Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study.

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

Reshaping the tumor microenvironment of cold soft-tissue sarcomas with oncolytic viral therapy: a phase 2 trial of intratumoral JX-594 combined with avelumab and low-dose cyclophosphamide.

Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors.We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, 'cold' STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.109 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate.Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon's design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

Pembrolizumab combined with low-dose cyclophosphamide and intra-tumoral injection of the toll-like receptor 4 agonist G100 in patients with advanced pretreated soft tissue sarcoma: results from the PEMBROSARC basket study.

Soft tissue sarcomas (STS) are heterogeneous mesenchymal tumors with limited therapeutic options in the advanced setting. Immune checkpoint inhibitors have been shown to have significant clinical activity in inflamed STS which are characterized by the presence of tertiary lymphoid structures (TLS). New strategies are needed to sensitize TLS-negative STS to immunotherapy. Engagement of the toll-Like Receptor 4 (TLR4) signal pathway contributes to the development of a favorable tumor microenvironment in solid tumors. G100 is a highly potent toll-like receptor 4 (TLR4) agonist. We hypothesized that intra-tumoral G100 would induce a robust local and potentially systemic anti-tumor immune response in the microenvironment of TLS-negative sarcoma, leading to improved response to PD1 inhibition. Twenty metastatic STS patients who had a superficial injectable lesion were treated with 50 mg of cyclophosphamide (CP) orally twice daily (1 week on and 1 week off), 200 mg of pembrolizumab intravenously on day 8 of a planned 21-day cycle and G100 20 µg one weekly intra-tumoral injection for at least 6 weeks and for a maximum of 12 weeks (1st injection one week before CP administration, ie. Day -7). Biopsies and blood were collected pre and post treatment. Of the 17 patients assessable for efficacy analysis, 2 were progression-free at 6 months, and the 6-month non-progression rate was 11.8% (95% CI: 1.5-36.4), indicating that the first endpoint of the study was not reached. In 8 patients, there was an increase in T-cell infiltration into tumor after treatment. The ratio CD8/Fox-P3 + CD4 on treatment decreased in 11 cases out of 14 suggesting a predominant induction of Treg. Soluble PDL1 levels at baseline were also with adverse outcome. G100 appears to modulate the tumor microenvironment with significant infiltration of T cells. However, clinical activity in combination with PD1 inhibition was limited and no clear correlation was observed between tumor shrinkage and increased inflammation. TLR4 stimulation might have both antitumor and pro-tumor consequences.Trial registration: This study was registered with ClinicalTrial.gov, number NCT02406781.

Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations: Results from a Multi-institutional European Retrospective Study.

PURPOSE: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort. EXPERIMENTAL DESIGN: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. RESULTS: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79-2.28]. The variables consistently associated with worse survival outcomes were high mitotic index and nongastric tumor location. CONCLUSIONS: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.

Implementing a Machine Learning Strategy to Predict Pathologic Response in Patients With Soft Tissue Sarcomas Treated With Neoadjuvant Chemotherapy.

PURPOSE: Neoadjuvant chemotherapy (NAC) has been increasingly used in patients with locally advanced high-risk soft tissue sarcomas in the past decade, but definition and prognostic impact of a good histologic response (GHR) are lacking. Our aim was to investigate which histologic feature from the post-NAC surgical specimen independently correlated with metastatic relapse-free survival (MFS) in combination with clinical, radiologic, and pathologic features using a machine learning approach. METHODS: This retrospective study included 175 consecutive patients (median age: 59 years, 75 women) with resectable disease, treated with anthracycline-based NAC between 1989 and 2015 in our sarcoma reference center, and with quantitative histopathologic analysis of the surgical specimen. The outcome of interest was the MFS. A multimodel, multivariate survival analysis was used to define GHR. The added prognostic value of GHR was investigated through the comparisons with the standard model (including histologic grade, size, and depth) and SARCULATOR nomogram using concordance indices (c-index) and Monte-Carlo cross-validation. RESULTS: Seventy-two patients (72 of 175, 41.1%) had a metastatic relapse. Stepwise Cox regression, random survival forests, and least absolute shrinkage and selection operator-penalized Cox regression all converged toward the same definition for GHR, ie, < 5% stainable tumor cells. The five-year MFS probability was 1 (95% CI, 1 to 1) in patients with GHR versus 0.73 (95% CI, 0.65 to 0.81) in patients without GHR (log-rank P = .0122). The final prognostic model incorporating the GHR was significantly better than the standard model and SARCULATOR (average c-index in testing sets = 0.72 [95% CI, 0.61 to 0.82] v 0.57 [95% CI, 0.44 to 0.70] and 0.54 [95% CI, 0.45 to 0.64], respectively; P = .0414 and .0091). CONCLUSION: Histologic response to NAC improves the prediction of MFS in patients with soft tissue sarcoma and represents a possible end point in future studies exploring innovative regimens in the neoadjuvant setting.

