Shi F, Chai W, Yang H
… +5 more, Cao W, Zhang S, Chen Z, Ouyang W, Cui Y
Clin Cancer Res
· 2026 Jul · PMID 41954613
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PURPOSE: This exploratory phase Ib study aimed to evaluate the efficacy and safety of AL2846, a multi-kinase inhibitor, in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) following disease pro...PURPOSE: This exploratory phase Ib study aimed to evaluate the efficacy and safety of AL2846, a multi-kinase inhibitor, in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) following disease progression on prior VEGFR-targeted therapy. PATIENTS AND METHODS: This multi-center, open-label, phase Ib study enrolled patients with RR-DTC treated with prior tyrosine kinase inhibitor (TKI) therapy. Eligible patients received oral 90 mg or 120 mg of AL2846 capsules, once daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and safety. RESULTS: From February 16, 2023 to March 13, 2025, 33 patients (90 mg, n = 21; 120 mg, n = 12) were enrolled in this study. All patients had disease progressed following one or two prior VEGFR-targeted therapy. The median age was 59 years (47, 63), and 17 (51.5%) patients were female. The ORR was 12.12%, with two partial responses observed in each dose group. The DCR was 100% in the 90 mg group and 91.67% in the 120 mg group, respectively. The median PFS in 90 mg was 18.33 months [95% confidence interval (CI), 10.97-not estimable], with a 6-month PFS rate of 94.4% and a 12-month PFS rate of 70.8%. The most common treatment-related adverse events (TRAE) included aspartate aminotransferase/alanine aminotransferase increased, hypertension, proteinuria, hypocalcemia, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 47.62% of patients in the 90 mg group and 41.67% in the 120 mg group. CONCLUSIONS: AL2846 showed an acceptable safety profile and a promising antitumor activity in previously TKI-treated patients with RR-DTC, with 90 mg having a more favorable effect.
Marinello A, Rotow JK, Lomibao M
… +18 more, Miliziano D, Leporati R, Feng J, Metro G, Brandão M, Gorria T, Nassar AH, Citarella F, Fila M, Fallet V, Ricciuti B, Taylor S, Remon J, Planchard D, Florez N, Besse B, Drilon A, Aldea M
Clin Cancer Res
· 2026 Jul · PMID 41945500
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PURPOSE: In RET-rearranged non-small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates o...PURPOSE: In RET-rearranged non-small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. EXPERIMENTAL DESIGN: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). RESULTS: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. CONCLUSIONS: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.
Anders P, Sextro M, Lingelbach K
… +29 more, Standvoss K, Pandhe S, Ghosh S, Böhm C, Tietz S, Krupar R, Tharun L, Eich ML, Ribbat-Idel J, Ramberger E, Liang X, Aumiller V, Merkelbach-Bruse S, Quaas A, Frost N, Schlachtenberger G, Heldwein M, Keilholz U, Hekmat K, Rückert JC, Büttner R, Grohe C, Horst D, Alber M, Ruff L, Klauschen F, Dernbach G, Seegerer P, Schallenberg S
Clin Cancer Res
· 2026 Jul · PMID 41945491
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PURPOSE: Antibody-drug conjugates (ADC) targeting trophoblast cell surface antigen 2 (TROP-2) and cMET are entering clinical trials in non-small cell lung cancer (NSCLC). Their translation depends on reliable biomarker a...PURPOSE: Antibody-drug conjugates (ADC) targeting trophoblast cell surface antigen 2 (TROP-2) and cMET are entering clinical trials in non-small cell lung cancer (NSCLC). Their translation depends on reliable biomarker assessment, a task still dominated by subjective visual scoring and inconsistent reproducibility. EXPERIMENTAL DESIGN: We built a modular Artificial Intelligence (AI) pipeline that detects cells, classifies carcinoma cells, and quantifies membranous and cytoplasmic expression. A membranous scorer trained on TROP-2 was applied zero-shot to cMET, human epidermal growth factor receptor 2 (HER2), and PD-L1. For TROP-2, cMET, and HER2, expression was quantified using the H-score, defined as (1× % weakly positive cells) + (2× % moderately positive cells) + (3× % strongly positive cells), with negative cells excluded (range, 0-300), and categorized as negative (0-50), weakly positive (50-100), moderately positive (100-200), or strongly positive (200-300). PD-L1 expression was assessed using both the H-score and the tumor proportion score (TPS), defined as the percentage of viable tumor cells showing membranous PD-L1 staining relative to all viable tumor cells, multiplied by 100. The analysis covered 1,142 resected NSCLCs, integrating expression maps with clinicopathologic, molecular, and tumor microenvironment (TME) features. RESULTS: The AI scorer recapitulated pathologist annotations with near-perfect correlation [Pearsons's correlation (r) = 0.98-0.99, Spearman's rho (ρ) = 97-98, Kendall's tau (τ) = 0.88-0.89, Lin's concordance correlation coefficient (CCC) = 0.97-0.98] for TROP-2 and generalized to other markers [cMET r = 0.99, ρ = 0.96, τ = 0.91, CCC = 0.96; HER2 r = 0.93, ρ = 0.72, τ = 0.60, CCC = 0.92; and PD-L1 (TPS) r = 0.85, ρ = 0.84, τ = 0.68, CCC = 0.82/(H-score) r = 0.87, ρ = 0.86, τ = 0.70, CCC = 0.85]. Its agreement with six pathologists matched interobserver variability (0.86-0.96). Expression maps revealed contrasting spatial and cellular patterns: TROP-2 dominated lung squamous cell carcinoma [LUSC; mean H-Scores 141.3/103.2 vs. 74.5/45.7 in lung adenocarcinoma (LUAD) for membrane/cytoplasm] and marked immune-deserted tumors. cMET prevailed in LUAD (mean 50.4 vs. 20.6 in LUSC), colocalized with fibroblast-rich, immune-active TME, and KRAS mutations. CONCLUSIONS: Foundation model-based scoring produces expert-level, scalable biomarker quantification. The resulting TME phenotypes-TROP-2-high immune-deserted versus cMET-high, immune-active-reveal therapeutic implications for combining ADCs with immunotherapies or kinase inhibitors.
