Suvannasankha A, Li M, Omofuma O
… +11 more, Hampp C, Phelan M, Breskin A, Shao P, Roccia T, Mukherjee N, Shrestha A, Lee D, Glass J, Kroog GS, Rodriguez Lorenc K
Clin Cancer Res
· 2026 Jun · PMID 42283723
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PURPOSE: This study aims to compare the risk of second primary malignancy (SPM) between patients with multiple myeloma (MM) who received CAR T therapy versus other systemic anticancer therapies (SACTs). PATIENTS AND METH...PURPOSE: This study aims to compare the risk of second primary malignancy (SPM) between patients with multiple myeloma (MM) who received CAR T therapy versus other systemic anticancer therapies (SACTs). PATIENTS AND METHODS: Adult patients with MM who initiated CAR T therapy or other SACTs were identified from Komodo Health claims data and weighted to balance baseline characteristics. Cumulative incidence of SPM was estimated over 24 months, and P values calculated for difference between 0 and 24 months. RESULTS: The study included 435 patients who received CAR T therapy and 12,268 patients who received other SACTs (median follow-up: 11.8 months). Compared with other SACTs, CAR T therapy was associated with similar risks of any SPM (at 24 months: 24.1% vs. 22.3%,P0-24 mo's = 0.31) and solid SPM (9.1% vs. 11.5%, P0-24 mo's = 0.32), but significantly higher risk of hematologic SPM (17.9% vs. 13.1%, P0-24 mo's = 0.04). In a sensitivity analysis requiring ≥2 claims to identify an SPM, difference in hematologic SPM risk was attenuated (5.5% vs. 4.9%, P0-24 mo's = 0.08). Notably, bone marrow examinations were more common following CAR T therapy (e.g., 47% vs. 13% at 0-3 months). CONCLUSIONS: In this real-world dataset with relatively short follow-up, patients with MM appeared to have a higher risk of hematologic SPM following CAR T therapy compared with other SACTs. However, misclassification and detection bias cannot be ruled out. The association warrants further evaluation. Physicians should be vigilant for myeloid malignancies after CAR T therapy.
Moses R, Powers J, Levine AS
… +5 more, Garber JE, MacFarland SP, Rana HQ, Murphy ME, Maxwell KN
Clin Cancer Res
· 2026 Jun · PMID 42283722
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In individuals with classic Li Fraumeni Syndrome (LFS) due to a loss of function pathogenic germline variant in TP53, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adr...In individuals with classic Li Fraumeni Syndrome (LFS) due to a loss of function pathogenic germline variant in TP53, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adrenal cortical carcinomas, brain tumors and leukemia. In adults with classic LFS, in addition to the classical malignancies, breast cancers and other cancers develop at earlier ages of onset compared to individuals without LFS. Increased genetic testing is identifying a higher frequency of germline TP53 variants with conflicting interpretations in clinical databases, some of which are likely hypomorphic, or of atypical penetrance. Studies of these hypomorphic TP53 variants reveal differential retention or loss of the myriad of p53 tumor suppressive functions. Many individuals with hypomorphic TP53 variants develop cancer, including both canonical and common types, though at later ages as compared to classic LFS. Therefore, further study is needed to understand the most critical tumor suppressive functions of p53 as are data-driven clinical guidelines for management of cancer risk. Herein, we review models of TP53 variant classification focusing on strategies to identify hypomorphic TP53 variants. We go on to review the biology and clinical phenotypes of TP53 hypomorphic variants that have detailed reports of their effects on p53 tumor suppressive functions. Using this framework, we propose possible modifications to the standard LFS screening protocol for individuals with hypomorphic TP53 variants that should be studied in prospective clinical trials.
Ruge L, John F, Verheyen M
… +19 more, Riedel R, Michels S, Nogova L, Scharpenseel H, Fischer R, Stilianakis S, Siemanowski-Hrach J, Fassunke J, Rasokat A, Kron A, Kirsch M, Serke M, Kappes J, Kambartel K, Siebolts U, Merkelbach-Bruse S, Büttner R, Wolf J, Scheffler M
Clin Cancer Res
· 2026 Jun · PMID 42268349
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INTRODUCTION: KRAS Q61 mutations represent a heterogeneous molecular subgroup and account for 1-7% of allKRAS mutations in non-small cell lung cancer (NSCLC). The prognostic value of this cohort and its response to diffe...INTRODUCTION: KRAS Q61 mutations represent a heterogeneous molecular subgroup and account for 1-7% of allKRAS mutations in non-small cell lung cancer (NSCLC). The prognostic value of this cohort and its response to different treatment regimens remain unclear. METHODS: Between 2011 and 2023, diagnostic samples from patients with NSCLC were analyzed by next-generation sequencing (NGS). Molecular data were correlated with clinical records and time-to-event analyses were performed using the Kaplan-Meier estimate. RESULTS: Of the 8862 analyzed probes, we identified 487 patients (5.5%) with KRAS Q61 mutations and further analyzed 365 patients. Most presented with Q61H (74.0%) and Q61L (20.8%) mutations which demonstrated distinct patterns in smoking history (7% versus 3.3% never-smokers) and co-mutational landscape. The most frequent co-mutations in Q61H were STK11 (45.8%), TP53 (32.1%) and KEAP1 (31.3%), whereas Q61L was mutually exclusive to STK11 and had a lower incidence of co-occuring KEAP1 mutations (11.5%). Median overall survival for the entire cohort was 12.3 months with a favorable survival of 22.1 and 65.4 months for patients receiving combined chemoimmunotherapy and immunotherapy as first-line treatment, respectively. Real-world progression-free survival was significantly prolonged in patients receiving immunotherapy, either as monotherapy or combined therapy, versus chemotherapy in the first-line setting (p<0.01). CONCLUSION: KRAS Q61H and Q61L were the predominant mutational subtypes and demonstrated distinct molecular and clinical characteristics, with differences in co-mutational landscape and survival differences. Immunotherapy-based regimens were associated with more favorable outcomes compared to chemotherapy, particularly in patients with high PD-L1 expression, underscoring the importance of subtype-specific molecular characterization in clinical decision-making.