Recent Advances in Desmoid Tumor Therapy.

The desmoid tumor is a locally aggressive proliferative disease within the family of soft-tissue sarcomas. Despite its relatively good prognosis, the clinical management of desmoid tumors requires constant multidisciplinary evaluation due to its highly variable clinical behavior. Recently, active surveillance has being regarded as the appropriate strategy at diagnosis, as indolent persistence or spontaneous regressions are not uncommon. Here, we review the most recent advances in desmoid tumor therapy, including low-dose chemotherapy and treatment with tyrosine kinase inhibitors. We also explore the recent improvements in our knowledge of the molecular biology of this disease, which are leading to clinical trials with targeted agents.

Familial adenomatosis polyposis-related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis.

INTRODUCTION: Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine). PATIENTS AND METHODS: We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves. RESULTS: We identified 37 patients (median age 29 years, range 7-44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3-12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years. CONCLUSIONS: This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.

Use of Cardioprotective Dexrazoxane Is Associated with Increased Myelotoxicity in Anthracycline-Treated Soft-Tissue Sarcoma Patients.

BACKGROUND: Dexrazoxane (DEX) is indicated as a cardioprotective agent for breast cancer patients receiving the anthracycline doxorubicin. Two meta-analyses in metastatic breast cancer reported an apparent increase in the severity of myelosuppression when DEX was used. So far, no data in soft-tissue sarcoma (STS) patients are available. METHODS: We retrospectively analyzed hematological toxicity data from 133 consecutive STS patients who received a chemotherapy regimen containing an anthracycline and ifosfamide (AI) in the perioperative or metastatic settings between January 2006 and December 2017. Of these, 46 received off-label DEX concurrently with the AI treatment. The differences between incidence of any of the explored outcomes were assessed according to the Fisher exact test. RESULTS: Compared with the non-DEX group, DEX treatment was associated with significantly higher rates of grade 3/4 hematological toxicities: leukopenia (56.5 vs. 28.7%; p = 0.0014), neutropenia (69.6 vs. 24.1%; p = 0.0001), febrile neutropenia (52.2 vs. 20.7%; p = 0.0004), anemia (41.3 vs. 28.7%; p = 0.1758), and thrombocytopenia (54.3 vs. 32.1%; p = 0.0159). Similarly, in the DEX group dose reductions were more frequent compared to the non-DEX group (39.1 vs. 19.5%; p = 0.0221). CONCLUSION: Adding DEX to AI in STS patients leads to higher rates of bone marrow suppression in all blood components, as well as to more frequent events of febrile neutropenia and dose reductions.

New frontiers in the medical management of gastrointestinal stromal tumours.

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.

Unexpected benefit from an 'old' metronomic chemotherapy regimen in advanced chordoma.

In this case report, we describe an older adult man affected by advanced chordoma progressing after treatment with cisplatin and imatinib. The patient was symptomatic for uncontrolled pain. We decided to treat the patient with metronomic cyclophosphamide, unexpectedly achieving long-lasting clinical and radiological benefit.

Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib.

