Lukas RV, Zhai L, Lauing KL
… +27 more, Kim M, Koch T, Penco-Campillo M, Bommi P, Dixit K, Kumthekar P, Sharp L, Lezon R, Garcia D, Sonabend AM, McCortney K, Castro BA, Chandler JP, Gondi V, Grimm SA, Miska JM, Heimberger AB, Dobinda K, Zhang H, Sachdev S, Juhasz C, James CD, Allen JM, Horbinski C, Lesniak MS, Stupp R, Wainwright DA
Clin Cancer Res
· 2026 May · PMID 42189896
·
Publisher ↗
BACKGROUND: We conducted a phase 1 trial to evaluate radiotherapy (RT) and nivolumab with the further addition of an IDO1 enzyme inhibitor (BMS-986205) in newly diagnosed patients with GBM IDHwt. METHODS: In the current...BACKGROUND: We conducted a phase 1 trial to evaluate radiotherapy (RT) and nivolumab with the further addition of an IDO1 enzyme inhibitor (BMS-986205) in newly diagnosed patients with GBM IDHwt. METHODS: In the current study, there were two primary cohorts of individuals. Cohort A included MGMT unmethylated GBM patients who received RT with concurrent and adjuvant nivolumab with escalating BMS-986205 doses. Cohort B included MGMT methylated GBM patients who received BMS-986205 at 25mg daily with RT, nivolumab, and temozolomide (TMZ) followed by adjuvant TMZ. Patient outcomes were correlated with flow cytometric, transcriptome, general metabolite, and microbial metabolite analyses. RESULTS: The treatments for both cohorts were moderately safe and tolerable. The treatment emergent adverse events (TEAE) mostly related to RT, TMZ, or the underlying disease and tumor progression. In cohort A, serious AEs and TEAEs were predominantly lower grade with no differences between the IDO1 enzyme inhibitor dosing cohorts. Dose-limiting toxicities (DLTs) reflected by increased transaminases (grade 3) were observed in 2 and 3 patients at 50mg and 100mg levels of BMS-986205, respectively, with malaise observed in the 50mg arm only. The 50mg daily schedule was established as the recommended phase 2 dose (RP2D) in combination with RT and nivolumab. A number of exploratory correlative studies were also conducted. CONCLUSIONS: This single arm small phase 1 trial establishes a safety profile and RP2D for RT in combination with nivolumab and BMS-986205 for newly diagnosed MGMT-unmethylated GBM patients. (ClinicalTrials.gov: NCT04047706).
Topham JT, Beckmann HM, Karasinska JM
… +25 more, Loree JM, Knox JJ, Kavan P, Jonker D, Welch S, Couture F, Lemay F, Tehfe M, Harb M, Aucoin N, Ko YJ, Tang PA, Ramjeesingh R, Meyers BM, Kim CA, Notta F, Zogopoulos G, Gallinger S, Du P, Jia S, Gill S, Tu D, O'Callaghan CJ, Schaeffer DF, Renouf DJ
Clin Cancer Res
· 2026 May · PMID 42189892
·
Publisher ↗
PURPOSE: Pre-existing and emerging molecular-targeted therapies have been identified for the treatment of pancreatic ductal adenocarcinoma (PDAC) and exemplify the need for incorporating tumor sequencing into routine cli...PURPOSE: Pre-existing and emerging molecular-targeted therapies have been identified for the treatment of pancreatic ductal adenocarcinoma (PDAC) and exemplify the need for incorporating tumor sequencing into routine clinical practice. Tumor profiling through circulating tumor DNA (ctDNA) represents an important opportunity in PDAC due to the aggressive nature of the disease. Circulating tumor fraction (CTF) levels are highly variable within and between cancer types and influence the accuracy of plasma-based tumor profiling, and the variability and factors related to CTF levels in PDAC are not well understood. EXPERIMENTAL DESIGN: ctDNA sequencing (PredicineATLAS) and clinical metadata from a cohort of 166 patients with metastatic PDAC (mPDAC) was generated as part of the PA.7 trial (NCT02879318). Patients were stratified into high CTF (>30% CTF; 35/166, 21.08%) and low CTF (131/166, 78.92%) groups for comparative analysis. Matched RNA-sequencing data was available for 20 patients. RESULTS: High CTF was associated with lower overall survival (OS; HR=1.87, 95% CI=1.27-2.75; p=0.0014) as well as clinical presentation that was indicative of higher disease burden, with CTF highest in patients that had liver metastases and distant metastases including bulky lymph nodes versus patients with no liver metastases (p<0.001). Exploratory gene expression analysis revealed positive association between CTF and up-regulation of cell cycle-related pathways, which included CDK4 (p=0.0093) and MT2A (p=0.012), as well as glycolytic (p=0.0028) and basal-like (p=0.029) subtyping genes. CONCLUSIONS: These data demonstrate the heterogeneity of CTF and its associated factors in mPDAC, which converge towards an aggressive phenotype from both clinical and molecular standpoints.
