Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab.

PURPOSE: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. PATIENTS AND METHODS: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response. RESULTS: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). CONCLUSIONS: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib.

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions: Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial.

BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma. METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039. FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis. INTERPRETATION: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab. FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.

Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma.

BACKGROUND: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12). RESULTS: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society.

Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033.

IMPORTANCE: After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients. OBECTIVE: To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study. INTERVENTIONS: Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors. RESULTS: Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex. CONCLUSIONS AND RELEVANCE: A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00009906.

Current imaging and therapy of malignant soft tissue tumors and tumor-like lesions.

Soft tissue tumors are histologically classified based on the tissue type they reflect. MR and computed tomography imaging remains the mainstay for the evaluation of a soft tissue mass including guiding the biopsy to the most aggressive portion of the lesion, tumor staging, and evaluating local recurrence and metastatic disease. Although some lesions may be readily identified based on their imaging characteristics, many soft tissue tumors remain indeterminate and require biopsy for diagnosis of histologic type and lesion grade, factors that have an impact on therapeutic options and long-term disease-free survival.In this article we review the current literature regarding imaging and treatment of soft tissue lesions in the musculoskeletal system. Positron emission tomography and specialized MR techniques, such as spectroscopy and diffusion-weighted imaging, are useful in the diagnosis of high-grade soft tissue sarcomas, although imaging overlap exists with benign and low-grade sarcomas. These modalities are proving useful in primary tumor staging, evaluation of therapeutic response, and metastatic disease assessment. We also discuss the roles of percutaneous ablation in the treatment of focal disease and palliative pain control, and review current targeted cancer therapies.

Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005).

BACKGROUND: Between 30% and 50% of women who have high-grade uterine leiomyosarcoma (uLMS) limited to the uterus at diagnosis remain progression-free at 2 years. Adjuvant pelvic radiation does not improve outcome. The objective of the current study was to determine the 2-year and 3-year progression-free survival (PFS) among a prospective cohort of women who received adjuvant gemcitabine plus docetaxel followed by doxorubicin. METHODS: Women with uterus-limited, high-grade uLMS and adequate organ function were eligible. Within 12 weeks of complete resection and after confirmation that they had no evidence of disease on computed tomography (CT) images, the patients received 4 cycles of fixed-dose-rate gemcitabine plus docetaxel. Those who were confirmed disease-free on CT scans after cycle 4 received 4 cycles of doxorubicin. CT imaging for recurrence was performed every 3 months for 2 years, then every 6 months for 3 years. RESULTS: In total, 47 women were enrolled (46 evaluable) in 3 years. Characteristics included a median age of 53 years; 1988 International Federation of Gynecology and Obstetrics stage I disease in 81% of patients, stage II disease in 15%, and serosa-only stage IIIA disease in 4%; American Joint Committee on Cancer stage II disease in 13% of patients and stage III disease in 87%; a median tumor size of 8 cm (range, 2.5-30 cm); and a median mitotic rate of 18 mitoses per 10 high-power fields (range, 5-83 mitoses per 10 high-power fields). At a median follow-up of 39.8 months, 21 of 46 patients developed recurrent disease (45.7%). The median time to recurrence was 27.4 months (range, 3-40 months). Seventy-eight percent of patients (95% confidence interval, 67%-91%) were progression-free at 2 years, and 57% (95% confidence interval, 44%-74%) were progression-free at 3 years. The median PFS was not reached and exceeded 36 months. CONCLUSIONS: Among women with high-grade, uterus-limited uLMS who received treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin, 78% remained progression-free at 2 years, and 57% remained progression-free at 3 years. A randomized trial of adjuvant chemotherapy versus observation to determine whether adjuvant chemotherapy can improve survival in women with uterus-limited uLMS is underway.

Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial.

PURPOSE: Aggressive fibromatoses (AF; desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. The Sarcoma Alliance for Research through Collaboration (SARC) initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or 1 of 10 sarcoma subtypes. Here, we report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib. EXPERIMENTAL DESIGN: Patients ≥10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg twice daily [body surface area (BSA) ≥ 1.5 m(2)], 200 mg twice daily (BSA = 1.0-1.49 m(2)), or 100 mg twice daily (BSA < 1.0 m(2)). Response outcomes at 2 and 4 months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of cKIT, platelet-derived growth factor receptor α (PDGFRα), PDGFRß, AKT, PTEN, FKHR, and ß-catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR. RESULTS: Fifty-one patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of 2- and 4-month progression-free survival rates were 94% and 88%, respectively, and 1-year progression-free survival was 66%. Objective response rate was 6% (3 of 51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available. CONCLUSION: Imatinib may have a role in the management of unresectable or difficult to resect desmoid tumors.

Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging.