Xu C, Wang SY, Nie M
… +25 more, Yang KY, Huang XQ, Qu S, Chen H, Shen LF, Huang J, Zhang F, Peng YP, Shi LL, Hong XH, Zhang ZJ, Tang LL, Guo L, Ouyang PY, Gao JM, Mao YP, Huang Y, Guo R, Liu LZ, Tian L, Li HJ, Li JB, Ma J, Xia Y, Cai QQ
Clin Cancer Res
· 2026 Jun · PMID 42268339
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PURPOSE: To evaluate the efficacy and safety of dual immunotherapy blocking T-cell immunoglobulin and mucin-domain containing protein-3 (TIM-3) and programmed cell death protein-1 (PD-1) in recurrent/metastatic nasophary...PURPOSE: To evaluate the efficacy and safety of dual immunotherapy blocking T-cell immunoglobulin and mucin-domain containing protein-3 (TIM-3) and programmed cell death protein-1 (PD-1) in recurrent/metastatic nasopharyngeal carcinoma. PATIENTS AND METHODS: The TP cohort enrolled patients with progression on prior PD-(L)1 blockade to receive intravenous TQB2618 plus penpulimab every 3 weeks. The TPGC cohort enrolled treatment-naïve patients to receive TQB2618, penpulimab, gemcitabine, and cisplatin every 3 weeks for 4-6 cycles, followed by maintenance dual immunotherapy. Primary endpoints were dose-limiting toxicity and objective response rate for the TP cohort, and progression-free survival for the TPGC cohort. This two-cohort trial is registered with ClinicalTrials.gov, NCT05563480. RESULTS: Between November 2022 and October 2023, 17 patients were enrolled in the TP cohort and 30 in the TPGC cohort. No dose-limiting toxicities were observed. In the TP cohort, disease control was achieved in ten (58.8%) of 17 patients, with no complete or partial responses; median progression-free survival was 1.6 months (95% CI, 0.0-3.2). In the TPGC cohort, objective response rate was 86.2%, including four (13.8%) complete responses. Median progression-free survival was 10.8 months (95% CI, 9.6-16.4), with a 12-month rate of 40.9%; median overall survival was unreached. Grade 3-4 treatment-related adverse events occurred in two (11.8%) patients in the TP cohort and 25 (83.3%) in the TPGC cohort, predominantly hematological toxicities. CONCLUSIONS: TQB2618 plus penpulimab combined with gemcitabine-cisplatin demonstrated encouraging antitumor activity and a manageable safety profile in treatment-naïve patients. However, the chemotherapy-free dual regimen showed limited efficacy in immunotherapy-refractory disease.
Schöffski P, Sanfilippo R, Martín-Broto J
… +19 more, Kawai A, Desai J, LoRusso P, Maki RG, Jones RL, Blay JY, Smrke A, Abdul Razak A, Italiano A, Sebio A, Bahleda R, Lee YC, van der Graaf WTA, Zhang X, Biyukov T, Teufel M, Fu E, Lahmar M, Wagner AJ
Clin Cancer Res
· 2026 Jun · PMID 42268294
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PURPOSE: The phase 2/3 Brightline-1 trial (NCT05218499) assessed the MDM2-p53 antagonist brigimadlin versus standard-of-care doxorubicin as first-line treatment for MDM2-amplified, locally advanced/metastatic dedifferent...PURPOSE: The phase 2/3 Brightline-1 trial (NCT05218499) assessed the MDM2-p53 antagonist brigimadlin versus standard-of-care doxorubicin as first-line treatment for MDM2-amplified, locally advanced/metastatic dedifferentiated liposarcoma (DDLPS). PATIENTS AND METHODS: Patients with MDM2-amplified, locally advanced or metastatic, unresectable, progressive, or recurrent DDLPS were eligible. In phase 2, patients received oral brigimadlin 30 or 45 mg, or intravenous doxorubicin 75 mg/m2 (all once every 3 weeks). Following a preplanned analysis, in phase 3 patients received brigimadlin 45 mg or doxorubicin 75 mg/m2. The primary endpoint was PFS by blinded central independent review. RESULTS: Between April 13, 2022, and Aug 22, 2023, 148 patients received brigimadlin 45 mg and 162 received doxorubicin. At data cutoff, median PFS was 8.4 months with brigimadlin versus 7.2 months with doxorubicin [Hazard Ratio 0.79 (95% Confidence Interval, 0.6-1.06), P = 0.096]; the primary endpoint was not met. The confirmed objective response rate was 22.3% with brigimadlin and 8.6% with doxorubicin. The most-common grade ≥3 adverse events with brigimadlin were neutropenia (n = 54, 36.7%) and thrombocytopenia (n = 41, 27.9%). Translational analysis demonstrated that brigimadlin activated the TP53 pathway but no biomarkers predictive of efficacy were identified. CONCLUSIONS: While brigimadlin showed activity in this patient population, the median PFS with doxorubicin was substantially longer than anticipated and the primary endpoint of PFS was not met. The safety profile of brigimadlin also did not appear to be more manageable than that of doxorubicin. The translational results will guide future clinical investigations of MDM2-p53 antagonists.