BACKGROUND: Rechallenge with imatinib is an option in advanced gastrointestinal stromal tumor (GIST) patients following progression with standard tyrosine-kinase inhibitors (TKIs), imatinib, sunitinib and regorafenib. We retrospectively collected data from metastatic Italian GIST patients treated with imatinib resumption after progression to conventional TKIs. METHODS: A total of 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected from six referral Italian institutions. Mutational analysis was recorded and correlated with survival and response according to RECIST 1.1 or CHOI criteria. RESULTS: Overall, 71 patients treated with imatinib 400 mg as rechallenge were included. Mutational status was available in all patients. The median follow up was 13 months. In patients who received a rechallenge therapy, the median time to progression (TTP) was 5.4 months [95% confidence interval (CI) 1.9-13.5] and overall survival (OS) was 10.6 months (95% CI 2.8-26.9). A correlation between mutational status, response rate, TTP and OS was not found but comparing deleted versus nondeleted KIT exon 11 patients, a significant difference was identified in terms of TTP and OS (p = 0.04 and p = 0.02, respectively). CONCLUSIONS: Our retrospective data confirm that imatinib rechallenge is a reasonable option in advanced GIST. The prognostic value of the specific KIT mutations was confirmed in our series.

Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft-Tissue Sarcoma Treated with Trabectedin.

OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.

Olaratumab: PDGFR-α inhibition as a novel tool in the treatment of advanced soft tissue sarcomas.

Advanced soft tissue sarcomas are aggressive cancers with limited therapeutic options. Recently, inhibition of platelet-derived growth factor receptor (PDGFR)-α by the monoclonal antibody olaratumab showed promising clinical activity. If confirmed, this would be one of the first examples of targeted therapy effective in advanced soft tissue sarcomas therapy independently of the histologic subtype. Here, we reviewed the biology of the PDGF/PDGFR axis, particularly focusing on its role in cancer, and then we discussed on the effects of PDGFR-α inhibition in the therapy of advanced soft tissue sarcomas.

Drug-induced hepatotoxicity in cancer patients - implication for treatment.

INTRODUCTION: All anticancer drugs can cause idiosyncratic liver injury. Therefore, hepatoprotective agents assume particular importance to preserve liver function. Hepatic injury represents 10% of cases of acute hepatitis in adults; drug-related damage is still misjudged because of relative clinical underestimation and difficult differential diagnosis. Chemotherapeutic agents can produce liver toxicity through different pathways, resulting in different categories of liver injuries, but these drugs are not homogeneously hepatotoxic. Frequently, anticancer-induced hepatotoxicity is idiosyncratic and influenced by multiple factors. AREAS COVERED: The aim of this paper is to perform a review of the literature regarding anticancer-induced liver toxicity. We described hepatotoxicity mechanisms of principal anticancer agents and respective dose reductions. Furthermore, we reviewed studies on hepatoprotectors and their optimal use. Tiopronin, magnesium isoglycyrrhizinate and S-Adenosylmethionine (AdoMet) demonstrated, in some small studies, a potential hepatoprotective activity. EXPERT OPINION: Actually, in the literature only small experiences are reported. Even though hepatoprotective agents seem to be useful in the oncologic setting, the lack of well-designed prospective Phase III randomized controlled trials is a major limit in the introduction of hepatoprotectors in cancer patients and these kind of studies are warranted to support their use and to give further recommendations for the clinical practice.

Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.

We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.

Lack of Correlation Between Liver Tests Abnormalities and Trabectedin Efficacy in the Treatment of Soft Tissue Sarcoma: a Retrospective Study.

Elevation in liver transaminases is common in patients treated with the marine antitumor agent trabectedin. However, the impact of trabectedin-related transaminase elevations on treatment outcomes is unclear. This retrospective study investigated the correlation between liver tests abnormalities and treatment outcomes in patients with unresectable advanced or metastatic soft tissue sarcomas (STS) treated with trabectedin 1.5 mg/m(2) once every 3 weeks at three reference centers in Italy. The effect of grade 3/4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) during the first two cycles and at any time during trabectedin treatment on progression-free survival (PFS) and overall survival (OS) were analyzed. Liver tests abnormalities during the first two cycles of chemotherapy or at any time during trabectedin treatment did not significantly affect PFS or OS. Nor were survival outcomes significantly different in the subgroups of patients with or without ALT/AST increases or with ALT/AST elevations ≥ 15 × the upper limit of normal (ULN) versus those with ALT/AST elevation < 15 × ULN. Although liver tests abnormalities are common in patients treated with trabectedin, elevations in ALT and AST are usually transient, occur during the first two cycles of treatment, and do not appear to affect survival.