Martín M, Rodriguez-Lescure A, Reboredo C
… +23 more, Chen E, Ruiz-Borrego M, Santaballa Bertran A, Rodríguez CA, Martinez Jañez N, Alba E, Tran K, Pelaez Fernandez I, Álvarez I, Seguí MA, De la Cruz A, Valero V, Antón-Torres A, Andrés R, Amillano K, Ponce-Lorenzo JJ, Dominguez Fernandez S, Herranz J, Rincon R, Caballero R, Guerrero-Zotano A, Rojo F, Symmans WF
Clin Cancer Res
· 2026 May · PMID 42189890
·
Publisher ↗
PURPOSE: To independently validate that low endocrine transcriptional activity measured by SETER/PR index in hormone receptor-positive breast cancer predicts benefit from dose-dense paclitaxel chemotherapy within a secon...PURPOSE: To independently validate that low endocrine transcriptional activity measured by SETER/PR index in hormone receptor-positive breast cancer predicts benefit from dose-dense paclitaxel chemotherapy within a second prospective-retrospective biomarker study. EXPERIMENTAL DESIGN: We conducted a blinded, prospective-retrospective biomarker analysis within the GEICAM/9906 trial (NCT00129922), which compared adjuvant FEC followed by weekly paclitaxel (FEC+P) versus six cycles of FEC in lymph node-positive breast cancer. SETER/PR index was measured in all available HR+/HER2- tumor RNA samples using a pre-specified cutpoint (<0.75). The primary endpoint was distant recurrence-free interval (DRFI); secondary endpoints were overall survival (OS) and breast cancer-specific survival (BCSS). RESULTS: Of 647 HR+/HER2- tumors, 567 (87.6%) passed assay quality control (279 FEC+P; 288 FEC). Low SETER/PR index was identified in 92 tumors (16.2%). There was a significant interaction between SETER/PR status and treatment on DRFI (p=0.046). Among patients with low SETER/PR index, FEC+P significantly improved DRFI (HR 0.46; 95% CI, 0.22-0.95; p=0.035), with similar results after adjustment (HR 0.48; 95% CI, 0.24-1.00; p=0.049). No treatment benefit was observed for SETER/PR ≥0.75 (HR 1.02; 95% CI, 0.70-1.47; p=0.931). Differences in OS and BCSS did not reach significance. CONCLUSIONS: Low endocrine transcriptional activity predicts benefit from adding weekly paclitaxel to anthracycline-based adjuvant chemotherapy in HR+/HER2- breast cancer. These findings independently validate SETER/PR index as a predictive biomarker for paclitaxel-based chemotherapy and support its potential role in guiding regimen selection.
Schmid P, Ma CX, Park YH
… +15 more, Lord S, Armstrong A, Im SA, Chen SC, Fernandes R, Jassem J, Wysocki PJ, Lu YS, Wang HC, Chung WP, Rao-Melacini P, Heider K, Stewart R, Vuković P, Jung KH
Clin Cancer Res
· 2026 May · PMID 42189888
·
Publisher ↗
PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with high recurrence rates and poor prognosis, often requiring multiple therapies. BEGONIA was a phase Ib/II, multiarm, platform study evaluating t...PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with high recurrence rates and poor prognosis, often requiring multiple therapies. BEGONIA was a phase Ib/II, multiarm, platform study evaluating the safety and efficacy of first-line treatment combinations with durvalumab (anti-PD-L1 antibody) for locally advanced unresectable/metastatic TNBC (mTNBC; NCT03742102). Here, we report results of three treatment arms. PATIENTS AND METHODS: Eligible female participants (≥18 years with untreated, unresectable, locally advanced/mTNBC) received durvalumab plus paclitaxel or were randomized to this treatment in combination with capivasertib (pan-AKT inhibitor) or oleclumab (anti-CD73 antibody). The primary objective was safety and tolerability; secondary endpoints included objective response rate (ORR). RESULTS: Twenty-three patients received durvalumab plus paclitaxel, 31 capivasertib combination, and 33 oleclumab combination. Maximum grade 3/4 adverse events occurred in 10/23 (43.5%), 25/31 (80.6%) and 8/33 (24.2%) patients in the durvalumab plus paclitaxel, capivasertib-combination, and oleclumab-combination arms, respectively. Confirmed ORR (95% confidence interval) was 56.5% (34.5-76.8) with durvalumab plus paclitaxel, 54.8% (36.0-72.7) with capivasertib combination, and 51.5% (33.5-69.2) with oleclumab combination. Responses were observed across biomarker subgroups, including PD-L1, PIK3CA/AKT1/PTEN alterations, and CD73, with a trend for improved activity in the PD-L1-positive subgroups. CONCLUSIONS: These findings support the clinical activity and tolerability of durvalumab plus paclitaxel in locally advanced unresectable/mTNBC, as expected for an immune checkpoint inhibitor in combination with chemotherapy. Addition of capivasertib or oleclumab to this treatment combination showed no substantial additional benefit. PD-L1 expression was associated with enhanced antitumor activity across all arms.