Garralda E, Markert C, Moreno V
… +30 more, Calvo E, Rohrberg K, Kim TM, Lee DH, Cohen JE, Lim DWT, Thistlethwaite FC, Cho BC, Kim YJ, Stemmer SM, Guidi M, Kraus D, Heichinger C, Tran VL, Mücke M, Michielin F, McIntyre C, Madden-Raja K, Marbach D, Davydov II, Hatje K, Lopes R, Wilson S, Rutishauser T, Codarri Deak L, Hüsser T, Schlenker R, Yángüez E, Kao H, Melero I
Clin Cancer Res
· 2026 Jul · PMID 41945490
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PURPOSE: The immunoglobulin G1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks programmed cell death protein 1 and lymphocyte activation gene-3 expressed on activated T cells. PATIENTS...PURPOSE: The immunoglobulin G1-based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks programmed cell death protein 1 and lymphocyte activation gene-3 expressed on activated T cells. PATIENTS AND METHODS: This first-in-human, open-label, phase I clinical trial of tobemstomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with three tumor-specific cohorts, enrolling checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small cell lung cancer (NSCLC) and CPI-naïve patients with esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetics (PK), drug receptor occupancy, and preliminary antitumor activity. RESULTS: Thirty-five (dose-escalation) and sixty-nine patients (expansion) were enrolled. Tobemstomig was well tolerated up to the highest tested dose of 2,100 mg once every 2 weeks. The MTD was not reached, and 2,100 mg once every 2 weeks was established as the RDE. Tobemstomig exhibited linear PK across the studied dose range. Partial responses were achieved by 2 of 4 (600 mg) and 4 of 13 (2,100 mg) patients during dose escalation, 6 of 41 patients with CPI-experienced melanoma [objective response rate (ORR): 15%; 95% confidence interval (CI), 6.6-26.9], and 1 of 8 patients with CPI-naïve ESCC (ORR: 12.5%; 90% CI, 0.6-47.1). Proof of mechanism was demonstrated in patients with CPI-experienced melanoma based on increases in the amounts of CD8+ T cells, expansion of stem-like CD8+ T cells, and the acquisition of cytotoxic effector functions, with limited changes in the regulatory T-cell compartment. CONCLUSIONS: Tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications. The encouraging antitumor activity associated with pharmacodynamic activity and proof of mechanism in patients with CPI-experienced melanoma indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.
Daver N, Blachly JS, Ghobadi A
… +11 more, Advani A, Muffly L, Garciaz S, Recher C, Kahali B, Sun J, Jung AS, Filosto S, Mao D, Granados E, Sallman DA
Clin Cancer Res
· 2026 Jul · PMID 41941266
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PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematologic malignancies, but success in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been limited due to underwhelmin...PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in many hematologic malignancies, but success in relapsed/refractory (R/R) acute myeloid leukemia (AML) has been limited due to underwhelming response rates and high on-target/off-tumor toxicity. This phase 1 dose-escalation trial evaluated the safety and efficacy of KITE-222, an autologous CAR T-cell therapy that recognizes C-type lectin-like molecule 1 (CLL-1), predominantly expressed on myeloid cells but absent on normal hematopoietic stem cells and other tissues. PATIENTS AND METHODS: Patients with R/R AML (≥50 kg) received a single intravenous infusion of 3 × 107 (cohort 1), 1 × 108 (cohort 2), or 3 × 108 (cohort 3) KITE-222 CAR+ T cells. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Key secondary endpoints included overall remission rate, incidence of adverse events (AE), and pharmacokinetics/pharmacodynamics. RESULTS: Twelve patients received KITE-222. One patient in cohort 3, who was the only patient to receive two courses of lymphodepleting chemotherapy, experienced a DLT (prolonged grade 4 neutropenia/thrombocytopenia) but achieved a best response of morphologic leukemia-free state on day 14 following infusion (confirmed on day 44). All patients experienced grade ≥3 AEs, none had grade ≥3 cytokine release syndrome, and one had grade ≥3 immune effector cell-associated neurotoxicity syndrome. Clinically meaningful responses were lacking across dose levels despite detectable CAR T-cell expansion. Although two of five cohort 3 patients with clear expansion had near-complete depletion of CLL-1+ bone marrow blasts after infusion, CLL-1- blasts persisted, and reductions in total blasts were not observed. CONCLUSIONS: Despite successful manufacturing and acceptable safety, KITE-222 lacked preliminary efficacy, warranting future studies that address CLL-1 heterogeneity and focus on improving in vivo expansion and antitumor activity.
