Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas.

TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.

Myxoid Liposarcomas: Systemic Treatment Options.

OPINION STATEMENT: Myxoid/round-cell liposarcoma (MRCL) account for 30% of liposarcomas and are the most chemo-sensitive subtype of liposarcoma. The 5-year local relapse and distant metastasis rates are 10% and 20%, respectively. In the advanced setting, the first-line median progression-free survival and overall survival is 9 and 30 months, respectively. The overall response rate (ORR) by RECIST with anthracycline-based chemotherapy is around 40% and with trabectedin is 20%, although response is higher when captured by CHOI criteria. Anthracycline-based combination chemotherapy regimens remain the standard of care first-line treatment option. However, trabectedin is also effective and may be considered in the first-line setting when anthracyclines cannot be prescribed. Beyond chemotherapy, new therapeutic classes are being developed, including autologous adoptive modified T cell receptor cellular therapies which have shown promising results thus far. These new therapies utilize the immunogenic potential of cancer testis antigens, NY-ESO-1 and MAGE-A4, which are expressed in the vast majority of MRCL. Early phase trials have shown encouraging results with up to 40% ORR and a median progression-free survival up to 8.7 months. Other innovative strategies are being developed, tailored to the molecular biology of MRCL. This review summarizes current evidence for the use of standard chemotherapy and the new biomarker-selected treatments under development.

Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors.

In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit BCR-ABL in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.

Retrospective evaluation of the role of gemcitabine-docetaxel in well-differentiated and dedifferentiated liposarcoma.

OBJECTIVE: Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) account for the majority of liposarcomas. Although gemcitabine-docetaxel is used as second-line treatment in soft tissue sarcomas, its efficacy in WDLPS/DDLPS is not established. This study retrospectively analyzed the efficacy of gemcitabine regimens in WDLPS/DDLPS. METHODS: All patients with WDLPS or DDLPS who received gemcitabine-based chemotherapy at our institution between September 2002 and January 2021 were included. Response was evaluated by an independent radiologist using RECIST 1.1. The Kaplan-Meier method was used to estimate distributions of survival outcomes and log-rank tests were used to compare survival outcomes between subgroups. RESULTS: Sixty-five WDLPS/DDLPS patients were included. Seven patients (10.8%) received a gemcitabine-based regimen more than once, totaling 72 treatments. The median age at the start of treatment was 66 years (range 32-80 years). Sixty-five (90.3%) regimens were gemcitabine-docetaxel, and 7 (9.7%) were gemcitabine alone. Majorities of treatments were for disease that was recurrent/metastatic (86.1%), was abdominal/retroperitoneal (83.3%), and had DDLPS components (88.9%), while 25.0% of treatments were for multifocal disease. The overall response rate was 9.7% (7/72). All responses were in patients with documented DDLPS. The median time to progression was 9.2 months (95% CI 5.3-12.3 months). The median overall survival from the start of therapy was 18.8 months (95% CI 13.1-32.4 months). CONCLUSION: Gemcitabine-docetaxel is an efficacious second-line treatment for DDLPS. Though cross study comparisons are not advisable, response to gemcitabine-docetaxel compares favorably to current standard options trabectedin and eribulin. This combination is a valid comparator arm for future second-line trials in DDLPS.

The immune landscape of undifferentiated pleomorphic sarcoma.

Introduction: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. Material and methods: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. Results: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001). Conclusion: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

New Drug Approvals for Sarcoma in the Last 5 Years.

Sarcoma and locally aggressive connective tissue tumors are a complex group of diseases with a growing number of histotypes in the most recent WHO classification. Most of these tumors are rare (incidence <6/105/y) or ultrarare (<1/106/y). Despite their rarity, sarcomas are often good models for the development of personalized medicine, and a large number of new clinical trials in select histotypes and molecular subsets were reported during the past 5 years, leading to a faster rate of new drug approvals. We analyzed the published literature and the abstracts reported in major congresses dedicated to sarcoma and connective tissue tumor management in the last 5 years. Several targeted therapies, cytotoxic treatments, and immunotherapies have demonstrated activity in dedicated histologic and molecular subtypes of sarcomas. The majority of the studies for ultrarare entities are uncontrolled studies, as a consequence of the rarity of histotypes, but randomized controlled trials were available in the less rare histotypes. Most successful trials were based on biomarker selection, which were often driver molecular alterations, while a large number of ongoing research programs aim to identify biomarkers in parallel to new drug development. Availability of the new agents varies across countries. This article describes the new drugs that made it through to the finish line and new agents with promising activity that are in later stages of investigation in the large family of malignant connective tissue tumors.