Mouri A, Kenmotsu H, Kagamu H
… +17 more, Azuma K, Saito R, Akamatsu H, Yonesaka K, Kakegawa M, Nagashima H, Takahashi S, Fujita M, Yanagitani N, Ninomiya K, Nishioka Y, Mori K, Kitano S, Tamada K, Yamamoto N, Gemma A, Mitsudomi T
Clin Cancer Res
· 2026 May · PMID 42189883
·
Publisher ↗
BACKGROUND: Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). In this prospect...BACKGROUND: Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). In this prospective observational study, we evaluated the changes in peripheral blood immune cell counts to elucidate the immunological mechanisms underlying cCRT and durvalumab therapy. METHODS: Peripheral blood mononuclear cell (PBMC) samples were collected at four time points: before cCRT, after cCRT, at the start of durvalumab, and 8 weeks after the start of durvalumab, and analyzed by multicolor flow cytometry. RESULTS: Of the 150 enrolled patients, 115 received durvalumab consolidation therapy after cCRT. The median PFS in the overall population was 24.2 months, and the 3-year PFS rate was 38.9%. PBMC analysis showed an increased effector fraction of CD4+ T cells before and after cCRT but no change in CD8+ T cells. Following durvalumab therapy, the effector fraction ratio of CD8+ T cells (CD62Llow CD8+ T cells) increased and positively correlated with increased CD62Llow CD4+ T cells during cCRT. Patients whose proportion of CD62Llow CD4+ T cells exceeded the threshold for cCRT had better PFS than those below the threshold. Patients whose CD62Llow CD8+ T cell proportion exceeded the threshold after durvalumab therapy showed prolonged PFS compared to those below the threshold. CONCLUSION: cCRT promotes an increase in effector CD4+ T cells, and the subsequent increase in CD8+ T cells following durvalumab therapy prolongs PFS. Peripheral blood effector-type CD4+ and CD8+ T cells are potential biomarkers for evaluating the immune status of patients and predicting treatment efficacy.
Chen EC, Liu Y, Bell HL
… +19 more, Ryan J, Wu J, Minihane EJ, Luskin MR, Winer ES, Vedula R, Volpe V, Stahl M, Roberts D, Galinsky I, Gerard M, Hersch M, Lee J, Neuberg D, Stone RM, DeAngelo DJ, Letai A, Lane AA, Garcia JS
Clin Cancer Res
· 2026 May · PMID 42189880
·
Publisher ↗
BACKGROUND: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neopla...BACKGROUND: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. PATIENTS AND METHODS: We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts. RESULTS: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects. CONCLUSION: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.
Guo J, Wu Y, Huang W
… +12 more, Ai G, Wang C, Luo N, Zhu J, Zhou Y, Shi W, Ding J, Ge Y, Feng W, Jin H, Zhao B, Cheng Z
Clin Cancer Res
· 2026 May · PMID 42189877
·
Publisher ↗
PURPOSE: Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase 1 trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to...PURPOSE: Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase 1 trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to overcome the immunosuppressive tumor microenvironment (TME). PATIENTS AND METHODS: A cohort of 18 patients with rOC who were heavily pretreated (median, 3.5 prior lines of therapy) underwent lymphodepletion with cyclophosphamide and hydroxychloroquine, followed by GC203 infusion. The primary endpoints were safety and tolerability. Secondary endpoints, assessed in the full analysis set (FAS) using RECIST 1.1 guidelines, encompassed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses included the Morisita Overlap Index (MOI) to quantify T cell receptor (TCR) repertoire similarity between infused TILs and circulating T cells. RESULTS: The GC203 regimen demonstrated a favorable safety profile. Treatment-related adverse events were primarily hematological, with grade≥3 lymphopenia and neutropenia each occurring in 57% of patients. All proved to be transient with a median resolution 7 days. The regimen achieved an unconfirmed ORR of 33.3% (6/18 patients) alongside a disease control rate (DCR) of 83.3%. Survival analyses revealed a median PFS of 7.2 months (95% CI: 1.0-13.4) and a median OS of 17.1 months (95% CI: 9.5-24.7). A key exploratory analysis identified the MOI as a significant predictor of treatment response, achieving an area under the curve (AUC) of 0.79. CONCLUSION: The GC203 regimen, combining piggyBac-mbIL-7 autologous TILs with anti-PD-1 antibody, demonstrates favorable safety and promising efficacy in heavily pretreated rOC, which supports its further development in this high-need population.
Shulman DS, Vo KT, Balis FM
… +21 more, Lindsay H, DeNardo BD, Place AE, Chi SN, Kamihara J, O'Neill AF, Church AJ, Crompton BD, Klega K, Tanhaemami M, Armant M, Pikman Y, Stegmaier K, Ezrre S, Czaplinski J, Walensky LD, Annis DA, Bhushan K, Kao PC, London WB, Dubois SG
Clin Cancer Res
· 2026 May · PMID 42189874
·
Publisher ↗
PURPOSE: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced maligna...PURPOSE: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies. EXPERIMENTAL DESIGN: Patients with TP53-wild-type malignancies were enrolled to a monotherapy arm (solid/CNS tumors) or combination arm with cytarabine (acute leukemia). Monotherapy dosing used the TARGET-CRM design for dose escalation. Pharmacodynamic assessment included serum MIC-1 as a biomarker of p53 activation. Circulating tumor DNA was analyzed for emergent TP53 mutations. RESULTS: Twenty-two patients enrolled; 20 received treatment (17 monotherapy, 3 combination). The most common diagnosis was Ewing sarcoma (n=5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and one patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLTs occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30-50-fold by 24 hours post-dose at dose levels 2-4, confirming on-target p53 activation. Among 19 response-evaluable patients, one partial remission occurred in a patient with relapsed ALL on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample. CONCLUSIONS: ALRN-6924 was well tolerated in children with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and evaluation of higher dose levels.
