylation-deficient BMAL1-K123 mutant effectively restored Bev sensitivity in vitro and in vivo. CONCLUSIONS: These findings reveal a novel mechanism through which lactate-mediated lactylation of BMAL1 promotes Bev resistance in GBM, supporting the lactate/BMAL1/TUBA1C/VEGFA axis as a promising therapeutic target for overcoming Bev resistance in GBM patients.
Clin Cancer Res
· 2026 Jul · PMID 41995717
·
Full text
PURPOSE: The primary objective of dose-finding oncology trials (DFOT) is to determine the recommended phase II dose. Although dose selection has traditionally relied on clinician-reported safety outcomes, the goal of DFO...PURPOSE: The primary objective of dose-finding oncology trials (DFOT) is to determine the recommended phase II dose. Although dose selection has traditionally relied on clinician-reported safety outcomes, the goal of DFOTs increasingly focuses on the integration of safety, activity, and tolerability within decision-making, in line with modern dose optimization strategies. Seamless phase I/II designs often use decision frameworks to quantify trade-offs between outcomes to guide dose selection. However, assigning numerical values to reflect such trade-offs can be difficult as clinical judgments and interpretations often vary between investigators. EXPERIMENTAL DESIGN: With stakeholders, including clinical teams and patients, potentially considering their own prioritization of outcomes, generalized pairwise comparisons, including the win ratio (WR), provide a statistical framework mirroring this clinical decision-making by evaluating treatment benefit against prioritized outcomes. Using the WR, doses are compared across prespecified prioritized outcomes sequentially, with the optimal dose yielding the largest proportion of favorable (winning) patient-pair comparisons. This article presents WIN-DOSE, a hierarchical, multi-outcome WR-based approach for dose optimization. We demonstrate the performance of WIN-DOSE in a two-arm randomized dose optimization trial incorporating dose-limiting toxicities for safety, preliminary response for activity, and both dose intensity and patient-reported outcomes for tolerability. RESULTS: When one dose is clearly favorable, WIN-DOSE consistently identifies the optimal dose. We also demonstrate how the WR can accommodate different trade-offs between safety, activity, and tolerability, supporting transparent and clinically relevant dose selection. CONCLUSIONS: The WR can support transparent and clinically relevant patient-centric dose selection decision-making, aligning with the broader goals of early-phase DFOTs.
Simicic D, Alcicek S, Blair L
… +13 more, Saint-Germain M, Zöllner HJ, Ritter Z, Blakeley JO, Davies-Jenkins CW, Holdhoff M, Laterra J, Bettegowda C, Schreck KC, Lin DD, Barker PB, Kamson DO, Oeltzschner G
Clin Cancer Res
· 2026 Apr · PMID 41995710
·
Publisher ↗
PURPOSE: IDH-mutant (mIDH) gliomas are slow-growing infiltrating tumors of astrocytic or oligodendroglial origin. Mutated metabolic enzymes IDH1 or IDH2 lead to production of 2-hydroxyglutarate (2HG) that can be measured...PURPOSE: IDH-mutant (mIDH) gliomas are slow-growing infiltrating tumors of astrocytic or oligodendroglial origin. Mutated metabolic enzymes IDH1 or IDH2 lead to production of 2-hydroxyglutarate (2HG) that can be measured with optimized in-vivo magnetic resonance spectroscopy (MRS). Since the 2HG oncometabolite plays a key role in the molecular pathogenesis of mIDH tumor, direct suppression of 2HG production has proven to be a viable intervention strategy; for example, with the small-molecule inhibitors ivosidenib (mIDH1) and vorasidenib (mIDH1/mIDH2). The aim of this study was to explore whether MRS measurements of 2HG can be used to non-invasively monitor response to treatment with mIDH inhibitors and to relate this response to changes in MRI assessed tumor volume. EXPERIMENTAL DESIGN: 18 patients with diagnosed IDH-mutated glioma were enrolled and received ivosidenib or vorasidenib therapy. MRI/MRS scans with 2HG-optimized single-voxel PRESS were performed before treatment and repeated (follow-up) with a median on-drug follow-up of 4.3 months. RESULTS: In the 14 patients that passed spectroscopy quality control (median follow-up 3.9 months) we observed a substantial and significant decrease of 2HG levels (p < 0.001) regardless of tumor and treatment type (astrocytoma/oligodendroglioma, ivosidenib/vorasidenib), while total choline (tCho) and glutamine, metabolites characteristically increased in glioma, also showed a significant decrease (p < 0.01). Volumetric assessment revealed a modest decrease on average, indicating tumor growth arrest. CONCLUSIONS: The striking reductions in tumor 2HG and tCho levels early following initiation of targeted therapy using an IDH inhibitor suggest that MRS may provide an important tool for monitoring treatment response of lower-grade gliomas.
