PURPOSE:STAT3 is important in promoting a pro-oncogenic tumor microenvironment. This first randomized trial of a STAT3-targeting ASO with pembrolizumab assessed whether this first-line combination would improve outcomes compared with pembrolizumab alone in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS:This multicenter, randomized, open-label, controlled study (NCT05814666) enrolled patients with previously untreated R/M-HNSCC with positive PD-L1 expression (combined positive score [CPS] ≥1). Patients were stratified by CPS (1-19; ≥20) and randomized 2:1 to danvatirsen 3mg/kg IV weekly (with 2 loading doses in week 1) plus pembrolizumab 200mg IV every 3 weeks or pembrolizumab alone. Patients received 21-day treatment cycles until progressive disease, unacceptable toxicity, or voluntary withdrawal. Primary endpoint was overall response rate (ORR: partial + complete response per RECIST-v1.1). RESULTS:69 patients were randomized and 66 treated (51 [77.3%] male), 45 with danvatirsen + pembrolizumab, 21 with pembrolizumab alone. Enrolment was stopped due to lack of response in the CPS 1-19 cohort after ≥1 scan (~6 weeks of treatment) and in the CPS ≥20 cohort after ≥2 scans (~12 weeks). In the final analysis, ORRs were 15.6% and 14.3%, respectively (risk difference 1.3, P=1.0). The treatment-emergent adverse-event rate was increased in the combination arm (97.8% vs 85.7%), and the combination side effect profile was similar to previous danvatirsen studies. CONCLUSIONS:Combination danvatirsen + pembrolizumab did not improve ORR compared to pembrolizumab alone in first-line treatment of R/M-HNSCC. Further exploration of STAT3-targeted approaches is needed within the context of immunotherapy.
PURPOSE:Circulating tumor cells (CTCs) provide a minimally invasive window into metastatic disease and treatment response, but their clinical utility has been constrained by manual, subjective, low-throughput identification in multi-channel fluorescence microscopy data. METHODS:To address this limitation, we developed and clinically validated the System for Enhanced Evaluation of Tumor Cells (SEE-TC), a deep learning approach for scalable, reproducible phenotyping of individual circulating cells. SEE-TC was developed and evaluated on more than 8.5 million cells from 3,386 blood samples spanning six cancer types, enabling generalization across heterogeneous imaging conditions, staining panels, and acquisition platforms. RESULTS:SEE-TC achieved single-cell segmentation accuracy on par with humans, learned biologically relevant latent cellular representations that correlate with established morphological and immunofluorescent biomarkers, and reliably distinguished CTCs from background populations without reliance on arbitrary thresholds. When applied longitudinally, SEE-TC provides a quantitative, patient-level readout of CTC burden over time which was significantly associated with worse overall survival across multiple cancer types. CONCLUSIONS:To our knowledge, this is the first fully automated AI approach to single-cell segmentation and CTC phenotyping. By transforming CTC analysis from a human-dependent task into a scalable and reproducible digital assay, SEE-TC enables high-fidelity longitudinal monitoring of tumor burden and supports broader clinical deployment of CTC-based liquid biopsies in precision oncology. It is currently being deployed to identify CTCs and quantify target expression for both prognostic and predictive biomarker evaluation in multiple prospective clinical trials on a commercial platform.
PURPOSE:MEDI1191 is a lipid nanoparticle-formulated mRNA designed to induce local interleukin-12 production and intensify antitumor T cell responses. We report dose-escalation results from a first-in-human, open-label, phase I study of intratumoral MEDI1191 plus intravenous durvalumab (NCT03946800). METHODS:Patients were ≥18 years with advanced/metastatic solid tumors and had progressed on ≥1 line of prior therapy (immunotherapy permitted). Cutaneous/subcutaneous (Parts 1A and 1B) or deep-seated lesions (Part 1D) were injected; patients had ≥1 noninjected lesions measurable per RECIST v1.1. Target lesions were noninjected. MEDI1191 and durvalumab were given sequentially (Part 1A) or concurrently (Parts 1B and 1D). Primary objectives were safety and determination of maximum tolerated dose (MTD). Secondary objectives included efficacy. RESULTS:As of February 27, 2023, 61 patients were treated. Patients had a median of 4 prior regimens (range, 1-17); 39 (63.9%) received prior anti-PD-(L)1 immunotherapy. Treatment-emergent adverse events (TEAEs) occurred in 96.7% of patients and 41.0% experienced Grade 3/4 TEAEs. There were no dose-limiting toxicities. The MTD was not reached. Objective response rate was 9.8%, including 1 confirmed complete response and 5 confirmed partial responses (PRs). Duration of response was 2.7-22.3 months; median was not reached. Responses occurred in injected lesions, local noninjected lesions, and distant lesions. Three of the 39 patients with prior anti-PD-(L)1 therapy had PRs. CONCLUSIONS:MEDI1191 and durvalumab were tolerated. Preliminary antitumor activity was encouraging in these heavily pretreated patients, including patients previously treated with immune checkpoint inhibitors.