Wang G, Kang T, Peng Y
… +14 more, Chen S, Chen X, Lin X, Lai Y, Zhan J, Yu Y, Li R, Yu H, Wang E, He J, Ke C, Zang J, Xu N, Miao W
Clin Cancer Res
· 2026 May · PMID 42189873
·
Publisher ↗
PURPOSE: We designed and synthesized a novel compound targeting CXCR4, JH120061. Using clinically established Pentixafor and Pentixather as references, we evaluated the potential of [68Ga]Ga/[177Lu]Lu-JH120061 in a serie...PURPOSE: We designed and synthesized a novel compound targeting CXCR4, JH120061. Using clinically established Pentixafor and Pentixather as references, we evaluated the potential of [68Ga]Ga/[177Lu]Lu-JH120061 in a series of preclinical and clinical studies. PATIENTS AND METHODS: Preclinical studies of [68Ga]Ga/[177Lu]Lu-JH120061 were conducted on CXCR4-expressing cell lines (HT1080-hCXCR4) and HT1080-hCXCR4 tumor-bearing mice. A head-to-head comparison of [68Ga]Ga-JH120061 with [68Ga]Ga-Pentixafor for PET/CT was conducted in patients with multiple myeloma (n = 5) and renal masses (n = 5). An expanded cohort of 53 patients with renal masses underwent [68Ga]Ga-JH120061 PET/CT to assess its performance in identifying renal malignancy. RESULTS: Preclinical studies revealed that JH120061 demonstrated high binding affinity for CXCR4, promising cellular uptake and retention. In a clinical study, [68Ga]Ga-JH120061 PET/CT detected more malignant lesions than [68Ga]Ga-Pentixafor (94 vs 81, P = 0.031) and showed significantly higher tumor uptake (SUVₘₐₓ 22.3 ± 12.9 vs. 9.4 ± 6.5, P < 0.001, at 60 min). Furthermore, [68Ga]Ga-JH120061 PET/CT exhibited excellent detectability for clear cell renal cell carcinoma (ccRCC), its tumor uptake was significantly higher than that in non-ccRCC (SUVₘₐₓ 28.9 ± 11.7 vs. 7.3 ± 2.4, P < 0.001). CONCLUSION: This study demonstrated that JH120061 may have excellent affinity for CXCR4. Notably, [68Ga]Ga-JH120061 PET/CT demonstrated a remarkable capability for detecting ccRCC. Future studies should further explore the potential of [68Ga]Ga/[177Lu]Lu-JH120061 in precision theranostics of CXCR4-positive tumors.
Clin Cancer Res
· 2026 May · PMID 42189671
·
Publisher ↗
B7-H4 (also known as B7x or B7S1) is a member of the B7 family and is expressed in a broad spectrum of malignancies, with particularly elevated levels in tumors arising from female reproductive organs. Functionally, B7-H...B7-H4 (also known as B7x or B7S1) is a member of the B7 family and is expressed in a broad spectrum of malignancies, with particularly elevated levels in tumors arising from female reproductive organs. Functionally, B7-H4 suppresses T cell activation and effector responses, thereby facilitating immune evasion within the tumor microenvironment (TME). In this review, we highlight recent advances in the biology of tumor-associated B7-H4, including its tissue distribution, subcellular localization, regulatory mechanisms of expression, and emerging therapeutic strategies targeting B7-H4 for cancer treatment.
Yeh CM, Yu CC, Lee AF
… +15 more, Cheng SM, Hsu CW, Chiang NJ, Hou YC, Tsai HJ, Chen SH, Yen CJ, Wang CJ, Chao YJ, Chuang SC, Du JS, Hwang DY, Shan YS, Chen LT, Su YY
Clin Cancer Res
· 2026 Jul · PMID 42162970
·
Full text
PURPOSE: Carbohydrate antigen 19-9 (CA19-9) has limited utility in the ∼10% of patients with pancreatic ductal adenocarcinoma (PDAC) who are Lewis-negative CA19-9 "nonproducers" (FUT3-null). This study aims to define the...PURPOSE: Carbohydrate antigen 19-9 (CA19-9) has limited utility in the ∼10% of patients with pancreatic ductal adenocarcinoma (PDAC) who are Lewis-negative CA19-9 "nonproducers" (FUT3-null). This study aims to define the prognosis of FUT3-null PDAC and establish a CA19-9 cutoff that can help identify this subgroup in clinical practice. EXPERIMENTAL DESIGN: Germline whole-exome sequencing was performed in a multicenter cohort of 615 patients with PDAC to determine FUT2/FUT3 genotypes. Receiver operating characteristic (ROC) analysis identified the optimal CA19-9 cutoff for FUT3-null status. Maximally selected rank statistics were used to derive CA19-9 cutoffs that best stratified overall survival (OS) in a training set (n = 307) and were tested in a validation set (n = 308). RESULTS: FUT3-null patients had similar demographics except for a lower median baseline CA19-9 level (2.4 vs. 496 U/mL in FUT3-intact patients) and a comparable median OS (13.5 months) to FUT3-intact patients with CA19-9 >200 U/mL (12.9 months). ROC analysis identified 7 U/mL as the optimal CA19-9 cutoff for FUT3-null (positive predictive value 95.1%; accuracy 87.9%). Using CA19-9 cutoffs of 7 and 200 U/mL (without genotyping), patients were stratified into four prognostic groups: >7 to 37 U/mL (median OS, 23.2 months), >37 to 200 U/mL (median OS, 22 months), >200 U/mL (median OS, 12.8 months), and ≤7 U/mL (likely FUT3-null; median OS, 13.5 months; P < 0.001). Findings were consistent in multivariable Cox models. CONCLUSIONS: CA19-9 nonproducers whose outcomes are comparable with those with CA19-9 >200 U/mL represent a high-risk subgroup. CA19-9 ≤7 U/mL is a practical surrogate for identifying these patients. When genotyping is unavailable, a dual-threshold model (≤7 and >200 U/mL) improves risk stratification.
