Immune checkpoint inhibitors (ICIs) have revolutionized our approach to cancer treatment in the past decade. While monoclonal antibodies to CTLA‐4 and PD‐1/PD‐L1 have produced remarkable and durable ...responses in a subset of patients, the majority of patients will still develop primary or adaptive resistance. With complex mechanisms of resistance limiting the efficacy of checkpoint inhibitor monotherapy, it is critical to develop combination approaches to allow more patients to benefit from immunotherapy. In this review, I approach the current landscape of ICI research from the perspective of sarcomas, a rare group of bone and soft tissue cancers that have had limited benefit from checkpoint inhibitor monotherapy, and little investigation of biomarkers to predict responses. By surveying the various mechanisms of resistance and treatment modalities being explored in other solid tumors, I outline how ICIs will undoubtedly serve as the critical foundation for future directions in modern immunotherapy.
A recent randomized phase II study of sunitinib or cediranib in alveolar soft part sarcoma established benchmark activity for commonly used tyrosine kinase inhibitors (TKI). The impact of TKIs, as ...well as immunotherapy, has redefined treatment paradigms and greatly improved outcomes for this historically dismal sarcoma. See related article by Nguyen et al., p. 1200.
Opinion statement
Angiosarcomas are rare vascular neoplasms that are among the most aggressive subtypes of soft tissue sarcomas. Surgical resection is often challenging even in localized disease, as ...the infiltrative nature of these cancers leads to frequent local and metastatic recurrences. Cytotoxic chemotherapy, including anthracycline-based regimens and taxanes can produce significant responses in a subset of patients but durability is limited with most patients ultimately succumbing to metastatic disease. Targeted therapy with tyrosine kinase inhibitors is usually well-tolerated but prone to development of resistance. Few head-to-head trials have addressed the optimal sequence of therapies, or demonstrated conclusive benefits of one therapy over another based on clinical and etiologic factors. Novel therapies in clinical trials, including antibodies to endoglin and checkpoint inhibitors have demonstrated exciting early activity in patients with angiosarcoma. Improved understanding of the genetic heterogeneity within various angiosarcoma subtypes may identify predictive biomarkers to match patients to effective existing and future therapies. Overall, angiosarcoma patients with optimal performance status are best served in clinical trials that incorporate novel combinations of cytotoxic chemotherapy, targeted therapies, and immunotherapies.
Recent work confirms a bench-to-bedside approach that circulating tumor DNA is associated with outcome and objective response to chemotherapy in patients with advanced leiomyosarcoma. Liquid biopsies ...may be used for risk stratification in future trials guiding treatment decisions by identifying patients who are likely to benefit from chemotherapy. See related article by Madanat-Harjuoja et al., p. 2579.
Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including ...chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Opinion statement
Despite their rarity, angiosarcomas are one of the most aggressive soft tissue sarcomas. Management can often be challenging due to their location and infiltrative nature. A ...multidisciplinary treatment approach is always warranted, but the recurrence remains high even for localized tumors despite multimodality treatment. In the metastatic setting, cytotoxic chemotherapies, targeted therapies, and, more recently, immunotherapy are used. The sequence of systemic therapies remains currently a topic of active investigation. Over the last couple of years, there have been significant advances in understanding angiosarcoma biology, most notably via patient-driven initiatives like the Angiosarcoma Project. The knowledge derived from such translational work has led to identifying potential biomarkers of response to treatments and exploring new therapeutic avenues. More clinical trials are underway to expand treatment options and improve patient outcomes.
VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor ...axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.
This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0–1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2–10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.
Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1–19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6–79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1–90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five 15% of 33 patients), autoimmune toxicities (five 15%), nausea or vomiting (two 6%), and seizures (two 6%). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.
Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.
Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. ...Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas.
We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue.
We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4). Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities.
This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.
In a randomized, placebo-controlled trial, oral nirogacestat twice daily led to 41% of patients having a tumor response, and 2-year progression-free survival was 76%. Most adverse events were low ...grade.
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal ...histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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