Ochoa-de-Olza M, Rayroux N, Imbimbo M
… +31 more, Orcurto A, Fahr N, Benedetti F, Dagher J, Spagnol G, Barras D, Ghisoni E, Navarro B, Mulvey A, Berthold D, Sarivalasis A, Zaman K, Stravodimou A, Digklia A, Duran R, Dromain C, Prior JO, Schaefer N, Zimmermann S, Obeid M, Chalkidis N, Zoi T, Bisig B, Trueb L, Gulhan DC, Sempoux C, Dafni U, Tissot S, Coukos G, Herrera FG, Dangaj Laniti D
Clin Cancer Res
· 2026 Apr · PMID 41995577
·
Publisher ↗
PURPOSE: Immune-checkpoint blockade (ICB) has demonstrated efficacy across tumor types. However, "cold" tumors characterized by low intraepithelial T-cell infiltration exhibit poor responsiveness. We investigated whether...PURPOSE: Immune-checkpoint blockade (ICB) has demonstrated efficacy across tumor types. However, "cold" tumors characterized by low intraepithelial T-cell infiltration exhibit poor responsiveness. We investigated whether low-dose radiotherapy (LDRT) could enhance ICB efficacy in patients with multimetastatic immune-excluded solid tumors. PATIENTS AND METHODS: We conducted a multi-cohort phase I clinical trial (RACIN) involving 25 patients treated with escalating doses of LDRT in combination with a backbone regimen of nivolumab, ipilimumab, aspirin or celecoxib, and low-dose cyclophosphamide. The primary endpoint were safety and tolerability; secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Exploratory endpoints analyses used paired pre- and post-LDRT tumor biopsies for single-cell profiling of the tumor microenvironment (TME). RESULTS: The combination therapy showed a manageable safety profile, with Grade ≥3 adverse events in 12-21% of patients. The overall DCR was 42%, with one ovarian cancer patient maintaining a complete response at three years. In responders, enhanced CD8⁺ TIL functionality associated with increased DNA damage response signatures and the presence of PD1⁺CD8⁺ TILs at baseline. In contrast, non-responders exhibited heightened immune regulatory innate lymphocytes such as CD8 MAIT and regulatory NK cells at baseline, accompanied by a lack of immune-stimulatory myeloid cells in the TME and increased TIL radiosensitivity post LDRT. CONCLUSIONS: These findingssuggest that LDRT combined with ICB is safe and may contribute to immunomodulatory activity in immune-excluded tumors. CD8⁺ TIL dynamics, DNA repair responsiveness, and TME composition may predict response and merit further validation in controlled larger studies.
Liu X, Li J, Li X
… +6 more, Yang X, Zhang Z, Yao S, Mi JQ, Wang W, Wang Y
Clin Cancer Res
· 2026 Apr · PMID 41985065
·
Publisher ↗
PURPOSE: Chimeric antigen receptor (CAR) T-cell immunotherapy in acute myeloid leukemia (AML) remains challenging due to the lack of specific cell surface antigens that are highly expressed on leukemic blasts but largely...PURPOSE: Chimeric antigen receptor (CAR) T-cell immunotherapy in acute myeloid leukemia (AML) remains challenging due to the lack of specific cell surface antigens that are highly expressed on leukemic blasts but largely absent in hematopoietic stem/progenitor cells (HSPCs) and healthy tissues. Targeting intracellular antigen via TCR-like CAR-T cells offers a promising alternative. This study aimed to develop nanobodies targeting the intracellular antigen PRAME and develop a novel nanobody-based TCR-like CAR-T cell therapy. EXPERIMENTAL DESIGN: We investigated PRAME expression level by analyzing the RNA sequencing data from 1,007 AML patients and healthy donor samples. We explored the relationships between PRAME expression and the prognosis of AML. Novel nanobodies targeting PRAME425-433/HLA-A2 were generated via alpaca immunization and yeast surface display, then used to construct TCR-like CAR-T cells. The antileukemia potency of the PRAME-targeted TCR-like CAR-T cells and their on-target/off-tumor toxicity against normal HSPCs were evaluated. RESULTS: PRAME was highly expressed in AML cells but largely absent in normal hematopoietic cells and healthy tissues, and is correlated with poor clinical outcomes in AML. The CAR-T cells based on the nanobody targeting PRAME425-433/HLA-A2 exhibited specific and potent anti-leukemic cytotoxicity against PRAME+HLA-A2+ AML cells in vitro and in vivo, whereas they showed negligible effects on the viability and function of normal HSPCs. CONCLUSIONS: This study demonstrates that PRAME is a promising target for the immunotherapy of AML, and nanobody-based TCR-like CAR-T cells targeting PRAME425-433HLA-A2 exhibit potent anti-leukemic activity with a favorable off-target safety profile.