Gan HK, Cher L, Inglis PL
… +24 more, Lwin Z, Gunjur A, Balasubramanian A, Schmidt A, Wichmann CW, Guo N, Lee ST, Thomas P, Scott FE, Shard C, Fluck K, Coombs N, Palmer J, Vail ME, Allen S, Patil A, Pal B, O'Keefe GJ, Gong SJ, Ninatti G, Day BW, Gomez GA, Janes PW, Scott AM
Clin Cancer Res
· 2026 Jun · PMID 42268288
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PURPOSE: To undertake a Phase 1 and Biodistribution study of the EphA3 antibody ifabotuzumab, and its zirconium labelled derivative 89Zr-ifabotuzumab, in glioblastoma patients. PATIENTS AND METHODS: This multi-site study...PURPOSE: To undertake a Phase 1 and Biodistribution study of the EphA3 antibody ifabotuzumab, and its zirconium labelled derivative 89Zr-ifabotuzumab, in glioblastoma patients. PATIENTS AND METHODS: This multi-site study was conducted in adults with recurrent glioblastoma whose tumors were measurable by Response Assessment in Neuro Oncology (RANO) criteria and were ECOG 0-1. Patients underwent a biodistribution PET scans with zirconium 89 (89Zr) ifabotuzumab (89Zr-Ifabotuzumab), followed by three infusions of ifabotuzumab at either 3.5 mg/kg or 5.25 mg/kg before undergoing a second study with 89Zr-Ifabotuzumab PET scans. Resected patient diagnostic tumor samples were collected for multiplex immunofluorescence and spatial transcriptomics analysis. RESULTS: Twelve patients were recruited, six treated with 3.5 mg/kg and six with 5.25 mg/kg of ifabotuzumab. 89Zr-Ifabotuzumab and associated PET scanning were well tolerated, as was ifabotuzumab. There were no objective responses, but one patient had prolonged stable disease. In addition, two patients showed changes in peri-tumor edema that were suggestive of modulation of tumor vasculature. 89Zr-Ifabotuzumab scans showed highly specific tumor uptake in all patients concordant with disease sites on MRI and PET imaging, without evidence of non-specific binding. Spatial transcriptomics and immunofluorescence analysis of the patient's archival tissue specimens showed EphA3 was expressed in the tumor microenvironment (TME) in all patients and tumor cells with different transcriptional states. CONCLUSIONS: Targeting EphA3 with ifabotuzumab in glioblastoma patients is safe and attractive, showing chronological stable expression across both tumour compartments (particularly in cells with mesenchymal phenotype) and non-tumour compartments (particularly the vascular compartment) with evidence of target modulation.
Clin Cancer Res
· 2026 Jun · PMID 42262381
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This commentary on a cohort study of patients with uncommon DPYD variants resulting in increased toxicities highlights the importance of expanding the current DPYD testing profile, the limitations of current testing, and...This commentary on a cohort study of patients with uncommon DPYD variants resulting in increased toxicities highlights the importance of expanding the current DPYD testing profile, the limitations of current testing, and the critical need to consider patients of African ancestry who can carry rare yet extremely toxic DPYD variants.
Chon HJ, Heo J, Kim DY
… +14 more, Lim HY, Macarulla T, Gomez Martín C, Moreno V, Reig M, Ryu MH, Yoon JH, Baumann P, Bhoi S, Jensen M, Tunblad K, Wallberg H, Oberg F, Evans TRJ
Clin Cancer Res
· 2026 Jun · PMID 42262258
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PURPOSE: Immunotherapy has significantly improved outcomes in advanced hepatocellular carcinoma (HCC). However, most patients eventually progress, and second-line options remain limited. Fostrox, a liver targeted prodrug...PURPOSE: Immunotherapy has significantly improved outcomes in advanced hepatocellular carcinoma (HCC). However, most patients eventually progress, and second-line options remain limited. Fostrox, a liver targeted prodrug, was administered in combination with lenvatinib, aiming at enhancing antitumour activity while avoiding further deterioration of residual liver function. PATIENTS AND METHODS: This multicentre, single arm Phase 1b/2a study evaluated safety, PK/PD and efficacy of fostrox (orally for 5 days in 21-day cycles), plus lenvatinib (standard doses), in locally advanced unresectable or metastatic HCC progressed on 1L/2L therapy (NCT03781934). A 3+3 dose escalation design was used to determine the recommended Phase2 dose. RESULTS: Twenty-one patients were enrolled and the median follow-up was 10.5 months. No dose limiting toxicities were observed and the RP2D of fostrox was established at 30 mg. All patients had adverse events (AEs); 81% grade ≥3 with possible relation to fostrox in 52.5% and lenvatinib in 66.7%. Fostrox related AEs were mainly transient neutropenia and thrombocytopenia. Other AEs, mainly attributed to lenvatinib, were grade I/II and consistent with monotherapy use. Fostrox dose reduction and/or discontinuation was 29% and 5%, and for lenvatinib 52% and 14%, respectively. There were no signs of treatment related liver function deterioration. ORR was 24%, DCR 81%, median TTP 10.9 months, median PFS 6.7 months and median OS 13.7 months. Fostrox PK analyses confirmed dose proportionality, and liver biopsies showed tumour selective DNA-damage. CONCLUSIONS: The combination of fostrox and lenvatinib demonstrated promising preliminary efficacy and tolerability post-immunotherapy, supporting further investigation as a second-line option in advanced HCC.