PURPOSE:MUC-16-targeted antibodies can deliver contrast agents (diagnostic) and/or cytotoxic payloads (therapy) to the tumor site. MUC-16 is overexpressed in 80% of epithelial ovarian cancer (EOC) and 65% of pancreatic ductal adenocarcinomas (PDAC). We previously developed a fully human antibody against MUC-16 (M16AB) and demonstrated the utility of [89Zr]Zr-DFO-M16AB as a PET imaging agent. Here, we developed [225Ac]Ac-Macropa-M16AB radioimmunoconjugate (RIC) and studied its efficacy against MUC-16-positive EOC and PDAC xenografts. EXPERIMENTAL DESIGN:[225Ac]Ac-Macropa-M16AB was characterized in vitro. The pharmacokinetics, biodistribution, hematological safety and dosimetry of [225Ac]Ac-Macropa-M16AB were studied in healthy mice. The efficacy of two doses (13 or 18.6 kBq) [225Ac]Ac-Macropa-M16AB administered at 10 days apart was evaluated in MUC-16-expressing cell line-derived xenograft (CDX) SW1990 and mice bearing PDAC and EOC patient-derived xenografts (PDX) with varying MUC-16 expression levels. RESULTS:In SW1990 CDX models [225Ac]Ac-Macropa-M16AB induced complete remission (CR) in 16.7% of mice, while the remaining 83.3% exhibited durable tumor growth suppression for ≥ 50 days, whereas all control animals progressed rapidly. [225Ac]Ac-Macropa-M16AB treatment resulted in 100% sustained CRs in high and medium-MUC16-expressing EOC and PDAC PDXs. While in the low MUC-16 expressing EOC PDX, the treatment demonstrated tumor growth inhibition and prolonged survival. [225Ac]Ac-Macropa-M16AB (3 x 15 kBq) administered in naive mice, 10-d apart was tolerated biochemically and haematologically, with only mild, dose-dependent hepatic and splenic changes observed on histopathology. CONCLUSION:The effectiveness of[225Ac]Ac-Macropa-M16AB which is dependent on the expression levels of MUC-16 indicates potential benefits for EOC and PDAC patients when translated in clinical trials.
PURPOSE:Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence and is associated with limited treatment options and poor prognosis, particularly in advanced disease. Recently, biologic strategies such as antibody-drug conjugates (ADCs) have expanded therapeutic opportunities across many tumor types, including HER2/neu-altered iCCA. However, validated and prevalent cell surface targets suitable for biologic therapies remain uncommon in iCCA, representing a critical bottleneck to the development of novel targeted treatments. In particular, gene-level analyses overlook tumor-enriched protein isoforms produced through alternative splicing. EXPERIMENTAL DESIGN:To address this gap, we applied a novel isoform-resolved proteogenomic approach comprising transcriptomics, in silico translation, and cell surfaceomics to identify prevalent cell surface targets in iCCA, and further assessed their specificity through analysis of expression data from the TCGA and GTEx datasets. RESULTS:This approach identified a unique peptide corresponding to FGFR2b, a splicing isoform of FGFR2, that demonstrated markedly higher tumor enrichment than the alternative FGFR2 isoform, FGFR2c. FGFR2b was the predominant FGFR2 isoform in BTC, including iCCA, in both our institutional cohort (88.6%) and TCGA (88.2%). FGFR2 fusions, in particular, were associated with high FGFR2b expression. High FGFR2b expression was associated with improved surgical outcomes, epithelial differentiation, and reduced CD8+ T-cell infiltration. Orthogonal validation using immunohistochemistry in a subset of 20 patients with available tissue samples confirmed membrane-bound FGFR2b expression in 31.6% of iCCA cases, including all patients with FGFR2 fusions. CONCLUSIONS:Our findings identify FGFR2b as a prevalent and compelling therapeutic target in iCCA and provide strong rationale for ongoing and future FGFR2b-targeted clinical trials.