Cosner Z, Guo Z, Nawrocki C
… +13 more, Patel B, Roberts HJ, Tanabe KK, Lau-Min KS, Walsh EP, Clark JW, Qadan M, Ferrone CR, Hong TS, Nieman LT, Ting DT, Wo JY, Franses JW
Clin Cancer Res
· 2026 Apr · PMID 41984885
·
Publisher ↗
PURPOSE: Although immune therapy regimens have significantly improved treatment options for patients with advanced hepatocellular carcinoma (HCC), optimal use of these regimens in earlier disease stages remains poorly de...PURPOSE: Although immune therapy regimens have significantly improved treatment options for patients with advanced hepatocellular carcinoma (HCC), optimal use of these regimens in earlier disease stages remains poorly defined. EXPERIMENTAL DESIGN: We conducted a single-institution, single-arm pilot study (NCT04857684) of neoadjuvant stereotactic body radiation therapy (SBRT) followed by two cycles of atezolizumab plus bevacizumab and subsequent surgical resection in patients with initially resectable HCC (n=8). The primary endpoint was safety as defined by the proportion of patients with grade 3-4 treatment-related adverse events (trAE) by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. And we dissected the detailed remodeling of the tumor immune microenvironment following treatment using single-cell-resolution spatial transcriptomics method. RESULTS: Only one patient experienced a grade 3 trAE. Seven of eight patients proceeded to surgery, and all achieved margin-negative (R0) resection; one patient did not proceed due to subsequent disagreement of resectability. One patient achieved a pathologic complete response, and all resected patients were relapse-free at data cutoff (median follow-up 16.3 months, range 2.1-19.9). Compared with unmatched treatment-naïve HCC specimens, post-treatment specimens showed significantly higher anti-cancer immune infiltration, including organized peritumoral aggregates. Immune infiltration and its proximity to tumor cells correlated with pre-operative radiographic response. CONCLUSIONS: This study provides proof-of-concept that neoadjuvant SBRT and immune therapy is safe and provides clear rationale for additional prospective clinical studies utilizing this strategy.
Moretto R, Studiale V, Hyun SW
… +21 more, Vetere G, Islam F, Carullo M, Conca V, Lo C, Neems D, Boulos H, DeSantis DF, Germani MM, Taravella A, Landi M, Ghelardi F, De Grandis MC, Murgioni S, Abran J, Sasser K, Pietrantonio F, Chiou VL, Sangli C, Nimeiri H, Cremolini C
Clin Cancer Res
· 2026 Apr · PMID 41973053
·
Publisher ↗
PURPOSE: Resection of liver metastases improves survival in metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD), but relapse remains common. Post-resection circulating tumor DNA (ctDNA) is a val...PURPOSE: Resection of liver metastases improves survival in metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD), but relapse remains common. Post-resection circulating tumor DNA (ctDNA) is a valid prognostic biomarker, however no data are available regarding the prognostic effect of pre-surgery ctDNA after upfront chemotherapy. EXPERIMENTAL DESIGN: Patients (N=116) with initially unresectable mCRC with LLD who underwent resection after upfront chemotherapy were included. Patients were sequenced with a tumor-naive ctDNA-based minimal residual disease (MRD) assay at baseline (pre-chemotherapy), pre-surgery, and post-surgery. RESULTS: Pre-surgery ctDNA status was not significantly associated with RFS. However, exploratory analyses demonstrated that a ≥50% reduction in VAF from baseline to pre-surgery was independently associated with improved RFS (median RFS: 21.0 vs. 9.8 months; HR: 2.19; p=0.014), aligned with multivariate analysis (p = 0.022). Post-surgery ctDNA positivity was strongly predictive of recurrence (HR: 6.66; p<0.001), with 100% specificity and 56.4% sensitivity. ctDNA dynamics from pre- to post-surgery further stratified recurrence risk, regardless of adjuvant chemotherapy status. ctDNA dynamics from pre- to post-surgery further stratified recurrence risk. Quantitative ctDNA measures (predicted tumor fragments per million) also correlated with RFS. CONCLUSIONS: Use of a tumor-naive MRD assay increased the accuracy of detecting ctDNA after chemotherapy treatment, when a significant drop of ctDNA amount is expected compared to tests routinely used in metastatic disease. Pre-surgery ctDNA dynamics were prognostic with respect to relapse-free survival and may help stratify patients' prognosis prior resection, potentially informing personalized treatment decisions.