An PG, Zhang J, Hu X
… +3 more, Zhang ZQ, Zhang T, Wu WJ
Clin Cancer Res
· 2026 Jul · PMID 41941265
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PURPOSE: The outcomes of salvage surgery for previously irradiated recurrent head and neck squamous cell carcinoma (HNSCC) remain suboptimal. This phase II trial evaluated the effects of preoperative tislelizumab (an ant...PURPOSE: The outcomes of salvage surgery for previously irradiated recurrent head and neck squamous cell carcinoma (HNSCC) remain suboptimal. This phase II trial evaluated the effects of preoperative tislelizumab (an anti-programmed cell death protein 1 monoclonal immunoglobulin G4 antibody) plus chemotherapy followed by salvage surgery and adjuvant tislelizumab in this setting. PATIENTS AND METHODS: Eligible patients (n = 34) with resectable recurrent HNSCC after radiotherapy received preoperative tislelizumab (200 mg), albumin-bound paclitaxel (260 mg/m2), and cisplatin (60-75 mg/m2) every 3 weeks for 2 cycles, followed by salvage surgery and 6 cycles of adjuvant tislelizumab. The primary endpoint was major pathologic response (MPR). Secondary endpoints included pathologic complete response (pCR), the objective response rate (ORR), 2-year event-free survival (EFS), 2-year overall survival (OS), and safety. RESULTS: The ORR was 35.3% (12/34). Of 26 surgical patients, R0 resection was achieved in 19 (73.1%). The MPR rate was 19.2% (5/26), with a pCR rate of 15.4% (4/26). At a median follow-up of 32 months, 2-year EFS was 39.6% and 2-year OS was 54.8%. All MPR patients remained disease free. Grade 1 to 2 adverse events were common; one grade 3 hyperglycemia occurred. High baseline B-cell receptor (BCR) repertoire diversity and clonal abundance (top 1%/10%) correlated with poor prognosis, with top 1% clonality showing strong prognostic power (AUC = 0.910; P = 0.006). CONCLUSIONS: Preoperative chemoimmunotherapy followed by surgery and adjuvant immunotherapy was feasible with encouraging survival in previously irradiated recurrent HNSCC. Baseline BCR repertoire characteristics may serve as a noninvasive prognostic biomarker.
Favours E, Tang H, Wong P
… +24 more, Ghilu S, Del Pozo V, Mironova E, Chen Y, Stearns T, Neuhauser S, Earley EJ, Erickson SW, Kwon JY, Jocoy EL, Groff D, Krytska K, Tsang M, Teicher BA, Mossé YP, Kolb EA, Hav M, Loo D, Houghton PJ, Bult CJ, Gorlick RG, Maris JM, Smith MA, Kurmasheva RT
Clin Cancer Res
· 2026 Apr · PMID 41941262
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INTRODUCTION: Vobramitamab duocarmazine (vobra-duo) is a duocarmycin-based, humanized antibody-drug conjugate (ADC) targeting B7-H3, with a drug-to-antibody ratio of ~2.7. Vobra-duo has demonstrated robust antitumor acti...INTRODUCTION: Vobramitamab duocarmazine (vobra-duo) is a duocarmycin-based, humanized antibody-drug conjugate (ADC) targeting B7-H3, with a drug-to-antibody ratio of ~2.7. Vobra-duo has demonstrated robust antitumor activity in multiple adult cancer models, along with favorable pharmacokinetic and safety profiles in cynomolgus monkeys. Early results from phase I/II clinical trials (NCT03729596) have shown manageable toxicity and promising objective responses in patients with metastatic castration-resistant prostate cancer. Given the high expression of B7-H3 in pediatric solid tumors, this target is emerging as a compelling therapeutic opportunity in pediatric oncology. METHODS: Antitumor activity of vobra-duo was evaluated in pediatric solid tumor xenograft models, including Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, osteosarcoma, malignant rhabdoid tumor, hepatoblastoma, and Wilms tumor. Tumor-bearing mice received a single intraperitoneal dose of vobra-duo (6 mg/kg) or a matched control ADC (SYD988, anti-CD20 ADC with identical linker and payload). Tumor progression was defined as a fourfold increase in tumor volume. Event-free survival was analyzed using Kaplan-Meier methods, and responses were categorized as partial, complete, or maintained complete response. RESULTS: Vobra-duo induced objective responses across multiple tumor types, whereas the control ADC showed limited activity. No clear association was observed between B7-H3 protein expression and therapeutic response. CONCLUSIONS: These findings demonstrate broad preclinical efficacy of vobra-duo in pediatric solid tumors and support further clinical investigation of B7-H3-targeted therapies in children.