Galvez-Cancino F, Parkes EE, Withers DR
… +1 more, Melero I
Clin Cancer Res
· 2026 Jun · PMID 42258254
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Next generation anti-CTLA-4 antibodies have been designed and tested to improve the efficacy and therapeutic index by leveraging enhanced Fc-mediated effector function with conditional tumour-restricted activation. The g...Next generation anti-CTLA-4 antibodies have been designed and tested to improve the efficacy and therapeutic index by leveraging enhanced Fc-mediated effector function with conditional tumour-restricted activation. The goal is to achieve robust antitumour activity without inducing systemic immune-related toxicity.
Jove M, Braña I, Oliva M
… +18 more, Hernando-Calvo A, Erasun C, Mato-Berciano A, Maliandi MV, Torres-Manjon S, Rojas LA, Connelly S, Bazan-Peregrino M, Moreno R, Martínez de Villarreal J, Real FX, Le C, Nuciforo P, Alemany R, Capellà G, Blasco C, Cascalló M, Mesía R
Clin Cancer Res
· 2026 Jun · PMID 42257887
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PURPOSE: VCN-01 is a hyaluronidase-expressing oncolytic adenovirus that increases immune checkpoint antibody tumor uptake in mice. VCN-01 was evaluated with durvalumab in recurrent/metastatic head and neck squamous cell...PURPOSE: VCN-01 is a hyaluronidase-expressing oncolytic adenovirus that increases immune checkpoint antibody tumor uptake in mice. VCN-01 was evaluated with durvalumab in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients refractory to anti-PD-(L)1. PATIENTS AND METHODS: Patients received intravenous VCN-01 (3.3E12 viral particles (vp), low dose (LD), or 1.0E13 vp, high dose (HD)), plus durvalumab (1500 mg/q4w) concomitantly (VCN-01 + durvalumab on day 1; Arm I) or sequentially (VCN-01 on day -14 + durvalumab on day 1; Arm II). Six patients were enrolled in Arm I LD, eight in Arm II LD, and six in Arm II HD. RESULTS: Two dose-limiting toxicities occurred in Arm I LD, one in Arm II LD, and none in Arm II HD. Anti-tumor responses were observed, with Arm II HD displaying the longest OS of 17.3 months (8.1-NE), although not statistically significant. Eleven patients (61.1%) were alive >12 months. VCN-01 was detected in blood and tumors, and hyaluronidase expression was confirmed. Changes in tumor immune markers were identified, including increased PD-L1 expression correlating with OS. Transcriptomic and radiomic analyses showed changes in the extracellular matrix and increased tumor perfusion. CONCLUSIONS: Sequential VCN-01 plus durvalumab was better tolerated than concomitant treatment. The recommended VCN-01 phase 2 dose (RP2D) was 1.0E13 vp, on the sequential schedule. Encouraging survival was observed in patients after progressing on anti-PD-(L)1 agents. Data supports VCN-01 replication associated with increased PD-1, PD-L1, and CD8 tumor expression. Sequential systemic delivery of VCN-01 and anti-PD-L1 therapy may represent an improved treatment for HNSCC.
Park CL, Demicco EG, Howarth K
… +14 more, Elliott M, Chung PWM, Birkeälv S, Alcaide M, Lee J, Segui N, Arones L, Phillips MJ, Hafstad V, Ferguson PC, Wunder J, Shultz DB, Salawu A, Abdul Razak AR
Clin Cancer Res
· 2026 Jun · PMID 42240449
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BACKGROUND: Soft tissue sarcoma (STS) is a heterogeneous disease characterized by high prevalence of structural variants (SV). Despite surgery and radiation, ~50% of localized STS recur; the role of adjuvant systemic the...BACKGROUND: Soft tissue sarcoma (STS) is a heterogeneous disease characterized by high prevalence of structural variants (SV). Despite surgery and radiation, ~50% of localized STS recur; the role of adjuvant systemic therapy remains controversial. We assessed circulating tumor DNA (ctDNA) tracking tumor-informed SVs throughout the perioperative course and surveillance to detect molecular residual disease. METHODS: Patients with localized, high-risk STS (size ≥5cm, grade ≥2) were enrolled. Bespoke assays targeting 4-16 SV-breakpoints per patient were generated to detect ctDNA. Blood was collected at diagnosis, post-radiation, postoperatively (≤8-weeks), and during follow-up with radiologic surveillance; ctDNA dynamics were correlated with clinical outcomes. RESULTS: 228 plasma samples from 32 patients were analyzed with a median ctDNA surveillance spanning 20.1 months and a median clinical follow-up of 43.8 months. Sensitivity of the assay was 97% (31/32) at baseline. 22 patients received preoperative radiation and had blood collected within the 8-week postoperative window. ctDNA was detectable within this period in 4/22 patients (18%). All 4 (100%) developed metastatic disease within 1 year (median 153 days). 3/18 patients (17%) who were ctDNA-negative in the 8-week window, developed metastatic recurrence (median 521 days), which was preceded by detectable ctDNA. Longitudinal assessment of the entire cohort showed that ctDNA concentration correlated with oncologic treatment and radiologic response. CONCLUSION: SV-based personalized ctDNA detection is feasible and highly sensitive in localized STS. In this proof-of-principle study, ctDNA detection in the 8-week postoperative window was associated with early recurrence. These data inform future trial-design of personalized adjuvant systemic therapy for localized STS.