Jhaveri K, Rugo HS, Cortés J
… +20 more, Oliveira M, Howell SJ, Dalenc F, Gomez HL, Hu X, Krivorotko P, Loibl S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Zhukova L, Nardone A, Wadsworth I, D'Cruz C, Wantenaar T, Das D, de Bruin EC, Turner NC
Clin Cancer Res
· 2026 May · PMID 42154572
·
Publisher ↗
PURPOSE: The PI3K/AKT pathway is frequently activated in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, with loss of phosphatase and tensin homolog (PTEN)...PURPOSE: The PI3K/AKT pathway is frequently activated in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, with loss of phosphatase and tensin homolog (PTEN) activity contributing to this activation. Capivasertib is a potent pan-AKT inhibitor, approved in combination with fulvestrant for the treatment of HR-positive/HER2-negative locally advanced/metastatic breast cancer with one or more PIK3CA/AKT1/PTEN tumor alterations. Next-generation sequencing (NGS) is commonly used to identify patients with PIK3CA/AKT1/PTEN tumor alterations. However, the utility of immunohistochemistry (IHC) to identify patients with PTEN-deficient tumors has not been explored in this context. EXPERIMENTAL DESIGN: This exploratory analysis was based on tumor samples collected from patients in the global Phase III CAPItello-291 study. RESULTS: PTEN IHC results were obtained for 367 tumor samples, with 70 (19.1%) identified as PTEN deficient by IHC. 346 (94.3%) samples with a PTEN IHC test result also had NGS test results available for PIK3CA/AKT1/PTEN alteration status. When comparing PTEN deficiency by IHC with PTEN alteration status by NGS, the overall, positive, and negative percent agreements were 87.0% (301/346), 71.9% (23/32), and 88.5% (278/314), respectively. Exploratory analysis in patients with PTEN-deficient tumors by IHC (n=70) showed improved progression-free survival in the capivasertib plus fulvestrant versus placebo plus fulvestrant treatment arm (median 9.3 vs 3.7 months; hazard ratio: 0.52, 95% confidence interval: 0.28-0.90). CONCLUSIONS: These results suggest potential utility for IHC in determining tumor PTEN status in breast cancer and raise the possibility of IHC identifying additional patients who could benefit from treatment with capivasertib and fulvestrant.
Granhøj JS, Mannering SMH, Madsen K
… +15 more, W Hendel H, Draghi A, Jedema I, Lievense J, Nijenhuis C, Nuijen B, V Zon M, W Rohaan M, Tak WS, Klobuch S, Borch TH, Met Ö, Haanen J, Donia M, Svane IM
Clin Cancer Res
· 2026 May · PMID 42149143
·
Publisher ↗
PURPOSE: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a highly personalized cancer immunotherapy. In the randomized Phase III clinical trial (TIL-NKI/CCIT), TIL therapy significantly improved progre...PURPOSE: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a highly personalized cancer immunotherapy. In the randomized Phase III clinical trial (TIL-NKI/CCIT), TIL therapy significantly improved progression-free survival (PFS) compared with ipilimumab in patients with unresectable stage IIIC and IV cutaneous melanoma. This study aimed to define phenotypic and functional characteristics of the infused TIL associated with the best overall response (BOR) and PFS. EXPERIMENTAL DESIGN: Using flow cytometry, we profiled infusion products from all 80 patients treated with TIL in the TIL-NKI/CCIT trial and correlated the results with BOR and PFS. We established autologous tumor cell lines from 24 patients and assessed the anti-tumor reactivity of the infused CD4+ and CD8+ T cells through co-culture assays and intracellular cytokine staining. We quantified tumor-reactive TIL relative to baseline tumor volume and monitored their persistence in the peripheral blood for up to 24 months after infusion. RESULTS: Responding patients received a higher absolute number of CD8+TCRαβ+ T cells than non-responders (p=0.0290). The frequency of infusion product CD8+TCRαβ+ T cells was strongly associated with PFS at six months (p<0.0001). The number of tumor-reactive CD8+ T cells infused, normalized to baseline tumor burden, correlated with BOR (p=0.0352) and PFS at six months (p=0.0007), with sustained peripheral blood persistence of tumor-reactive CD4+ and CD8+ T cells predictive of durable clinical response. CONCLUSION: CD8+ T cell phenotype, tumor reactivity, and in vivo persistence emerged as strong predictors of clinical outcome. Our data identify CD8+ T cells as a key determinant of therapeutic efficacy.