Hoff CO, Heeke S, Mitani Y
… +11 more, de Sousa LG, Siqueira JM, Li K, Bonini F, Bell D, Marques-Piubelli ML, Lin SY, Wargo JA, El-Naggar AK, McGrail DJ, Ferrarotto R
Clin Cancer Res
· 2026 Jul · PMID 41973043
·
Publisher ↗
PURPOSE: The phase II axitinib plus avelumab trial in recurrent/metastatic adenoid cystic carcinoma (ACC) demonstrated favorable response rates and progression-free survival (PFS), leading to its inclusion in National Co...PURPOSE: The phase II axitinib plus avelumab trial in recurrent/metastatic adenoid cystic carcinoma (ACC) demonstrated favorable response rates and progression-free survival (PFS), leading to its inclusion in National Comprehensive Cancer Network guidelines as the first immunotherapy-based option for ACC. We sought to identify biomarkers predictive of clinical benefit from axitinib plus avelumab. PATIENTS AND METHODS: Twenty-eight patients with ACC enrolled in the study. Pretreatment tumors underwent whole-exome sequencing, transcriptomic profiling, imaging mass cytometry, and tumor, oral rinse, and stool microbiome characterization using 16S rRNA gene sequencing. Associations with PFS were assessed using the Cox proportional hazards model, incorporating ACC subtype (ACC-I vs. ACC-II) as a covariate. RESULTS: ACC comprises 2 proteogenomically distinct subtypes: aggressive, NOTCH1-activated ACC-I and more indolent ACC-II. Here, the median PFS was 1.8 months for ACC-I versus 11.4 months for ACC-II [hazard ratio (HR), 0.14; P < 0.0001)], representing the first demonstration of subtype-specific clinical trial outcomes in ACC. Clinical benefit was not associated with PD-L1 expression, tumor mutational burden, or recurrent genomic mutations. Instead, improved PFS correlated with the presence of intratumoral Escherichia and gut Bifidobacterium and Akkermansia. Transcriptomic profiling identified a 167-gene immune-enriched signature predictive of PFS benefit with axitinib plus avelumab. This signature also predicted benefit from ipilimumab plus nivolumab but not from regorafenib monotherapy, suggesting its specificity for immunotherapy-based combinations. CONCLUSIONS: Clinical trial outcomes with axitinib plus avelumab differ significantly by ACC subtype. Furthermore, the identified 167-gene immune-related signature predicts clinical benefit to immunotherapy-based combinations in ACC. These findings provide a framework for future biomarker-driven trial design and patient stratification strategies for this rare malignancy.
Gray JE, Neal JW, Patel JD
… +14 more, Liu SV, Veillon R, Reck M, Cappuzzo F, Cobo M, Reguart N, Fuentes Pradera J, Cho BC, Mok T, Mekan S, Safavi F, Fernando N, Chisamore M, Garon EB
Clin Cancer Res
· 2026 Apr · PMID 41961582
·
Publisher ↗
PURPOSE: EVOKE-02 (NCT05186974) is a multicohort, phase II trial evaluating first-line sacituzumab govitecan (SG) plus pembrolizumab with or without platinum-based chemotherapy in patients with metastatic non-small cell...PURPOSE: EVOKE-02 (NCT05186974) is a multicohort, phase II trial evaluating first-line sacituzumab govitecan (SG) plus pembrolizumab with or without platinum-based chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC). METHODS: Adults with mNSCLC, no prior systemic treatment, and no actionable genomic alterations received SG 10 mg/kg intravenously (reduced to 7.5 mg/kg following a preplanned safety evaluation), on days 1 and 8, plus pembrolizumab 200 mg intravenously on day 1 and carboplatin area under the curve 5 on day 1 of in 21-day cycles. The primary endpoint was objective response rate (ORR) per independent review committee; secondary endpoints included progression-free survival (PFS) and safety. RESULTS: As of June 3, 2024, 54 and 41 patients had nonsquamous and squamous histology, respectively. ORR (95% confidence interval [CI]) was 45.1% (3.1-59.7) for nonsquamous and 39.0% (24.2-55.5) for squamous histology. Median (95% CI) PFS was 8.1 (5.2-15.0) months for nonsquamous and 8.3 (4.3-11.2) months for squamous histology. ORR (95% CI) was 66.7% (34.9-90.1) for programmed cell death-ligand 1 tumor proportion score greater than or equal to 50%. SG dose was adjusted to 7.5 mg/kg due to myelosuppression. Grade greater than or equal to 3 treatment-emergent adverse events (TEAEs) occurred in 57 patients (86.4%). TEAEs leading to discontinuation of any study drug occurred in 12 patients (18.2%). CONCLUSIONS: SG plus pembrolizumab and carboplatin had activity in mNSCLC. When combined with pembrolizumab and carboplatin, SG was tolerated at a dose of 7.5 mg/kg.