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma.

Liposarcoma (LPS) is a common soft tissue sarcoma that encompasses diverse subtypes of well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic LPS. There is heterogeneity among the various LPS types with regard to prognosis, molecular pathogenesis, and response to treatment. Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) are most common types, which share common genetic alteration of chromosome 12q13-15 amplification resulting in amplification of oncogenes, including MDM2 (Mouse double minute 2), CDK4 (cyclin-dependent kinase 4), and HMGA2 (High mobility group protein AT-hook 2). Despite sharing the same molecular alteration, DDLPS has a worse prognosis, with a higher recurrence rate and higher propensity for metastases compared to WDLPS. Here we provide an overview of the LPS treatment landscape focusing on recent developments in the treatment of DDLPS with a focus on selinexor. Selinexor, a selective inhibitor of XPO1, was recently evaluated in a phase 3 trial, the first prospective randomized trial in DDLPS, and we discuss its efficacy in context of other available agents for DDLPS.

Real-world use of palbociclib monotherapy in retroperitoneal liposarcomas at a large volume sarcoma center.

Palbociclib has been evaluated in early phase trials for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) patients, with reported median progression-free survival (PFS) of 18 weeks. Here, we report on real-world use and surgical outcomes associated with palbociclib treatment. We retrospectively reviewed 61 consecutive patients with retroperitoneal WDLPS (n = 14) or DDLPS (n = 47) treated with palbociclib monotherapy between 1 March 2016 and 28 February 2021 at The University of Texas MD Anderson Cancer Center. At palbociclib initiation, median age was 64 (interquartile range [IQR] 56-72). In WDLPS and DDLPS cohorts, the median number of prior systemic treatments was 0 (IQR 0-0) and 2 (IQR 0-4), respectively. Median number of prior surgeries was 2 (WDLPS IQR 1-2.75) and 2 (DDLPS IQR 1-3). Median PFS was 9.2 (WDLPS IQR 3.9-21.9) and 2.6 months (DDLPS IQR 2.0-6.1), with median time on treatment of 7.4 months (WDLPS IQR 3.5-14.2) and 2.7 months (DDLPS IQR 2.0-5.7). Twelve patients ultimately underwent surgical resection. Resections were macroscopically complete (R0/R1) in half (n = 6/12), among whom only one patient experienced relapse after resection (median follow-up 7.5 months). All patients who underwent macroscopically incomplete resections progressed after surgery with median time to progression of 3.3 months (IQR 2.3-4.4). Surgery after palbociclib treatment was not associated with improved overall survival. Efficacy of palbociclib monotherapy for patients with advanced WDLPS and DDLPS is disappointing. While palbociclib may have been used to delay surgery, there was no clear benefit from treatment and few patients achieved prolonged tumor control.

Feasibility Technique of Low-passage In Vitro Drug Sensitivity Testing of Malignant Pleural Effusion from Advanced-stage Non-small Cell Lung Cancer for Prediction of Clinical Outcome.

BACKGROUND/AIM: Individualized proper chemotherapy using in vitro drug sensitivity testing has been proposed as a novel therapeutic modality and shown to have better efficacy than empiric chemotherapy. However, issues around establishing a patient-derived cell culture or xenograft, the timing of the testing obtained, and the validity of testing represent major limitations to translating the use of such a technique to clinical practice. PATIENTS AND METHODS: In this study, we assessed the feasibility of an in vitro drug sensitivity technique for testing malignant pleural effusion from advanced-stage non-small cell lung cancer. RESULTS: Our technique was able to produce a turnaround time for in vitro drug sensitivity testing of less than 1 week, with a success rate of more than 90% of cases. Correlated with the individual clinical outcome, using the area under the dose response curve (AUC) could define the level of in vitro drug sensitivity as: responsive (AUC>0.25), intermediate response (0.1≤AUC≤0.25), or resistance (AUC<0.1). CONCLUSION: Data obtained from this method of drug testing were correlated with the clinical outcome. The present drug sensitivity evaluation may benefit the development of individual precision chemotherapy.