BACKGROUND:We aimed to identify circulating and tumor immune features predictive of oncological outcomes under Atezolizumab-Bevacizumab (AtezoBev) therapy for hepatocellular carcinoma (HCC). METHODS:We conducted a prospective study in 31 patients treated with first-line AtezoBev, integrating sequential PBMC immunophenotyping, cytokine profiling and whole-blood RNA sequencing. Tumor RNA-sequencing data from clinical trial (GO30140/IMbrave150, 209 AtezoBev and 58 sorafenib-treated patients), together with 163 MSI-H colorectal cancer (CRC) treated by immunotherapy were used to assess the predictive value of immune signatures. RESULTS:Based on PBMC analysis at baseline (87% of male, age 65 years and 65% of BCLC-C), high baseline circulating γδ T-cells was associated with disease control (p=0.006) and longer progression free survival (PFS) (p=0.02). In tumor RNA-seq, a high intratumoral γδ T signature was also associated with higher response (p<0.01), longer PFS (p<0.001), and longer overall survival (p=0.003) exclusively in AtezoBev-treated patients, but not for those treated by sorafenib. In MSI-H CRC treated by immunotherapy, a high γδ T-cell signature was associated with longer PFS (p=0.034). An increase in circulating CD8⁺TIGIT⁺ cells was associated with shorter PFS (p=0.04), whereas an increase in CD8⁺PD-1⁺ cells correlated with longer PFS (p=0.03). Paired transcriptomic analyses confirmed an early induction of T cell-associated interferon-γ signaling at 3 weeks after the first injection of AtezoBev in patients that experienced response. CONCLUSIONS:High baseline circulating and tumor γδ T cells and early circulating CD8⁺PD-1⁺ T Cell expansion were associated with better outcome under AtezoBev. Early increase in circulating CD8⁺TIGIT⁺ cells was associated with treatment resistance.
BACKGROUND:Alveolar soft part sarcoma (ASPS) is an ultra‑rare soft tissue sarcoma. Current standard therapy with PD‑1/PD‑L1 inhibitors achieves limited response rates (<40%). Lymphocyte‑activation gene 3 (LAG‑3) is co‑expressed with PD‑1 on exhausted T cells, and dual blockade has shown synergy in some solid tumors but remains unexplored in sarcoma. This trial evaluated the efficacy of IBI110 (anti‑LAG‑3) plus sintilimab (anti‑PD‑1) in advanced ASPS. METHOD:This open‑label, phase II study enrolled 28 patients from July 2022 to September 2023 (median follow‑up 33.6 months). Both drugs were given intravenously at 200 mg every 3 weeks. The primary endpoint was overall response rate (ORR) by RECIST v1.1. RESULTS:Among 28 patients, 8 (28.6%) were resistant to prior immune checkpoint inhibitors (ICIs) and 20 (71.4%) were ICI‑naïve. The overall ORR was 51.8% (14/27 evaluable), including 4 complete responses and 10 partial responses. During a median follow-up of 33.6 months, the median PFS and OS were not reached in the whole population. In ICI‑naïve patients, ORR was 60% with median PFS/OS not reached; in ICI‑resistant patients, ORR was 25% with median PFS of 14.9 months and median OS of 25.4 months. Median time to response was 3.3 months; median DoR was not reached. Grade 3-4 treatment‑related adverse events occurred in 9 patients (32.1%), with no treatment‑related deaths. Exploratory analysis showed that responders had significantly higher baseline LAG‑3⁺ cell density in tumor specimens. CONCLUSION:Dual LAG‑3/PD‑1 blockade demonstrated promising and durable antitumor activity with manageable safety in both ICI‑naïve and ICI‑resistant advanced ASPS, warranting further investigation.