Gregucci F, Lee-Poturalski C, Dirrim M
… +28 more, Stewart J, Caruthers D, Stiles CD, Hentrich K, Cardenas J, Chan TA, Yu DS, Tran P, Simone N, Sawant A, Schwarz J, Robinson C, Haas-Kogan D, Michor F, Vanpouille-Box C, Ng J, Hasan Y, Yu J, Ren L, Marchionni L, Hugo G, Berbeco R, Nakamura JL, Lindsay J, Yang X, Deasy JO, Weichselbaum RR, Formenti SC
Clin Cancer Res
· 2026 Jun · PMID 41941260
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The Radiation Oncology-Biology Integration Network (ROBIN) initiative addresses critical gaps in radiation oncology by integrating advanced biological research, technologic innovation, and clinical practice. ROBIN levera...The Radiation Oncology-Biology Integration Network (ROBIN) initiative addresses critical gaps in radiation oncology by integrating advanced biological research, technologic innovation, and clinical practice. ROBIN leverages "omics" technologies, data science, and integrative analyses to elucidate the mechanisms governing tumor and normal tissue responses to radiotherapy (RT). Through five specialized centers-OligoMET, ImmunoRad, GenRad, METEOR, and KIDSROBIN-the network covers a broad spectrum of cancer and radiation biology research. Each center conducts translational programs linked to clinical trials, targeting key domains, including metastasis biology, RT-immune system interactions, and genomic determinants of treatment response. KIDSROBIN assures the invaluable inclusion of pediatric cancers to the consortium. By collecting clinically annotated human biospecimens and applying single-cell and spatially resolved omics, ROBIN enables mechanistic insights into radiation effects directly in patients. A central pillar of the initiative is its commitment to data standardization and sharing, using cloud-based platforms to generate accessible and interoperable datasets. ROBIN also prioritizes education and cross-disciplinary training to cultivate the next generation of scientists in radiation biology and oncology. This integrated approach positions ROBIN to drive transformative advances in radiation oncology and multimodal cancer therapy, informing personalized treatment strategies and improving patient outcomes. This review provides an overview of the ROBIN program and its key strategies, research activities, and contributions to advancing radiation biology and oncology. The vision and leadership of Dr. Norman Coleman have been foundational to the development of the ROBIN initiative, inspiring a collaborative ecosystem that bridges science and clinical practice to drive meaningful impact in patient care.
Jhaveri K, Eli LD, Hurvitz SA
… +16 more, Brufsky A, Bose R, de Miguel M, Unni N, Reid S, Quinn DI, Mahalingam D, Saura Manich C, García-Sáenz JÁ, Martínez-Bueno A, Guerrero-Zotano A, Trédan O, Wildiers H, Bischof GF, Bebchuk J, Solit DB
Clin Cancer Res
· 2026 Apr · PMID 41941252
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PURPOSE: HER2 mutations occur in 1-3% of triple-negative breast cancers (TNBCs), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastat...PURPOSE: HER2 mutations occur in 1-3% of triple-negative breast cancers (TNBCs), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib+trastuzumab (N+T; neratinib 240 mg/day, IV trastuzumab 8 mg/kg initially then 6 mg/kg q3w). We report final results from the neratinib and N+T TNBC cohorts. EXPERIMENTAL DESIGN: Primary endpoint: investigator-assessed objective response rate at first post-baseline tumor assessment (ORRfirst); secondary endpoints included: confirmed ORR by investigator; clinical benefit rate (CBR); progression-free survival (PFS); exploratory endpoint: circulating tumor (ct) DNA collected at baseline, during treatment, and at end of treatment. RESULTS: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40.0% (95%CI12.2-73.8) for neratinib (n=10) and 35.3% (95%CI 14.2-61.7) for N+T (n=17). CBRs were 40.0% (95%CI 12.2-73.8) and 47.1% (95%CI 23.0-72.2), respectively; median PFS was 2.89 (95%CI 0.95-5.52) and 6.24 months (95%CI 2.10-8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase of on-pathway (ERBB3) and off-pathway (KRAS, TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation. CONCLUSIONS: N+T in patients with HER2-mutant metastatic TNBC appeared to prolong responses versus neratinib alone, representing a novel approach for biomarker-defined metastatic TNBC patients. Based on these and previously published data, neratinib-based combinations are endorsed by NCCN guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations.
Clin Cancer Res
· 2026 Jun · PMID 41926699
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In this issue of CCR Translations, it is explored whether removing fewer than usual tumor-draining lymph nodes (LN) at surgical resection might offer better outcomes in patients subsequently receiving immunotherapy. Thes...In this issue of CCR Translations, it is explored whether removing fewer than usual tumor-draining lymph nodes (LN) at surgical resection might offer better outcomes in patients subsequently receiving immunotherapy. These LNs likely host coordinated adaptive immune responses and may be a key reason why neoadjuvant immunotherapy is exhibiting remarkable clinical success. See related article by Long et al., p. 2467.