Braganca Xavier C, Shah PA, Yakimova D
… +11 more, Kravets A, Belousov D, Kudryavtseva K, Massaro M, Paradiso F, Kotlov N, Zhao D, Pant S, Hensley M, Hong DS, Rodon J
Clin Cancer Res
· 2026 Jun · PMID 42240448
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PURPOSE: Comprehensive genomic profiling has prognostic and predictive value for patients with pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: We reviewed clinical and molecular data from 4,009 samples from patients who...PURPOSE: Comprehensive genomic profiling has prognostic and predictive value for patients with pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: We reviewed clinical and molecular data from 4,009 samples from patients who had undergone the BostonGene Tumor Portrait test between 28.10.2021 and 08.10.2024, and 2,181 samples from the BostonGene pancreatic adenocarcinoma meta-cohort, collected from various data hosts and processed by BostonGene automated pipelines. RESULTS: In this high-purity pancreatic adenocarcinoma cohort, 24% harbor homozygous MTAP deletion, and the co-occurrence of KRAS mutations and MTAP loss was common (18.9% of all pancreatic adenocarcinomas). This association identified a subgroup with worse survival outcomes. MTAP-deficient tumors harbor more fibrotic, less immune-enriched microenvironments and have shorter survival. Within the co-mutated tumors, the most frequently detected KRAS variants were G12D, G12V, and G12R, with the last one slightly more related to immune-enriched TME features than the other KRAS variants. CONCLUSIONS: Comprehensive genomic profiling is essential for patients with PAAD and carries both prognostic and predictive value. MTAP loss KRAS-mutant PAAD represents a subgroup of immune-excluded PAADs with a poor prognosis.
Fritsche LG, Higgins LM, Schipper M
… +10 more, Strohbehn G, McMahon BH, Crivelli S, Dai X, Yoo S, Vanderwerff B, Bertucci-Richter E, Elliott D, Green MD, Bryant AK
Clin Cancer Res
· 2026 Jun · PMID 42240401
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BACKGROUND: Immune checkpoint inhibitor (ICI)-induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRSs) for autoimmune hypothyroidism predict thyroid ir...BACKGROUND: Immune checkpoint inhibitor (ICI)-induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRSs) for autoimmune hypothyroidism predict thyroid irAEs in European-ancestry patients; performance in non-European populations is unclear. METHODS: In the Veterans Affairs Million Veteran Program (2011-2023), we identified ICI-treated patients with germline genotyping and a chemotherapy-treated control cohort, excluding those with thyroid disease or prior thyroid-directed treatments. Harmonized ancestry and race (HARE) defined Non-Hispanic White (NHW) and Black (NHB) groups. Thyroid irAEs within one year were defined using laboratory criteria capturing both hyperthyroid and hypothyroid phases. We compared two PRSs: a published European-derived PRS, and an updated PRS selected across multiple GWAS sources and methods (including MVP multi-ancestry GWAS) to maximize discrimination in African-ancestry individuals in a held-out test set. HARE-stratified multivariable Cox models estimated time to thyroiditis; a 6-month landmark analysis assessed overall survival. RESULTS: The ICI cohort included 4,289 patients (3,473 NHW; 816 NHB). The baseline PRS was associated with thyroiditis in NHW (adjusted hazard ratio [aHR] per SD 1.33, 95% CI 1.19-1.50) but not NHB patients or controls. The updated PRS improved risk stratification in NHW (aHR 1.45, 1.28-1.63) and predicted thyroiditis in NHB patients (aHR 1.48, 1.11-1.98), but not in controls. Thyroiditis within 6 months was associated with improved survival, but neither PRS was. CONCLUSIONS: Germline polygenic liability to hypothyroidism predicts ICI-induced thyroiditis in NHW and NHB patients when PRSs are selected via ancestry-stratified validation. Careful exploration of the dataset-method space is critical for equitable PRS development.