Anthracyclines are one of the most commonly used and potent chemotherapeutic agents. Doxorubicin (Adriamycin) is one common anthracycline used to treat many solid tumors including breast, sarcomas, gynecologic and hematological malignancies, such as leukemias and lymphomas. However, its use is often limited due to dose-dependent cardiotoxicity. As a result, patients receiving doxorubicin should have close monitoring of their left ventricular function. The gated cardiac blood pool (GBP) study is one of the most accurate and reproducible methods of assessing left ventricular function. This report presents an overview of (1) the incidence, clinical course, mechanisms, pathology, prevention, and monitoring of doxorubicin-induced cardiotoxicity (DIC), (2) the use of GBP studies in monitoring for DIC, and (3) 2 algorithms for the use of GBP studies in monitoring for DIC. This report concludes with a proposed algorithm for the use of GBP studies in DIC. With an understanding of DIC, GBP studies, and various algorithms, the interpreting physician may help the oncologist identify DIC earlier, more accurately, and before it becomes clinically apparent.

Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model.

PURPOSE The purpose of this trial was to assess the efficacy of imatinib in patients with one of 10 different subtypes of advanced sarcoma. PATIENTS AND METHODS Eligible patients were treated daily with imatinib dosed at 300 mg twice a day (for body-surface area > or = 1.5 m(2)). The primary end point was response (clinical benefit response [CBR]), defined as complete (CR) or partial response (PR) at 2 months, or stable disease, CR, or PR at 4 months. Rules for early termination within each disease type were based on a Bayesian hierarchical probability model (BHM) accounting for correlation of the responses of the 10 subtypes. Available tissue samples were analyzed for molecules within the KIT/platelet-derived growth factor receptor (PDGFR) signal transduction pathway. Results One hundred eighty-five assessable patients with one of 10 subtypes of sarcoma were treated. One CR and three PRs were achieved. A CBR was achieved in 28 patients treated overall and by subtype: two angiosarcomas (n = 16), 0 Ewing (n = 13), one fibrosarcoma (n = 12), six leiomyosarcomas (n = 29), seven liposarcomas (n = 31), three malignant fibrous histiocytomas (n = 30), five osteosarcomas (n = 27), one malignant peripheral-nerve sheath tumor (n = 7), 0 rhabdomyosarcoma (n = 2), and three synovial sarcomas (n = 22). Variable expression and mutations within the KIT/PDGFR pathway were observed. CONCLUSION This is the first phase II study of a new agent in sarcoma to include sufficient patients with each of the common histologic subtypes to permit generalizable conclusions. The BHM is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Although rare dramatic responses were seen, imatinib is not an active agent in advanced sarcoma in these subtypes.

Reactivation of chronic hepatitis B infection related to imatinib mesylate therapy.

Imatinib (Gleevec, Novartis), an inhibitor of BCR-ABL, platelet-derived growth factor, and KIT receptor tyrosine kinases, is widely used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. We describe a case of activation of chronic hepatitis B infection associated with imatinib therapy.

Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].

PURPOSE: Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. PATIENTS AND METHODS: In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. RESULTS: One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. CONCLUSION: Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: The current study was conducted to evaluate the antitumor activity and toxicity of gemcitabine in patients with advanced sarcoma. METHODS: Twenty-five patients with advanced sarcomas, who previously were untreated for metastatic disease, were treated on an Eastern Cooperative Oncology Group Phase II study. Patients ranged in age from 27 to 79 years, with a median age of 59 years. The most common histology was leiomyosarcoma (54%). The grades of the tumors were high in 40%, moderate in 24% and low in 12%. Gemcitabine was given at a dose of 1250 mg/m(2) as a 30-minute infusion weekly for 3 weeks followed by 1 week of rest. RESULTS: One of the 25 patients (4%) (90% confidence interval [90% CI], 0-18%) achieved a partial response lasting 8 months. The estimated overall median survival was 15 months. The 1-year estimated survival rate was 63% (90% CI, 47-84%). The estimated median progression-free survival (PFS) was 13 months with a 1-year PFS rate of 56% (90% CI, 41-76%). Grade 3-4 toxicities (by CTC criteria) were observed in all 25 patients. No lethal toxicity (Grade 5) related to treatment was found. CONCLUSIONS: The results of the current study demonstrated that gemcitabine given at this schedule and dose in this population of patients with advanced sarcoma had limited activity.

Immediate reconstruction after mastectomy for breast cancer does not prolong the time to starting adjuvant chemotherapy.

BACKGROUND: Immediate breast reconstruction is often performed after mastectomy for breast cancer. There has been concern that this will result in a delay in initiating chemotherapy and, as a consequence, may adversely impact survival. In this study we sought to determine whether immediate breast reconstruction affects the interval between surgery and adjuvant chemotherapy. METHODS: A single institution retrospective analysis was made using the institutional tumor registry and chart reviews. RESULTS: Forty-nine patients were identified who had undergone mastectomy with immediate reconstruction followed by adjuvant chemotherapy. They were compared with 308 patients undergoing mastectomy without reconstruction. Patients who underwent reconstruction were overall younger (46 versus 55, P <0.001), and had more advanced disease. The time to chemotherapy was significantly longer in the group receiving no reconstruction: 53 versus 41 days (P = 0.039). The type of reconstruction did not affect the time to chemotherapy. CONCLUSIONS: Immediate reconstruction after mastectomy does not increase the time to chemotherapy compared with mastectomy alone.