PURPOSE:Treatment intensification with androgen receptor pathway inhibitors (ARPIs) has become the standard of care for patients with metastatic prostate cancer. However, there remains an unmet need to identify biomarkers for treatment resistance. Here, we identify SPEN inactivation as a driver of ARPI resistance. EXPERIMENTAL DESIGN:Pre-clinical studies were performed in LNCaP and VCaP cell lines. Data from a nationwide prostate cancer clinico-genomic database were extracted. Log-rank test and Cox proportional hazards models were used to compare time to next treatment (TTNT) on ARPI with/without SPEN mutations. SPEN immunohistochemistry was performed on a rapid autopsy metastatic tissue microarray. RESULTS:SPEN was identified as a top enzalutamide resistance hit in an unbiased genome-wide loss-of-function screen. SPEN inactivation results in upregulation of cell cycle proliferation and basal/stem cell activity as well as increased translation of pro-oncogenic genes. In a large patient cohort (N=6828), SPEN mutations are enriched following treatment with ARPIs (2.1% to 3.6%, p=0.001) and correlate with shorter TTNT on ARPI in patients with metastatic hormone-sensitive prostate cancer (6.4 vs 29.7 months, HR 2.67, p=0.02). In a metastatic rapid autopsy cohort (N=181), low SPEN H-score is associated with shorter time on abiraterone (5.0 vs 7.9 months, p=0.023) in metastatic castration-resistant prostate cancer. CONCLUSIONS:In real-world cohorts, loss of SPEN function across genomic, transcriptomic, and protein levels is associated with reduced benefit from ARPI therapy in metastatic prostate cancer. These findings identify SPEN inactivation as a clinically relevant biomarker of ARPI resistance that warrants prospective evaluation to guide treatment selection.
PURPOSE:Immune checkpoint inhibitors have limited activity as monotherapy in biliary cancers. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic immune cell growth factor which achieved prolonged survival when combined with ipilimumab in melanoma. We conducted a single-center, phase II trial to evaluate the efficacy and safety of combining GM-CSF with pembrolizumab in patients with advanced biliary cancers after prior chemotherapy but no prior immune checkpoint inhibitor. EXPERIMENTAL DESIGN:Pembrolizumab 200 mg was administered intravenously in 21-day cycles, along with two cycles of GM-CSF 250 µg subcutaneously days 1 through 14. The primary endpoint was objective response rate. RESULTS:Among 42 patients enrolled, the median age was 61 years, 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% confidence interval: 4, 26), including two patients with complete response, and 26% of patients had progression-free survival ongoing at 6 months. Treatment was well-tolerated with treatment-related grade 3-4 events in 7% and treatment-related serious adverse events in 10%. Tumor PD-L1 expression was present in 46% and was associated with a higher rate of 6-month progression-free survival. Paired tumor biopsies showed upregulation of CD8+ T cell populations and antigen processing pathways after the addition of GM-CSF. CONCLUSIONS:the addition of GM-CSF to pembrolizumab was well-tolerated but did not meet the pre-specified response rate for efficacy. A subset of patients experienced deep responses and prolonged stable disease. GM-CSF elicited changes in the tumor immune microenvironment that could guide future combination approaches.
PURPOSE:Mucosal melanoma (MM) is a rare subtype of melanoma with inferior response rates and outcomes to immunotherapy. Vascular endothelial growth factor (VEGF) signaling may contribute to immune resistance and represents a potential therapeutic target. We evaluated nivolumab plus axitinib in untreated, advanced MM in a Western population, and explored escalation to triplet strategies for PD-1-refractory disease. PATIENTS AND METHODS:In this single center, investigator-initiated phase II study, patients with previously untreated unresectable or metastatic MM received nivolumab every 4 weeks and axitinib twice daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. A sequential phase Ib exploratory cohort evaluated treatment intensification with addition of ipilimumab or stereotactic body radiotherapy (SBRT) at progression, with safety as the primary endpoint. RESULTS:Among 20 evaluable patients, the ORR was 45% (95% CI, 23-68), including 4 complete responses (20%) and 5 partial responses (25%). Median duration of response was 21 months (95% CI 8.6-NR). Median progression-free survival was 6.4 months (95% CI 3.5-NR); median overall survival was not reached. Grade 3-5 treatment-related adverse events occurred in 67%, including two treatment-related deaths. Seven patients received triplet therapy (n=5 ipilimumab, n=2 SBRT), with no unexpected toxicities observed. CONCLUSIONS:Nivolumab plus axitinib demonstrated meaningful activity in advanced mucosal melanoma and warrants further evaluation in randomized studies. The addition of ipilimumab or SBRT after progression was feasible and may inform future studies, including biomarker‑directed intensification to triplet strategies.
