Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.

BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.

Outcomes of systemic therapy in metastatic phyllodes tumor of the breast.

PURPOSE: Metastatic phyllodes tumors of the breast (MPT) are rare breast neoplasms, limiting development of standardized treatment approaches. We sought to characterize the largest group of MPT thus far reported, evaluating systemic therapy outcomes. METHODS: Adult patients diagnosed with MPT between 1993 and 2015 and followed at MD Anderson Cancer Center were selected for retrospective chart review. Systemic therapy was sorted into: adriamycin/ifosfamide (AI), other anthracycline regimens, other ifosfamide regimens, gemcitabine-based regimens, and other. Given one patient may have received more than one regimen, we assumed that the effects of each regimen were independent from previous therapy. Median overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Log-rank test was performed to evaluate the difference in OS between patient characteristics groups, and the differences in PFS between the five chemotherapy regimens. RESULTS: We identified 50 MPT patients, with 31 patients receiving 61 systemic regimens. Median OS was 10.7 months (95% CI: 8.67, 16.5). AI had a PFS of 9.10 months (95% CI: 5.03, 14.2), other ifosfamide regimens had a PFS of 5.10 months (95% CI: 0.67, 12.1), other anthracycline regimens had a PFS of 3.65 months (95% CI: 1.17, 7.90), gemcitabine-based regimens had a PFS of 2.80 months (95% CI: 1.83, 4.60), and other regimens had a PFS of 1.67 months (95% CI: 1.13, 7.77). CONCLUSION: MPT patients are a unique population with limited characterization to date. Our study demonstrates activity of multiple sarcoma-directed chemotherapy regimens, with ifosfamide-containing regimens having the longest PFS.

Hes4: A potential prognostic biomarker for newly diagnosed patients with high-grade osteosarcoma.

BACKGROUND: Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis. PROCEDURE: Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome. We probed the R2: Genomics Analysis and Visualization Platform for RNA expression levels of Notch targets in mixed high-grade OS pretreatment biopsies. We used human OS cell lines in vitro and in mice to determine the role of the Notch target hairy/enhancer of split 4 (Hes4) in OS. RESULTS: We found that in OS patients, high expression of Hes4 is correlated with decreased metastasis-free and overall survival. Human OS cells that overexpress Hes4 are more immature and have an increased invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4-overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did control cells. CONCLUSIONS: Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of OS cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis.

Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation.

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.

Short-Term Changes in Skeletal Muscle Mass After Anthracycline Administration in Adolescent and Young Adult Sarcoma Patients.

Identification of anthracycline-induced muscle loss is critical for maintaining health in adolescent and young adult (AYA) cancer patients. We used routine chest computed tomography (CT) scans to investigate changes in skeletal muscle of 16 AYA sarcoma patients at thoracic vertebrae 4 (T4) after anthracycline treatment. CT images were examined at three time points (prechemotherapy, postchemotherapy, and 1 year). Significant changes in total skeletal muscle index and density were seen after chemotherapy (p = 0.021 and p = 0.016, respectively) and at 1 year versus baseline (both p < 0.05). This study supports the use of T4 as an early indicator of skeletal muscle loss in AYAs.

Impact of a Genetic Evaluation Initiative to Increase Access to Genetic Services for Adolescent and Young Adults at a Tertiary Cancer Hospital.

Purpose: Adolescents and young adults (AYAs) with cancer are at increased risk for inherited cancer predisposition syndromes. Genetic counseling (GC) is important for accurate risk assessment, diagnosis, and management of inherited cancers. Numerous barriers prevent AYA access to genetic services. This study describes outcomes of a genetic evaluation initiative (GEI) regarding utilization of genetic services among AYAs. Methods: To improve AYA access to GC, the AYA program at UT MD Anderson Cancer Center implemented GEI, a process for identifying and referring eligible patients for GC. We collected retrospective electronic medical record data between July 12, 2018 and July 12, 2019 to capture AYA's clinical characteristics, genetic referral, scheduled appointments, counseling, testing, and results. Results: In total, 516 AYAs were referred to the AYA clinic during the study period with a median age of first cancer diagnosis of 17 years. One hundred sixty-six AYAs were identified who would benefit from genetic evaluation, 57 (34.3%) of whom had previously undergone counseling. One hundred nine patients were recommended for referral to GC, and 64.2% (70/109) were referred by the AYA team. To date, 58.6% (41/70) met with a genetic counselor and 75.6% (31/41) completed genetic testing, which yielded 1 pathogenic, 2 uncertain, and 29 benign results. Conclusion: The GEI resulted in a 72.0% relative increase in the rate of GC utilization and represents a novel approach to increasing AYA patient access to cancer genetic services in this population.

Tumor-targeted IL-12 combined with tumor resection yields a survival-favorable immune profile.

BACKGROUND: Although accumulated evidence provides a strong scientific premise for using immune profiles to predict survival in patients with cancer, a universal immune profile across tumor types is still lacking, and how to achieve a survival-associated immune profile remains to be evaluated. METHODS: We analyzed datasets from The Cancer Genome Atlas to identify an immune profile associated with prolonged overall survival in multiple tumor types and tested the efficacy of tumor cell-surface vimentin-targeted interleukin 12 (ttIL-12) in inducing that immune profile and prolonging survival in both mouse and patient-derived xenograft tumor models. RESULTS: We identified an immune profile (IFNγHiCD8HiFOXP3LowCD33Low) associated with prolonged overall survival across several human tumor types. ttIL-12 in combination with surgical resection of the primary tumor transformed tumors to this immune profile. Intriguingly, this immune profile transformation led to inhibition of metastasis and to prolonged survival in both mouse and patient-derived xenograft malignant models. Wild-type IL-12 combined with surgery was significantly less effective. In the IL-12-sensitive C3H mouse strain, in fact, wild-type IL-12 and surgery resulted in shorter overall survival than in mice treated with control pDNA; this surprising result is believed to be attributable to IL-12 toxicity, which was absent in the mice treated with ttIL-12. The ttIL-12-induced immune profile associated with longer overall survival was also associated with a greater accumulation of CD8+ T cells and reduced infiltration of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The underlying mechanism for this transformation by ttIL-12 treatment was induction of expression of CXCL9 and reduction of expression of CXCL2 and CCL22 in tumors. CONCLUSIONS: ttIL-12 when combined with surgery led to conversion to the IFNγHiCD8HiFOXP3LowCD33Low immune profile, eliminated relapse and metastasis, and prolonged overall survival.