Smoragiewicz M, Bernard-Tessier A, Linch M
… +15 more, Shen J, Shore ND, Parikh O, Chi KN, Sokolova AO, Culine S, McKean M, Gleave M, Devitt ME, Zhi E, Gong J, Landrette S, Colasanto M, Patel V, Gao X
Clin Cancer Res
· 2026 Jun · PMID 42227954
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PURPOSE: Resistance to androgen receptor pathway inhibitors (ARPIs) necessitates development of regimens to improve outcomes in metastatic prostate cancer (mPC). This phase 1b clinical trial evaluated safety/tolerability...PURPOSE: Resistance to androgen receptor pathway inhibitors (ARPIs) necessitates development of regimens to improve outcomes in metastatic prostate cancer (mPC). This phase 1b clinical trial evaluated safety/tolerability and pharmacokinetics of bavdegalutamide, an oral PROteolysis TArgeting Chimera (PROTAC) androgen receptor (AR) degrader, combined with abiraterone in patients with mPC experiencing prostate-specific antigen (PSA) progression on abiraterone. METHODS: Patients received bavdegalutamide 420 mg, abiraterone ≤1000 mg, and corticosteroid daily. Assessments included safety (dose-limiting toxicities [DLTs]; treatment-emergent adverse events [TEAEs]), pharmacokinetics, PSA control rate, ≥50% PSA decline (PSA50), and radiographic progression-free survival (rPFS). RESULTS: Forty-five patients were treated; seven had AR ligand-binding domain (LBD) mutations. Median duration of exposure was 35.7 weeks; 13 patients were continuing bavdegalutamide at data cutoff. No DLTs were observed. There were no clinically significant effects of bavdegalutamide on abiraterone pharmacokinetics. Bavdegalutamide 420 mg daily was selected as the recommended phase 2 dose. TEAEs were mostly grade 1/2 (82.2%), and 17.8% were grade 3. Dose modifications or discontinuations due to TEAEs occurred in 48.9% and 13.3% of patients, respectively. The most common bavdegalutamide-related TEAEs were fatigue (48.9%) and nausea (46.7%). PSA control rate was 48.9% (95% confidence interval [CI], 33.7‒64.2). PSA50 response rate was 24.4% (95% CI, 12.9‒39.5), including in 5/7 patients with AR LBD mutations. Median time to PSA progression was 2.8 months (95% CI, 1.5‒6.5). Median rPFS was 16.3 months (95% CI, 8.2‒not calculable). CONCLUSIONS: Bavdegalutamide combined with abiraterone demonstrated a manageable safety profile with no major drug-drug interaction and evidence of clinical activity in mPC.
Visa L, Badia-Ramentol J, Fernández MC
… +22 more, Saurí T, Macias I, Zhang N, Adeva J, Zumstein L, Peinado P, Ponz-Sarvisé M, Ceniceros L, Fabregat-Franco C, Caramés C, Lopez AM, Salinas P, Monzonis X, Masfarré L, Sibilio A, Riva F, Cubillo A, Faull I, Macarulla T, Iglesias M, Bellosillo B, Montagut C
Clin Cancer Res
· 2026 Jun · PMID 42223536
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PURPOSE: NGS tissue testing is recommended in advanced biliary tract cancers (aBTC) due to increasing approval of targeted therapies. However, tissue NGS is frequently limited by poor access and insufficient tumor. We ex...PURPOSE: NGS tissue testing is recommended in advanced biliary tract cancers (aBTC) due to increasing approval of targeted therapies. However, tissue NGS is frequently limited by poor access and insufficient tumor. We exploited ctDNA as an alternative for molecular profiling in aBTC. METHODS: We retrospectively analyzed 10,937 patients with aBTC to characterize the molecular landscape and assess the clinical validity of ctDNA profiling. In a second retrospective cohort of 126 pts from nine Spanish referral centers with available clinical and tumor tissue annotations, paired tissue and ctDNA NGS testing and turnaround time (TAT), were evaluated. Blood samples were analyzed using a comprehensive ctDNA NGS assay (Guardant Health). Genomic alterations (GA) were classified according to ESCAT. RESULTS: In the global cohort, ctDNA-NGS revealed a molecular landscape comparable to tissue-based sequencing, including detection rates of ESCAT actionable GA. Higher ctDNA burden was associated with worse overall survival (27.7 months (95%CI 24.1-33.8) in undetectable ctDNA, 18.5 months (95%CI 16.7-20.2) in low ctDNA burden, and 13.6 months (95%CI 12.5-15.0) in high ctDNA burden; log-rank p< 0.0001). In the independent cohort, ctDNA-NGS was available in 90% of patients versus 50% for tissue NGS. Overall concordance for ESCAT GA was 83%, including 80% for FGFR2 fusions. Median TAT was shorter for ctDNA than tissue (8 vs. 27 days). Survival appeared longer in the small subset receiving ESCAT-matched therapy. CONCLUSIONS: In this retrospective analysis, ctDNA represents a practical alternative to tumor tissue for NGS-based biomarker testing in aBTC, offering improved access and faster results.