PURPOSE:The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. PATIENTS AND METHODS:We analyzed 68,920 tumor-normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. Oncogenic or likely oncogenic SMARCA4 alterations were curated using OncoKB and classified based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. RESULTS:SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non-small cell lung cancer (NSCLC; 7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and class 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including one who attained a complete response. CONCLUSIONS:SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.
In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.
PURPOSE:Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. EXPERIMENTAL DESIGN:We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). RESULTS:ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. CONCLUSIONS:Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
Although BRIGHTLINE-1 was headlined as a "negative trial," brigimadlin showed clear biological activity, with median PFS of 8.4 months, ORR of 22.3%, and translational evidence of p53 reactivation. Its failure largely reflects flawed control-arm assumptions, as doxorubicin outperformed retrospective expectations and established a new prospective benchmark in DDLPS.
On January 19, 2024, the FDA granted traditional approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after at least one line of prior systemic therapy. Substantial evidence of effectiveness was obtained from BLC3001 (THOR, NCT03390504) Cohort 1, which was an open-label trial in which 266 patients with FGFR3-altered la/mUC were randomized 1:1 to receive erdafitinib (8 mg once daily with potential up-titration to 9 mg) versus chemotherapy (docetaxel 75 mg/m2 every 3 weeks or vinflunine 320 mg/m2 every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Statistically significant improvements in OS, progression-free survival, and objective response rate were demonstrated for erdafitinib compared with chemotherapy. Median OS was 12.1 months (95% CI: 10.3, 16.4) in the erdafitinib arm and 7.8 months (95% CI: 6.5, 11.1) in the chemotherapy arm (HR: 0.64, 95% CI: 0.47, 0.88; p=0.0050). Based on BLC3001 Cohort 2 results showing no OS benefit of erdafitinib versus pembrolizumab (HR 1.18, 95% CI: 0.92, 1.51), the approval includes a limitation of use: erdafitinib is not recommended for the treatment of patients who are eligible for and have not received prior PD-(L)1 inhibitor therapy. This article summarizes the data and the FDA thought process supporting traditional approval of erdafitinib, including the rationale for not requiring specific types of prior systemic therapy in the indication statement.
PURPOSE:Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations. PATIENTS AND METHODS:In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). RESULTS:Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities. CONCLUSION:Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.
PURPOSE:Behavioral weight loss interventions (BWL) consisting of remote coaching and self-monitoring have limited effectiveness in breast cancer (BC) survivors. We conducted a single-arm phase II study evaluating addition of Contrave® for <5% weight loss (%WL) after 2-months of BWL. METHODS:Women with prior stage 0-III BC and BMI ≥27 kg/m2 were eligible and initiated BWL. We collected weight, patient-reported outcomes, and labs at baseline, 2- and 6-months. At 2-months, participants with ≥5%WL (FAST-BWL) continued BWL; those with <5%WL (SLOW-BWL) received BWL+Contrave®. The primary endpoint was proportion of SLOW-BWL with ≥5%WL at 6-months, with 30 participants providing 80% power with 5% type I error. Paired t-tests, Kruskal-Wallis tests and mixed-effects models were utilized. RESULTS:Of 55 participants, 2 withdrew prior to 2-months. At 2-months, 15 (28.3%) were FAST-BWL with mean%WL (SD) of 7.2% (1.5); and 38 (71.7%) were SLOW-BWL with mean%WL of 1.2% (2.2). Mean%WL between 2-6 months was similar in SLOW-BWL (3.8%±3.6) and FAST-BWL (3.6%±2.6). At 6-months, mean%WL was 5.1% (2.9) for SLOW-BWL and 10.8% (3.5) for FAST-BWL; 13/15 (86.7%) FAST-BWL and 16/38 (42%) SLOW-BWL had ≥5%WL. Physical function and pain improved with ≥5%WL (p=0.03 and p=0.02, respectively). SLOW-BWL had improved HbA1c (p=0.003) and triglycerides (p=0.04). Gastrointestinal symptoms were reported in 74% of SLOW-BWL. Of six withdrawals on Contrave®, one was due to adverse events. CONCLUSION:Adding Contrave® for BC survivors with minimal initial benefit from BWL results in clinically meaningful weight loss (≥5%) in 42% following 6 months of treatment, which also improves selective cardiometabolic risk factors.