Abi Jaoude J, Lau A, Yuan Y
… +25 more, Meimoun NS, De B, Liao K, Kouzy R, Nieves-Jimenez HR, Poenisch F, Balter PA, Brock KK, Sawakuchi GO, Vauthey JN, Tzeng CD, Shamsutdinova D, Lazar AJ, Chatterjee D, Holliday EB, Smith GL, Minsky BD, Das P, Koong AC, Lee SS, Tran Cao HS, Javle M, Kwong L, Koay EJ, Ludmir EB
Clin Cancer Res
· 2026 May · PMID 41923341
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PURPOSE: Ablative radiotherapy (RT) improves clinical outcomes in patients with unresectable intrahepatic cholangiocarcinoma (ICC). Applicability to "supermassive" ICC remains uncertain given smaller tumor diameters in p...PURPOSE: Ablative radiotherapy (RT) improves clinical outcomes in patients with unresectable intrahepatic cholangiocarcinoma (ICC). Applicability to "supermassive" ICC remains uncertain given smaller tumor diameters in previous studies. We hypothesize that supermassive ICCs are not mutationally or histopathologically different from nonsupermassive ICCs and so would respond favorably to ablative RT. EXPERIMENTAL DESIGN: This is a retrospective study of patients with supermassive ICC treated at the University of Texas MD Anderson Cancer Center (MDACC) and the National Cancer Database (NCDB). Patients treated at MDACC with unresectable ICC, ≥10 cm in diameter, treated with ablative RT or chemotherapy alone were included. Among NCDB patients, patients treated with chemotherapy alone were included. We analyzed overall survival (OS), tumor-related liver failure (TRLF), and treatment toxicity. We further analyzed mutational status and histopathology in supermassive and nonsupermassive ICC tumors. RESULTS: We identified 63 patients treated at MDACC. Patients treated with RT showed improved OS compared with patients treated with chemotherapy alone (median OS: 28.7 vs. 11.9 months; adjusted HR = 0.4; P = 0.02). Patients treated with chemotherapy alone had a higher rate of TRLF compared with those who received RT (47.1% vs. 12.1%; P = 0.01). The RT cohort had improved OS compared with a frequency-matched NCDB chemotherapy-only cohort of supermassive ICC (37.6 vs. 8.9 months, P < 0.001). No major differences in mutational status or histopathology were noted between supermassive and nonsupermassive ICC tumors. CONCLUSIONS: Patients with supermassive ICC did not show a distinct mutational or histopathologic profile compared with those with nonsupermassive ICC and had promising outcomes with manageable toxicity when treated with ablative RT.
Vista WR, Malik V, Sheehan MC
… +9 more, Ismail J, Hocine HR, Ganbaatar U, Misawa K, Guzman Valle J, Banerjee S, Solomon SB, Adusumilli PS, Srimathveeravalli G
Clin Cancer Res
· 2026 Jul · PMID 41920765
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PURPOSE: One recurring challenge in cell therapy for solid tumors is poor tumor infiltration of adoptively transferred T cells. We previously showed that a subablative dose of tumor-targeted radiation generates a chemoki...PURPOSE: One recurring challenge in cell therapy for solid tumors is poor tumor infiltration of adoptively transferred T cells. We previously showed that a subablative dose of tumor-targeted radiation generates a chemokine gradient that promotes infiltration, proliferation, and a memory phenotype of chimeric antigen receptor (CAR) T cells in solid tumors. However, radiation is cytotoxic to infiltrating CAR T cells, limiting its repeated use. EXPERIMENTAL DESIGN: We hypothesized that irreversible electroporation could generate a chemokine gradient that promotes CAR T-cell infiltration into solid tumors and that selective irreversible electroporation (sIRE) tuned for selective cancer cell lysis (thus sparing infiltrating CAR T cells) can be used in a repeated fashion. Using experimental screening and simulation models, we optimized sIRE parameters to kill cancer cells while sparing T cells. RESULTS: Using 3D tumor mimics and mouse models of malignant pleural mesothelioma, we confirmed the therapeutic benefit of repeated sIRE. Chemokine secretion by cancer cells injured by sIRE promoted migration and tumor infiltration of systemically administered CAR T cells and facilitated sustained immunity in a tumor-rechallenge model. CONCLUSIONS: By leveraging a dual-purpose translational strategy-through direct cancer cell-targeted cytotoxicity and augmented CAR T-cell infiltration-sIRE can reduce cancer burden while preserving and enhancing CAR T-cell function.