McConathy J, Koshkin VS, Menda Y
… +9 more, Rodon J, Goenka AH, Moy RH, Morse S, Demange A, Blumenstein L, Babaoglan B, Aimone P, Hope TA
Clin Cancer Res
· 2026 Jun · PMID 42223513
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PURPOSE: Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FA...PURPOSE: Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). PATIENTS AND METHODS: LuMIERE is a prospective, open-label, non-randomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions (SUVmax ≥1.5× SUVmean of mediastinal blood pool). 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). RESULTS: Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n=3; 5.55 GBq, n=6; 7.40 GBq, n=7; 9.25 GBq, n=11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced Grade 4 lymphopenia and one patient who received 9.25 GBq experienced Grade 3 hemoptysis; these were the only treatment-related Grade ≥3 TEAEs. All-cause Grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined as 9.25 GBq. Preliminary RECIST efficacy findings demonstrated partial response in one patient and stable disease in 10 patients (maintained for at least two assessments in six patients). CONCLUSIONS: 177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.
Kavanagh FG, Instrum RS, Boe LA
… +14 more, Eagan AJ, Scholfield DW, Finnegan EA, Wong RJ, Morris LG, Ow TJ, Wong W, Barker CA, Riaz N, Pulitzer MP, Busam KJ, Patel SG, Fetten J, Ganly I
Clin Cancer Res
· 2026 May · PMID 42213493
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PURPOSE: Neoadjuvant PD-1 blockade has shown marked efficacy before surgery in patients with head and neck cutaneous squamous cell cancer (CSCC). However, the potential for PD-1 blockade as a definitive, non-operative th...PURPOSE: Neoadjuvant PD-1 blockade has shown marked efficacy before surgery in patients with head and neck cutaneous squamous cell cancer (CSCC). However, the potential for PD-1 blockade as a definitive, non-operative therapy remains uncertain. PATIENTS AND METHODS: We conducted a single-institution retrospective study(2018-2023)of patients with locally advanced resectable stage III/IV CSCC treated with cemiplimab. Patients received neoadjuvant cemiplimab followed by surgery or cemiplimab monotherapy without surgery. The primary endpoint was objective radiological (assessed using iRECIST)and clinical response rate; secondary endpoints included disease-specific survival (DSS),progression-free probability(PFP),histopathologic response, and exploratory genomic biomarkers. RESULTS: Fifty-one patients received cemiplimab monotherapy alone (median age;78.8 years) and 21 received neoadjuvant cemiplimab followed by surgery (median age;73 years). The 2-year DSS and PFP for cemiplimab monotherapy were 90% (95% CI, 80-100%) and 82% (95% CI, 72-94%), respectively. The 2-year DSS and PFP for neoadjuvant cemiplimab with surgery were 95% (95% CI, 86-100%) and 78% (95% CI, 62-100%), respectively. Tumor-infiltrating lymphocytes (TILs) were higher in patients with complete or partial response than in patients with progressive or stable disease (p=0.005, q=0.026), with absent TILs more frequent in non-responders. Tumor mutational burden was greater in complete (55.7) and partial (14.9) response than in progressive disease (4.9; p=0.02, q=0.04). CONCLUSIONS: n this retrospective, non-randomized cohort, definitive-intent cemiplimab monotherapy was associated with durable disease control in selected patients with locally advanced resectable head and neck CSCC. This study provides a promising real-world organ preservation experience for patients with advanced head and neck CSCC treated with cemiplimab monotherapy that does not compromise oncologic outcomes.
Ma P, Zhou Y, Ma W
… +7 more, Wang Y, Cai H, Sui Y, Zhao L, Zhang Y, Wang S, Li N
Clin Cancer Res
· 2026 May · PMID 42207176
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PURPOSE: To evaluate intrathecal QH104, an allogeneic B7 homolog 3 (B7-H3)-targeted chimeric antigen receptor (CAR) γδ T-cell therapy, in patients with leptomeningeal metastasis (LM). PATIENTS AND METHODS: In this phase...PURPOSE: To evaluate intrathecal QH104, an allogeneic B7 homolog 3 (B7-H3)-targeted chimeric antigen receptor (CAR) γδ T-cell therapy, in patients with leptomeningeal metastasis (LM). PATIENTS AND METHODS: In this phase 1 study (NCT06592092), three patients with LM from B7-H3-positive solid tumors were enrolled, including two with lung adenocarcinoma and one with triple-negative breast cancer. QH104 was administered at a fixed dose of 3 × 107 cells per infusion via lumbar puncture or an Ommaya reservoir. The primary objective was to evaluate clinical response. Secondary objectives included safety, overall survival, quality of life, and pharmacokinetic/pharmacodynamic profiling. RESULTS: QH104 was generally well tolerated, with no grade ≥4 treatment-related adverse events (TRAEs). One patient developed grade 3 immune effector cell-associated neurotoxicity syndrome. All TRAEs resolved with supportive care. All patients had stable disease on days 14 and 30 according to the Response Assessment in Neuro-Oncology-Leptomeningeal Metastases criteria, with symptom improvement in two patients. Cerebrospinal fluid (CSF) cytology converted to and remained negative through day 30 in one patient with positive baseline cytology. B7-H3-CAR γδ T cells persisted in CSF for at least one week and were accompanied by increased interferon gamma (IFN-γ) levels. Single-cell sequencing suggested IFN-γ-associated immune remodeling in CSF, including expansion of an inflammatory macrophage state and subsequent lymphocyte recruitment. CONCLUSIONS: This study provides preliminary proof of concept for intrathecal allogeneic B7-H3-CAR γδ T-cell therapy in LM, with early evidence of safety, clinical activity, local persistence, and IFN-γ-associated immune remodeling in CSF.