Gariazzo E, Elkrief A, Concannon K
… +37 more, Ognissanti D, Dodi A, Favorito V, Di Federico A, De Giglio A, Brunetti L, Santo V, Pecci F, Aldea M, Garbo E, Alessi JV, LoPiccolo J, Paoloni F, Nishino M, Sholl LM, Florez N, Rotow J, Frumm SM, Hong L, Zhang J, Gibbons D, Wang X, Landi L, Cipriani L, Rakaee M, Cortellini A, Tiseo M, Cappuzzo F, Ardizzoni A, Awad MM, Heymach JV, Scalera S, Maugeri-Saccà M, Metro G, Vokes N, Schoenfeld A, Ricciuti B
Clin Cancer Res
· 2026 May · PMID 42149140
·
Publisher ↗
PURPOSE: Predictive biomarkers of response to immune checkpoint inhibitors (ICI) remain poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic a...PURPOSE: Predictive biomarkers of response to immune checkpoint inhibitors (ICI) remain poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic alterations (AGA). We aimed to identify clinical and molecular predictors of response to ICI-based regimens in patients who have never smoked and lack AGA. EXPERIMENTAL DESIGN: We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoked, treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning-based algorithm, and immune cells biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the SU2C cohort. RESULTS: Among 741 patients with AGA-negative NSCLC and no history of tobacco use, objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) 4.5 months, and median overall survival (mOS) 16.8 months. PD-L1≥90% and TMB≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all p<0.01). PD-(L)1+CTLA-4 combinations outperformed chemo-immunotherapy and PD-(L)1 monotherapy in terms of mPFS and mOS. Transcriptomic analysis revealed enrichment of innate and adaptive immune pathways in responders, including increased MHC class I/II antigen presentation and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping confirmed higher immune cell infiltration in patients who experienced durable clinical benefit. CONCLUSIONS: We demonstrated how combination therapies may improve ICI outcomes in patients with AGA-negative NSCLC and no history of tobacco exposure. Very high PD-L1, TMB, and immune-enriched phenotypes may guide treatment personalization.
Ehret F, Horick NK, Yeap BY
… +13 more, Curry WT, Nahed B, Daartz J, Johnson JM, Dagher SA, Raza SM, DeMonte F, Yeboa DN, Swanson TA, McAleer MF, Leland P, McGovern SL, Shih HA
Clin Cancer Res
· 2026 May · PMID 42149137
·
Publisher ↗
BACKGROUND: Outcomes for grade 2 and 3 meningiomas are poor. A few studies suggest a benefit from radiation therapy dose escalation. This trial evaluates the safety and efficacy of dose escalation with intensity-modulate...BACKGROUND: Outcomes for grade 2 and 3 meningiomas are poor. A few studies suggest a benefit from radiation therapy dose escalation. This trial evaluates the safety and efficacy of dose escalation with intensity-modulated proton therapy (IMPT) for grade 2 and 3 meningiomas. METHODS: This prospective single-arm phase 1 trial enrolled patients with grade 2 meningioma with residual disease or recurrence, or patients with grade 3 meningioma after gross total resection. Patients underwent dose-escalated IMPT to 66 Gy (relative biological effectiveness, RBE) for grade 2 gross disease and 63 Gy(RBE) for grade 3 tumor beds. The primary endpoint was acute dose-limiting toxicity (DLT). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and late toxicity. RESULTS: Twenty-one patients with 16 grade 2 and five grade 3 meningiomas were enrolled and treated between 2016 and 2023. The median clinical and radiographic follow-up periods were 3.4 and 3.2 years, respectively. No DLT was observed. Five new late grade 3 toxicities occurred in four patients. Three treatment failures were observed in two grade 2 and one grade 3 tumors. Two deaths occurred in patients with grade 2 meningiomas. The 1-, 2-, and 3-year PFS rates were 100%, 95.0%, and 88.2%, respectively. The corresponding OS rates were 100%, 95.0%, and 95.0%, respectively. CONCLUSIONS: This first prospective trial investigating dose-escalated IMPT for high-grade meningiomas demonstrated a favorable early safety profile and clinical outcomes. Phase 2 and 3 studies are warranted to confirm the superiority of dose escalation for high-grade meningiomas.