Vemulamanda S, Kothari A, De Cecco L
… +36 more, Kim S, Kulkarni A, Upadhyay P, Cavalieri S, Courtine C, Mirmozaffari Y, Brown J, Sewell A, Flamand Y, Xie Y, Zheng L, Marur S, Hackman T, Singer B, Hakim JA, Ramkissoon L, Li Y, Rehmani H, Li X, Sheth S, Chen X, Dorth J, Pan Q, Graboyes E, Chera B, Burtness B, Ferris RL, Leemans R, Brakenhoff RH, Hoebers F, Scheckenbach K, Poli T, Licitra L, Yarbrough WG, Issaeva N, Schrank TP
Clin Cancer Res
· 2026 Jul · PMID 41920764
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PURPOSE: Patients with human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) have relatively favorable outcomes, but standard treatments like radiation or chemoradiation frequently result in...PURPOSE: Patients with human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) have relatively favorable outcomes, but standard treatments like radiation or chemoradiation frequently result in long-term toxic side effects. Appropriate patient selection has been a barrier to effectively de-escalate therapy for HPV+ HNSCC, and the absence of accurate biomarkers likely contributed to failure of recent promising de-escalation trials that rely on histologic tumor characteristics, history of tobacco use, or tumor response to chemotherapy; This deficiency underlines the need to develop and validate an assay to accurately detect two subtypes of HPV+ HNSCC-one with good prognosis and one with poor prognosis. EXPERIMENTAL DESIGN: These two subtypes are distinguished by the activity of NF-κB in tumors. We first developed a DNA-based marker panel consisting of genes that when mutated would lead to NF-κB activation. Additionally, we developed a custom NanoString assay to determine the expression of NF-κB target genes. These assays were tested to determine their accuracy in detecting tumor subtype. RESULTS: We demonstrate that the NF-κB gene signature score, as determined using the NanoString assay, could more accurately classify HPV+ HNSCC as compared with the DNA-based marker panel. Patients with a high NF-κB gene signature score demonstrated significantly increased overall survival, indicating more sensitivity to (chemo)radiation treatment. CONCLUSIONS: The NF-κB gene signature score can accurately predict response to standard (chemo)radiation in HPV+ HNSCC. This molecular biomarker holds promise for clinical use in identifying patients who are likely to benefit from treatment de-escalation strategies, potentially reducing long-term side effects without compromising therapeutic efficacy.
Bharadwaj S, Corredor G, Al-Shakhshir H
… +9 more, Medina S, Almahfouz SN, Dhamdhere R, Pathak T, Fu P, Liu Y, Gandhi S, Badve S, Madabhushi A
Clin Cancer Res
· 2026 Jun · PMID 41915435
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PURPOSE: Trastuzumab-based chemotherapy has improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, but treatment benefit varies among patients. Predictive signatures are needed to id...PURPOSE: Trastuzumab-based chemotherapy has improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, but treatment benefit varies among patients. Predictive signatures are needed to identify patients most likely to respond to these therapies. EXPERIMENTAL DESIGN: We developed Density and Spatial architecture of Tumor-Infiltrating Lymphocytes (DeSTIL), a computational signature derived from hematoxylin and eosin slides. The signature captures spatial organization of immune cells and interactions with nonimmune cells. DeSTIL was trained on HER2+ breast cancer slides from The Cancer Genome Atlas (n = 250) and validated in a phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 randomized clinical trial (n = 221), which compared chemotherapy plus trastuzumab, lapatinib, or combination. The DeSTIL scores were dichotomized into positive and negative groups, and event-free survival (EFS) was assessed using Cox proportional hazards with interaction terms. RESULTS: In NSABP B-41, DeSTIL-positive patients (n = 61) showed significantly improved event-free survival (EFS) with trastuzumab compared with the combination arm [hazard ratio (HR) = 0.09; 95% confidence interval (CI) = 0.01-0.77; P = 0.006] and a significant signature-treatment interaction (P = 0.024). No EFS difference was observed in DeSTIL-negative patients (n = 160). Gene expression analysis supported the image-derived signature stratifying DeSTIL-positive and DeSTIL-negative tumors. In an exploratory pathologic complete response analysis, a classifier trained on University Hospitals Cleveland slides achieved AUCs of 0.70 in the training cohort and 0.63 in the trastuzumab arm of the NSABP B-41 validation cohort. CONCLUSIONS: DeSTIL identifies a subset of HER2+ patients who derive greater benefit from trastuzumab. These findings support the potential of computationally derived immune architecture to inform selection of standard HER2-targeted therapies.
Strickler JH, Raimbourg J, Cohen JE
… +16 more, Ghiringhelli F, Sharma MR, Kitagawa C, Lee KH, O'Neil B, de Miguel M, Saada-Bouzid E, Li R, Rudra-Ganguly N, Luo A, Parikh A, Morrison-Thiele G, Neagu Aristide M, Hunter Z, Burns M, Kuboki Y
Clin Cancer Res
· 2026 Jun · PMID 41910595
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PURPOSE: Gastrointestinal tumors, including esophageal and gastric/gastroesophageal junction adenocarcinoma (GEA), have a high mortality rate and present significant treatment challenges. Telisotuzumab adizutecan (Temab-...PURPOSE: Gastrointestinal tumors, including esophageal and gastric/gastroesophageal junction adenocarcinoma (GEA), have a high mortality rate and present significant treatment challenges. Telisotuzumab adizutecan (Temab-A, ABBV-400), a novel antibody-drug conjugate targeting the c-Met protein (also known as MET protein), has shown encouraging results in patients with advanced GEA. PATIENTS AND METHODS: This phase I, open-label, multicenter study assessed the safety, efficacy, and pharmacokinetics (PK) of Temab-A monotherapy (3 mg/kg every 3 weeks intravenously) in patients with advanced GEA. Patients ≥18 years of age with advanced/metastatic GEA who had received 1 to 2 prior systemic therapies were included. The primary objectives were the evaluation of safety, PK, and efficacy; efficacy endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). c-Met expression and MET amplification were retrospectively assessed. RESULTS: Forty-two patients with advanced GEA were enrolled; the median age was 60 years. The median follow-up duration was 12.6 months. All patients had one or more treatment-emergent adverse events (TEAE), with 88% experiencing grade ≥3 TEAEs. The most common hematologic TEAEs were anemia (67%), nausea (52%), and decreased appetite (36%). The ORR was 29%, the clinical benefit rate was 71%, and the median DOR was 4.2 months. The median PFS was 4 months, and the median OS was 5.8 months. Exploratory biomarker analyses showed ORR enrichment in patients with higher c-Met protein expression and MET focal amplification. CONCLUSIONS: Temab-A monotherapy demonstrated antitumor activity and a manageable safety profile in patients with advanced GEA. The findings support further clinical development of Temab-A, particularly in combination with other agents to improve outcomes for patients with 2L+ GEA.