PURPOSE:While immune checkpoint inhibitors (ICI) are generally the preferred first-line treatment for metastatic BRAF V600-mutated melanoma, a subgroup that remains incompletely defined requires initial tumor control with BRAF/MEK-targeted therapy (TT). The purpose of this study was to evaluate circulating thymidine kinase activity (TKa), a blood-based marker of cellular proliferation, as a biomarker of outcome and treatment sequencing in patients enrolled in the randomized phase II SECOMBIT trial (NCT02631447). PATIENTS AND METHODS:Serum TKa was analyzed in samples from patients at baseline and during treatment. Patients were stratified by median baseline TKa and survival outcomes were compared across three strategies for first- and second-line treatment: TT followed by ICI (arm A), ICI followed by TT (arm B), and a "sandwich" strategy with short-term TT induction prior ICI (arm C) followed by TT. RESULTS:In TKa-low (n=41) vs. TKa-high (n=40) patients, the first progression-free survival (PFS) at 5 years was 43.3% vs. 27.5% (p=0.062), the total PFS was 60.8% vs. 35.0% (P=0.004) and overall survival (OS) was 70.7% vs. 36.9% (p<0.001), respectively. TKa-low patients had, compared to TKa-high, significantly longer total PFS and OS in arms A and B. Notably, TKa-high patients showed improved outcomes with the sandwich strategy compared with other sequences. Longitudinal analyses revealed an early TKa rise in majority of patients receiving ICI and increasing TKa levels at disease progression. CONCLUSIONS:These findings suggest that circulating TKa could serve as a clinically actionable biomarker for risk stratification, treatment sequencing, and on-treatment disease monitoring.
PURPOSE:This single-center, open-label, Phase 1 trial evaluated the safety and tolerability of chimeric antigen receptor (CAR)-T cells targeting interleukin-13 receptor α2 (IL13Rα2) in patients with malignant gliomas. PATIENTS AND METHODS:Adults with World Health Organization Grade 3-4 gliomas, recurrent after standard treatment and expressing IL13Rα2 (confirmed by immunohistochemistry), received a single intravenous infusion of autologous CAR-T cells. Primary objectives were to measure the maximum-tolerated dose (MTD) and recommended Phase 2 dose. Secondary objectives included assessment of pharmacokinetics, objective response rate, progression-free survival (PFS), and overall survival (OS). RESULTS:Ten patients were sequentially assigned to three dosing cohorts (1.0×107, 3.0×107, 1.0×108 cells/kg). The MTD was not reached, as no dose-limiting toxicities were observed, and all adverse events (AEs) were Grade ≤3 without irreversible sequelae. The most common treatment-related AEs were pyrexia (70%) and elevated transaminase (70%). CAR-T cell levels in blood reached peak concentrations at a median of 7 days (range 3-14), and the transgene was detected in cerebrospinal fluid from five of six patients treated at the higher two doses. Nine patients were evaluable for survival analysis, among whom six were available for response assessment at 3 months; best response was stable disease in three cases. Median PFS was 2.6 months (95% confidence interval [CI]: 0.95-5.75), and median OS was 10.9 months (95% CI: 8.2-26.6). CONCLUSIONS:Intravenous IL13Rα2-targeted CAR-T therapy was well tolerated and demonstrated preliminary safety. Further studies are warranted to optimize dosing and preconditioning regimens and identify exploratory biomarkers for efficacy evaluation.