El Ahmar N, Paul MA, Simsek B
… +25 more, Matar S, Jegede OA, Laimon YN, Savla V, Mohanna R, de Oliveira GR, Bagheri Sheshdeh A, Denize T, West DJ, Seager MD, Sun M, Choueiri TK, Xie W, Freeman GJ, Sharpe AH, Braun DA, Haas NB, Hammers H, Bilen MA, Stein M, Sosman JA, Wu CJ, McDermott DF, Atkins MB, Signoretti S
Clin Cancer Res
· 2026 May · PMID 42149133
·
Full text
PURPOSE: We investigated components of the immune tumor microenvironment as determinants of clinical outcome to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with frontlin...PURPOSE: We investigated components of the immune tumor microenvironment as determinants of clinical outcome to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with frontline nivolumab in the phase 2, non-randomized HCRN GU16-260 trial. EXPERIMENTAL DESIGN: Pre-treatment primary ccRCCs from 72 patients were analyzed by multiplex immunofluorescence and image analysis to assess non-terminally exhausted CD8+ (CD8⁺PD-1⁺TIM3⁻LAG3⁻) tumor-infiltrating lymphocytes (TILs), PD-1+ regulatory T cells (Tregs), total and peritumoral tertiary lymphoid structures (TLS), and CD163+ tumor-associated macrophages (TAMs). Clinical endpoints included objective response rate (ORR) and progression-free survival (PFS). RESULTS: Densities of CD8⁺PD-1⁺TIM3⁻LAG3⁻ TILs, total and peritumoral TLS, and CD163⁺ TAMs, as continuous variables, were associated with improved ORR (Odds Ratio: 1.54 [1.10-2.16] for TILs; 1.18 [1.02-1.37] for total TLS; 1.10 [1.02-1.18] for peritumoral TLS; 2.21 [1.33-3.69] for TAMs) and longer PFS (Hazard Ratio: 0.79 [0.67-0.95] for TILs; 0.92 [0.85-0.99] for total TLS; 0.94 [0.90-0.98] for peritumoral TLS; 0.77 [0.61-0.97] for TAMs). Although % of PD-1+ Tregs as continuous variable was not associated with outcomes, at an optimal cut-off, high % of PD-1+ Tregs tended to be associated with lower ORR (12.5% vs 43.6%, p=0.093) and was associated with shorter PFS (3.4 vs 10.9 months, p<0.001). The biomarkers were not strongly correlated with each other and their integration in multi-biomarker models further stratified outcomes. CONCLUSION: Individual immune cell populations within the ccRCC microenvironment are associated with response/resistance to frontline anti-PD-1 therapy. Our findings support the development of combined immune marker models to identify patients with divergent outcomes.
Sweis RF, Long GV, Daud A
… +11 more, Stemmer SM, Jimeno A, Perets R, Kummar S, Patel MR, Khattak A, Abadier M, Van L, Guo R, Do KT, Sullivan RJ
Clin Cancer Res
· 2026 May · PMID 42149124
·
Publisher ↗
PURPOSE: mRNA-2752, a lipid nanoparticle (LNP)‒encapsulated, mRNA-based therapeutic encoding OX40L, IL-36γ, and IL-23, has demonstrated modulation of the tumor microenvironment (TME) and antitumor efficacy in combination...PURPOSE: mRNA-2752, a lipid nanoparticle (LNP)‒encapsulated, mRNA-based therapeutic encoding OX40L, IL-36γ, and IL-23, has demonstrated modulation of the tumor microenvironment (TME) and antitumor efficacy in combination with immune checkpoint inhibitors (CPI) in CPI-resistant models. PATIENTS AND METHODS: In this phase 1 study (NCT03739931) of intratumoral mRNA-2752 monotherapy (Arm A) or mRNA-2752 plus durvalumab (Arm B) in advanced solid tumors, the primary objectives were safety, tolerability, determination of maximum tolerated dose (MTD), and objective response rate (ORR) per RECIST v1.1 in CPI‒resistant melanoma (Arm B only). RESULTS: Among 134 patients (Arm A, n=19; Arm B, n=115), the MTD was not reached; a recommended dose for expansion of ≤8 mg was selected. Dose-limiting toxicities included two grade 2 cytokine-release syndrome events in Arm B. Treatment-related adverse events were mostly grade 1/2; grade 3 mRNA-2752-related adverse events occurred in 1 patient (5.3%) in Arm A and 29 patients (25.2%) in Arm B. In the CPI-resistant melanoma cohort (n=28), across doses, the confirmed ORR was 17.9% (95% CI, 6.1%‒36.9%) and disease control rate was 42.9% (95% CI, 24.5%‒62.8%). Increased peripheral cytokine levels and sustained inflammatory responses in the TME were observed, particularly in patients with an objective response. CONCLUSIONS: mRNA-2752 monotherapy or in combination with durvalumab demonstrated antitumor activity with manageable safety in patients with heavily pretreated, relapsed, or resistant solid tumors, particularly in patients with CPI-resistant melanoma. In addition, biomarker analyses demonstrated a sustained inflammatory response within the TME. Together, these findings support investigation of mRNA-based therapeutics for patients with advanced cancer.