Makker V, Lee JY, Oh DY
… +6 more, Oaknin A, Puvvada S, Jung L, McEwen R, Michelini F, Meric-Bernstam F
Clin Cancer Res
· 2026 Jul · PMID 41954657
·
Full text
PURPOSE: Accurate HER2 status assessment is crucial to identify patients with HER2-expressing tumors. In this post hoc analysis of DESTINY-PanTumor02 (NCT04482309), we report concordance between local and central HER2 im...PURPOSE: Accurate HER2 status assessment is crucial to identify patients with HER2-expressing tumors. In this post hoc analysis of DESTINY-PanTumor02 (NCT04482309), we report concordance between local and central HER2 immunohistochemistry (IHC) results. PATIENTS AND METHODS: This open-label, phase II study evaluated trastuzumab deruxtecan (T-DXd; 5.4 mg/kg once every 3 weeks) for HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced, unresectable, or metastatic solid tumors after ≥1 systemic treatment or without alternative treatments. RESULTS: In total, 267 patients received T-DXd; 75.7% were enrolled based on local test results. Concordance between local and central HER2 test results was 58.6% for IHC 3+, 54.5% for IHC 2+, and 73.4% for IHC 3+ and IHC 2+ tumors combined. CONCLUSIONS: The moderate concordance observed between local and central IHC testing in DESTINY-PanTumor02 highlights the need for a validated diagnostic test and standardized algorithm for HER2 status assessment in solid tumors to ensure appropriate patient identification for HER2-directed therapies.
Aref AT, Pathan M, Habib R
… +24 more, Hains PG, Lim SH, Anees A, Ma L, Heads J, Wang D, Loudon C, McLeod D, Caixeiro N, Noor Z, Craft GE, Bucio-Noble D, Koh JM, Robinson PJ, Zhong Q, Gowrishankar K, Micklethwaite KP, Moustou E, Datseri G, Balleine RL, Lee CS, Souglakos J, Nagrial AM, Reddel RR
Clin Cancer Res
· 2026 Jul · PMID 41954643
·
Publisher ↗
PURPOSE: Despite advances in colon cancer management, stage III disease lacks robust, clinically applicable prognostic biomarkers. We aimed to use proteomic profiling to provide a quantitative, tissue-based approach to i...PURPOSE: Despite advances in colon cancer management, stage III disease lacks robust, clinically applicable prognostic biomarkers. We aimed to use proteomic profiling to provide a quantitative, tissue-based approach to improve recurrence risk stratification. EXPERIMENTAL DESIGN: We performed data-independent acquisition mass spectrometric proteomic analysis of tumor samples from three independent stage III colon cancer cohorts (n = 759). Differential protein expression between tumor and matched normal adjacent tissue was analyzed in the training cohort (cohort 1) using the limma package, and a univariate Cox model identified candidate biomarker proteins. A risk score based on the levels of six proteins (ITIH1, PPIE, LTBP1, KPNA2, IGFBP7, and CKAP4) was developed using multivariate Cox regression in the training cohort (n = 175) and validated in two external cohorts (cohort 2, n = 386; cohort 3, n = 198). Kaplan-Meier and multivariate Cox regression analyses assessed the prognostic value of the score for recurrence. RESULTS: The six-protein risk score categorized patients in the training cohort as high- or low-risk for recurrence [hazard ratio (HR) 5.7, P < 0.001], and this was validated in the two separate cohorts (cohort 2: HR 1.8, P < 0.001; cohort 3: HR 1.8, P = 0.02). Integrating the proteomic score with clinical risk factors further enhanced prognostic accuracy (P < 0.001 in all three cohorts). The combined proteomic-clinical risk score consistently identified a subgroup of patients with very low recurrence risk across cohorts. CONCLUSIONS: The validated six-protein risk score improves prognostic stratification beyond standard clinical factors in stage III colon cancer, providing a robust framework for risk-adapted clinical investigation. Prospective, treatment-stratified clinical trials are warranted to determine whether this prognostic information can inform adjuvant therapy decision-making.