Cai J, Zhao B, Ji D
… +15 more, Zhou F, Bai S, Fang X, Nie M, Bai B, Zhang Y, Li J, Li H, Li Y, Fei D, Qin X, Qin C, Zhao S, Xia Y, Cai Q
Clin Cancer Res
· 2026 Jun · PMID 41910591
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PURPOSE: The purpose of the study was to evaluate the safety and preliminary antitumor activity of LM-101, an anti-SIRPα antibody that blocks the CD47-SIRPα interaction, as monotherapy and in combination with rituximab o...PURPOSE: The purpose of the study was to evaluate the safety and preliminary antitumor activity of LM-101, an anti-SIRPα antibody that blocks the CD47-SIRPα interaction, as monotherapy and in combination with rituximab or toripalimab in relapsed/refractory lymphoma and advanced head and neck cancer. PATIENTS AND METHODS: Adult patients with relapsed/refractory lymphoma or advanced head and neck cancer were eligible. In the dose escalation phase, patients received LM-101 with accelerated titration at 3 mg/kg every 3 weeks, followed by a 3 + 3 escalation at 10, 20, 30, and 40 mg/kg. In the combination therapy safety lead-in phase, LM-101 was given at the recommended phase II dose (RP2D) with rituximab in lymphoma and with toripalimab in head and neck cancer. The primary objective was safety. Secondary objectives included antitumor activity (ClinicalTrials.gov: NCT05615974). RESULTS: Between January 17, 2023, and October 6, 2025, 36 patients received LM-101 monotherapy (n = 17), LM-101 plus rituximab (n = 10), or LM-101 plus toripalimab (n = 9). No dose-limiting toxicities were observed. The RP2D was 40 mg/kg every 3 weeks. Grade ≥3 hematologic treatment-related adverse events (TRAE) included lymphopenia (5.9% with monotherapy; 40% with LM-101 plus rituximab), neutropenia (5.9%; 20%, respectively), and leukopenia (5.9%; 20%, respectively). Nonhematologic TRAEs were infrequent and predominantly grades 1 to 2. Objective response rates were 17.6% (3/17) with monotherapy and 50.0% (4/8) with LM-101 plus rituximab. Disease control rates were 75.0% (6/8) for LM-101 plus rituximab and 42.9% (3/7) for LM-101 plus toripalimab (with no objective responses observed). CONCLUSIONS: LM-101 was well tolerated. The preliminary efficacy signal supports further evaluation of LM-101 plus rituximab in relapsed/refractory lymphoma.
Poissonnier A, Rugo HS, Horton W
… +16 more, Kim T, DeLuca A, Egeland EV, Cotechini T, Sivagnanam S, Mori M, Yu Y, Park B, Beelen N, Murugan D, Kirchberger N, Kummar S, Mayer IA, Blackwell K, Hwang ES, Coussens LM
Clin Cancer Res
· 2026 Mar · PMID 41894563
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PURPOSE: Significant correlations exist between presence of intratumoral macrophages, tumor progression, and poor outcomes in triple-negative breast cancer (TNBC) with limited therapeutic options available for advanced s...PURPOSE: Significant correlations exist between presence of intratumoral macrophages, tumor progression, and poor outcomes in triple-negative breast cancer (TNBC) with limited therapeutic options available for advanced stage disease. Preclinical studies revealed that inhibition of myelomonocytic colony stimulating factor 1 (CSF1) or its receptor (CSF1R), plus cytotoxic chemotherapy decreased primary tumor growth kinetics and pulmonary metastases by CD8+ T cell-dependent mechanisms. This translational study evaluated CSF1R inhibition combined with eribulin in metastatic TNBC and explored rational preclinical combination strategies with PD-1/PD-L1-blockade based on clinical immune correlate analyses. EXPERIMENTAL DESIGN: A nonrandomized, open-label phase 1b/2 trial (NCT01596751) evaluated pexidartinib (PLX3397, PLX), a CSF1R inhibitor (CSF1Ri), plus eribulin mesylate in heavily pretreated individuals with metastatic TNBC. Clinical efficacy was assessed alongside peripheral blood correlates. Preclinical studies in transgenic mammary adenocarcinoma models examined biomarker-driven therapy combinations. RESULTS: The 12-week progression-free survival rate was 36% (95% CI, 22.2%-58.4%), with 44.8% of patients achieving clinical benefit; a subset experienced disease control beyond 6-months. Patients with partial response or stable disease demonstrated increased baseline leukocyte activation, including enrichment of CD8+ and CD4+ memory T cells and increased PD-1 expression on CD4+ T cells. In preclinical studies, CSF1Ri expanded the therapeutic index of PD-1 blockade, yielding transient tumor regression in ~60% of mice and a transient expansion of effector and resident memory T cells. CONCLUSIONS: These clinical and preclinical findings provide rationale for therapies to increase therapeutic index of aPD-1 therapy by diminishing presence of T cell-suppressive myelomonocytic cells to improve outcomes for patients with refractory disease.