Yamaguchi A, Coll RP, Wang J
… +17 more, Bae SW, Tran H, Huang B, Mashimo T, Schuler FW, Lin SJ, Sharma S, Dhakshinamoorthy S, Ta RT, Georgiou DK, Karacosta LG, Malik S, Khan S, Yallapu MM, Kopetz S, Chauhan SC, Manning HC
Clin Cancer Res
· 2026 May · PMID 42149121
·
Full text
PURPOSE: The high mortality associated with metastatic colorectal cancer (mCRC) illuminates an unmet need for innovative therapeutic modalities. Radiopharmaceutical therapy (RPT) offers a potent, molecular scale approach...PURPOSE: The high mortality associated with metastatic colorectal cancer (mCRC) illuminates an unmet need for innovative therapeutic modalities. Radiopharmaceutical therapy (RPT) offers a potent, molecular scale approach for managing and treating cancers with distant micrometastases. However, its clinical use in mCRC remains an unrealized opportunity. We have therefore identified the transmembrane glycoprotein mucin 13 (MUC13) as a promising antigen for developing a targeted RPT and have undertaken preclinical evaluation of its potential through utilizing a monoclonal antibody tool representative of a future class of translatable therapeutics. EXPERIMENTAL DESIGN: The immunoreactivity and transcriptome of CRC patients (n=72 primary, 100 liver metastasis) were characterized using annotated clinical datasets. Preclinical assessment of MUC13 as an RPT target for mCRC was then performed in mice using a monoclonal MUC13-targeted antibody "C14" labeled with either zirconium-89 (89Zr) for positron emission tomography (PET) measurement of mCRC-associated MUC13 density or terbium-161 (161Tb) for targeted RPT. RESULTS: Strong MUC13 immunoreactivity was observed in ~70% of mCRCs and inversely correlated with overall survival (P<0.01). MUC13 levels were visualized by PET and agreed with immunohistochemically determined antigen presence. Furthermore, MUC13-targeted RPT exhibited in vivo proof-of-concept efficacy and enhanced survival in preclinical CRC models. Resulting imaging, therapeutic, and pathological analyses elucidated relationships between target density, therapeutic outcome, and a potential genetic signature. CONCLUSIONS: MUC13-targeted RPT response was not only associated with radiopharmaceutical accumulation but also appeared to be balanced by DNA damage repair gene expression, suggesting a potential sensitivity signature that could complement a future clinical theranostic approach in MUC13-positive mCRC.
Ninomiya T, Fang C, Hamano H
… +19 more, Morinaga T, Zhou W, Koyama T, Miki S, Zhu L, Naoi Y, Ennishi D, Katsuta T, Ohashi K, Morizane S, Ohki-Ikeda T, Nishi T, Ueda Y, Ishino T, Maeda Y, Okamoto I, Zamami Y, Nagasaki J, Togashi Y
Clin Cancer Res
· 2026 May · PMID 42148884
·
Publisher ↗
PURPOSE: Many patients with various cancers have received immune checkpoint inhibitors (ICIs) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some c...PURPOSE: Many patients with various cancers have received immune checkpoint inhibitors (ICIs) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematological malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies. EXPERIMENTAL DESIGN: We performed immunohistochemical staining on the clinical samples from patients with B cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments. RESULTS: A higher incidence of B cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). Our identified lymphomas had a large amount of CD4+ T follicular helper (TFH)-cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL-4/IL-4R, IL-21/IL-21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL-4R, IL-21R, and CD40. CONCLUSIONS: Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings where ICIs are used.
Seguchi K, Fujisawa T, Ikeda S
… +19 more, Oyama Y, Nonomura N, Morizane C, Iwata H, Okano S, Watari H, Namikawa K, Kadowaki S, Ueno M, Oki E, Boku S, Yuki S, Yamagami W, Nishina T, Kudo T, Takahashi N, Bando H, Yoshino T, Nakamura Y
Clin Cancer Res
· 2026 May · PMID 42148883
·
Publisher ↗
PURPOSE: Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene, with loss of MTAP occurring in approximately 15% of solid tumors; however, its molecular and clinicopathological significance remains incomple...PURPOSE: Methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene, with loss of MTAP occurring in approximately 15% of solid tumors; however, its molecular and clinicopathological significance remains incompletely defined. EXPERIMENTAL DESIGN: We conducted a multicenter observational study using two nationwide Japanese genomic screening programs, defining MTAP loss as homozygous deletion. In the MONSTAR-SCREEN-1 study (cohort A; n = 773), patients underwent tissue-based next-generation sequencing to evaluate MTAP status, co-alterations, clinical outcomes, and therapeutic efficacy. In MONSTAR-SCREEN-2 (cohort B; n = 714), multiomic analyses were conducted using whole exome and whole transcriptome sequencing, including xCell immune deconvolution and gene set enrichment analysis (GSEA), to characterize the tumor immune microenvironment and signaling pathways associated with MTAP loss. RESULTS: Among 764 patients in cohort A, MTAP loss was identified in 71 cases. MTAP loss strongly co-occurred with CDKN2A/B deletions and was associated with lower tumor mutational burden and microsatellite stable status. Patients with MTAP loss had significantly shorter overall and progression-free survival under immune checkpoint blockers (ICB) treatment. In MTAP loss tumors, transcriptomic analyses of cohort B revealed reduced infiltration of T cells, while GSEA showed enrichment of cell-cycle, RNA-processing, and DNA repair pathways, and depletion of immune-related and metabolic pathways. CONCLUSIONS: MTAP loss defines a clinically adverse subset across advanced solid tumors, characterized by co-deletion of CDKN2A/B and type I interferon cluster genes, reduced T-cell infiltration, and resistance to ICB. These findings provide a mechanistic context for ICB resistance.