Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial.

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10-4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response.

PURPOSE: Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. Materials and Methods: We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. RESULTS: Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10-4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. CONCLUSION: Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Therapeutic Implications of TGF-ß Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties.

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-ß signaling pathway. Moreover, we selected the combination treatment comprising TGF-ß inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-ß inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-ß inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

Phase II Clinical Trial of Eribulin-Gemcitabine Combination Therapy in Previously Treated Patients With Advanced Liposarcoma or Leiomyosarcoma.

PURPOSE: Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin-gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma. PATIENTS AND METHODS: In this nonrandomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks ≤20.0% and ≥40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples. RESULTS: Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the TGFß pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome. CONCLUSIONS: Eribulin-gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.

Whole-Genome and Transcriptome Sequencing Identified NOTCH2 and HES1 as Potential Markers of Response to Imatinib in Desmoid Tumor (Aggressive Fibromatosis): A Phase II Trial Study.

PURPOSE: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/ß-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. MATERIALS AND METHODS: We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. RESULTS: Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. CONCLUSION: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor.

Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA.

BACKGROUND: Developing personalized strategies for cancer has shown good efficacies. METHODS: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. RESULTS: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). CONCLUSIONS: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Porous platinum nanoparticles as a high-Z and oxygen generating nanozyme for enhanced radiotherapy in vivo.

Radiotherapy (RT), along with surgery and chemotherapy, is a major modality of cancer therapy. Nevertheless, insufficient deposition of radiation energy in tumors and hypoxia-associated radioresistance remain the greatest challenges in RT. Here, we propose porous platinum nanoparticles as a new nanomedicine platform for solving these two problems at the same time using a single agent. Because of the combined advantages of a high-Z element and oxygen generation capability, porous platinum nanoparticles can significantly increase radiation-induced DNA damage, ROS stress, and cell cycle arrest by effectively depositing X-ray radiation energy within the cancer cells. Further, porous platinum nanoparticles increase tumor oxygenation by converting endogenic H2O2 to O2, thus greatly enhancing RT with no apparent in vivo toxicity to animals. This study presents a new nanomedicine strategy based on the use of porous high-Z metal nanoparticles with oxygen generation function for the synergistic enhancement of RT in cancer treatment.

Gradient-Field-Plasma Modification of Imprinted Nanopatterns.

We report on a one-step progressive modification of imprinted nanopatterns for the induction of a structural and physicochemical gradient in a single chip with the use of gradually attenuated oxygen plasma. Imprinted line patterns could be easily tapered off to up to 60% of their original line width, which was found to be dependent upon the rate of plasma attenuation. Gradually modified nanopatterns are believed to have a continuous variation of physicochemical properties along the pattern gradient, which in this study was exemplified in contact angle variation, which was observed to be more than a factor of about 5 in 2 cm separation on a sample surface. It was also demonstrated for modified patterns used as replica molds for pattern reversal in consecutive processes. Furthermore, it was also proven that this gradual modification method is applicable to various imprint patterns of different structures and resist materials.