Zeng J, Cui S, Hippe DS
… +13 more, Fu J, Yaseen F, He Y, Kang J, Grassberger C, Vesselle HJ, Kinahan PE, Eaton KD, Baik CS, Santana-Davila R, Lee S, Rengan R, Bowen SR
Clin Cancer Res
· 2026 May · PMID 42207168
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PURPOSE: FLARE-RT tested personalized functional-lung-avoidance and response-adaptive radiotherapy intensification for unresectable non-small cell lung cancer (NSCLC) using FDG-PET/CT and SPECT/CT. We report mature outco...PURPOSE: FLARE-RT tested personalized functional-lung-avoidance and response-adaptive radiotherapy intensification for unresectable non-small cell lung cancer (NSCLC) using FDG-PET/CT and SPECT/CT. We report mature outcomes and failure patterns. METHODS: 49 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on FLARE-RT (NCT02773238) from 2016-2021 and initiated chemoradiation. Patients with Week 3 FDG-PET response received 60Gy in 30 fractions. Patients with non-response received concomitant boosts Weeks 4-6 to residual metabolic disease of 74-90Gy total guided by FDG uptake. Overall survival (OS, primary endpoint) and progression free survival (PFS) were estimated via Kaplan-Meier. Locoregional progression (LRP) and distant metastasis (DM) cumulative incidence were estimated via Aalen-Johansen, with death and alternative progression pattern as competing risks. Predictors of treatment failure modes were identified through Fine-Gray regression. RESULTS: At 52.3 months median follow-up, 1-year and 2-year OS were 81.6% (95%CI:71.5-93.2%) and 54.2% (CI:41.8-70.4%), respectively; 1-year and 2-year PFS were 53.1% (CI:40.9-69.0%) and 40.5% (CI:28.8-57.0%), respectively. Cumulative incidence for 1-year and 2-year LRP was 12.2% (CI:4.9-23.2%) and 18.5% (CI:9.0-30.6%), respectively; 1-year and 2-year DM were 34.7% (CI:21.7-48.1%) and 43.1% (CI:28.9-56.5%), respectively. Higher pre-RT FDG-PET total lesion glycolysis (TLG) correlated with increased LRP (HR=1.87 [CI:1.41-2.49], p<0.001), whereas higher mid-RT TLG correlated with DM (HR=1.52 [CI:1.05-2.21], p=0.03). 25 of 49 patients received durvalumab and exhibited lower 1-year DM (20.0% vs. 54.2%, p=0.04) with equivocal 1-year LRP (20.0% vs. 4.2%, p=0.27). CONCLUSION: Biological image-guided FLARE-RT achieved durable locoregional control with consistent survival outcomes relative to RTOG0616 (60Gy arm) and RTOG1106 (adaptive arm). This informs biomarker-guided and risk-adaptive therapy for unresectable NSCLC.
Banda K, Davies HR, Kumar Y
… +12 more, Memari Y, Degasperi A, Radke M, Rodriguez I, Gooley TA, Katz R, Menghi F, Harding T, Lin K, Liu ET, Nik-Zainal S, Swisher EM
Clin Cancer Res
· 2026 May · PMID 42201779
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PURPOSE: To evaluate HRDetect, a mutational-signature-based algorithm, for prognostic utility in tubo-ovarian carcinoma (OC), and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis c...PURPOSE: To evaluate HRDetect, a mutational-signature-based algorithm, for prognostic utility in tubo-ovarian carcinoma (OC), and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis can refine genomic classification beyond the traditional homologous recombination deficient (HRD) versus proficient (HRP) framework. EXPERIMENTAL DESIGN: WGS was performed on matched tumor-normal pairs from 185 patients with advanced-stage OC from the University of Washington (UW) cohort. HRDetect scores were calculated using substitution signatures, rearrangement signatures, microhomology-mediated deletions, and global loss of heterozygosity. An independent validation cohort (ARIEL2, n = 77) of platinum-sensitive OC treated with rucaparib, was analyzed to correlate HRDetect with PARP inhibitor (PARPi) response. RS analysis and unsupervised hierarchical clustering were employed to delineate genomic subgroups. RESULTS: In the UW cohort, 51.4% of cases were classified as HRDetect-high and had significantly prolonged median overall survival versus others (6.2 vs 4.1 years; HR=0.6; 95% CI=0.41-0.87; p=0.007). 48.4% of HRDetect-high tumors harbored BRCA1/2 mutations or BRCA1 promoter methylation, while 22.1% lacked BRCA1/2 alterations. A substantial fraction (23.2%) fell into an HRDetect-intermediate category, highlighting greater genomic heterogeneity than currently appreciated. RS profiling uncovered eleven genomic clusters, with specific RS profiles (RS1, RS14, RS18) correlating with poor survival. In ARIEL2, HRDetect-high tumors showed better PARPi responses, with improved progression-free survival (11.1 vs 7.1 months; HR=0.44; 95% CI=0.26-0.74; p=0.03) and response rates (54% vs 22.5%). CONCLUSIONS: HRDetect predicts survival and sensitivity to PARPi in OC. Combined with RS-based clustering, it reveals unappreciated genomic heterogeneity, and supports a nuanced stratification framework to improve precision oncology in OC.