Zeng Z, Huang W, Zeng F
… +8 more, Xiong L, Liu C, Chen Z, Zheng Y, Cai J, Huang L, Zhang X, Liu A
Clin Cancer Res
· 2026 Jun · PMID 41894181
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PURPOSE: Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive and poorly differentiated subtype of non-small cell lung cancer (NSCLC) associated with a poor prognosis. We conducted a prospective, single-arm, phas...PURPOSE: Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive and poorly differentiated subtype of non-small cell lung cancer (NSCLC) associated with a poor prognosis. We conducted a prospective, single-arm, phase II trial to evaluate the efficacy and safety of tislelizumab in combination with anlotinib as first-line therapy in patients with advanced PSC. PATIENTS AND METHODS: Eligible patients with advanced PSC without EGFR or ALK mutations received tislelizumab plus anlotinib as first-line treatment until disease progression or unacceptable toxicities. The primary endpoint was the objective response rate (ORR) assessed per RECIST version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between August 2021 and June 2025, a total of 29 patients were enrolled, with a median age of 71 years (range: 39-79). Two patients (6.90%) achieved a complete response, and 14 (48.28%) achieved a partial response, yielding an ORR of 55.17% [95% confidence interval (CI), 35.69%-73.55%]. The DCR was 96.55% (95% CI, 82.24%-99.91%). After a median follow-up duration of 16.73 months, the median PFS was 9.40 months (95% CI, 3.67-13.30 months), and the median OS was 14.37 months (95% CI, 9.03-17.50 months). The most common treatment-related adverse events (TRAE) were hyperuricemia and maculopapular rash. Grade 3 to 4 TRAEs occurred in eight patients (27.59%), with no treatment-related deaths reported. CONCLUSIONS: The combination of tislelizumab and anlotinib demonstrated promising antitumor activity with a manageable safety profile as first-line therapy in patients with advanced PSC.
Clin Cancer Res
· 2026 Jun · PMID 41894179
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Desmoid tumors are a locally invasive neoplasm that can exhibit unpredictable clinical behavior. Although treatment options are numerous, few are supported by level 1 evidence. A recent phase III trial evaluated the effi...Desmoid tumors are a locally invasive neoplasm that can exhibit unpredictable clinical behavior. Although treatment options are numerous, few are supported by level 1 evidence. A recent phase III trial evaluated the efficacy of long-used pegylated liposomal doxorubicin in patients with progressive desmoid tumors. See related article by Xu et al., p. 2198.
Butt OH, Singhal K, Luo J
… +18 more, Rettig MP, Foltz JA, Huang J, Zhou AY, Tao Y, Griffith OL, Griffith M, Johanns TM, Ansstas G, Zhang C, Tang J, Christ S, Ferrando-Martinez S, Lee BH, DiPersio JF, Chheda MG, Fehniger TA, Campian JL
Clin Cancer Res
· 2026 Jul · PMID 41880597
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PURPOSE: Standard care for high-grade gliomas (HGG) involves maximal surgical resection followed by radiation and temozolomide. Postoperative adjuvant therapy frequently causes lymphopenia, which is associated with poor...PURPOSE: Standard care for high-grade gliomas (HGG) involves maximal surgical resection followed by radiation and temozolomide. Postoperative adjuvant therapy frequently causes lymphopenia, which is associated with poor prognosis. Interleukin 7 (IL7) is essential for lymphocyte development, homeostasis, and survival. NT-I7 (efineptakin alfa), a long-acting recombinant IL7, reverses lymphopenia and improves survival in murine glioma models. However, the safety, maximum tolerated dose (MTD), and impact of NT-I7 on immune cells in patients with HGG remain unknown. PATIENTS AND METHODS: We conducted a phase I trial (NCT03687957) examining the MTD and effect of NT-I7 on lymphocytes in patients with newly diagnosed HGG. The primary endpoint was dose-limiting toxicity; secondary endpoints included absolute lymphocyte count (ALC) changes over time, overall response, progression-free survival, and overall survival. Exploratory endpoints included immune profiling at different time points using single-cell RNA sequencing (scRNA-seq) in a subset of patients. RESULTS: NT-I7 was well tolerated with a MTD of 720 µg/kg. Moreover, NT-I7 significantly increased ALCs for more than 12 weeks in duration. Early elevations in CD4+, CD8+ T cells and NK cells further coincided with increased TNF and CXCL9 cytokine levels. Comprehensive immune profiling of peripheral blood T cells revealed selective clonotype expansion within CD8+, but not CD4+, T cells following NT-I7 administration. Finally, a subset of our patients with MGMT promoter-unmethylated glioblastoma, which are typically associated with a poorer prognosis, demonstrated promising clinical responses. CONCLUSIONS: NT-I7 has the potential to maintain and increase lymphocyte counts in patients with HGG and warrants further investigation, particularly in combination with immune-based therapies.