Contemporary Therapy for Advanced Soft-Tissue Sarcomas in Adults

Pang, Angela; Carbini, Mariana; Maki, Robert G.

doi:10.1001/jamaoncol.2016.0241

Cited by 21 publications

(19 citation statements)

References 65 publications

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“…Patients with metastatic soft tissue sarcomas generally have a poor prognosis, with low response rates after first line chemotherapy [3]. Of note, the tyrosine kinase inhibitor pazopanib was approved by the FDA in 2012 on the basis of a phase III randomized trial showing improved PFS in the second line setting; the overall response rate was only 6% [8].…”

Section: Discussionmentioning

confidence: 99%

“…Despite new studies elucidating the genomic basis and the sensitivity to chemotherapy of specific subtypes, the overall prognosis of patients with metastatic sarcoma remains poor in most cases. Since 2012, new drugs such as pazopanib, and for more specific subtypes, trabectedin and eribulin, have been approved for patients who have relapsed after front line chemotherapy, but the response rates for these agents remains suboptimal [3]. Immunotherapy has recently provoked great interest in oncology after phase III clinical trials have shown significant efficacy in chemotherapy-resistant malignancies such as metastatic melanoma or renal cell carcinoma, and activity in chemotherapy-sensitive histologies including non-small cell lung cancer, head and neck cancer, MSI-high colon cancer and Hodgkin’s lymphoma.…”

Section: Introductionmentioning

confidence: 99%

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Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

et al. 2016

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BackgroundManipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand.MethodsWe retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment.ResultsTwenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24–78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400–800 mg daily. The most common side effect was grade 1–2 LFT elevations; grade 3–4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.ConclusionsThese data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-016-0064-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

et al. 2016

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“…Our work strongly implicates Rb as a biomarker for CDK4/6 inhibitor combinations, similar to data from other cancer types such as breast cancer and glioblastoma. Selection for enrollment based on biomarkers is more likely to be successful versus the standard approach of enrollment by histologic criteria alone (39). The frequency of Rb positivity within sarcoma appears to differ among histologic subtypes, and not be universally expressed in any subtype.…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest

Francis

Alexander

Liu

et al. 2017

Molecular Cancer Therapeutics

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Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G1 phase of the cell cycle, and upon drug removal cells progress through the cell cycle as expected within 6–24 hours. Using a long-term high-throughput assay that allows us to examine drugs in different sequences or concurrently, we found that palbociclib-induced cell cycle arrest poises Rb-positive sarcoma cells (SK-LMS1 and HT-1080) to be more sensitive to agents that work preferentially in S-G2 phase such as doxorubicin and Wee1 kinase inhibitors (AZD1775). The synergy between palbociclib and AZD1775 was also validated in vivo using SK-LMS1 xenografts as well as Rb-positive patient-derived xenografts (PDX) developed from leiomyosarcoma patients. This work provides the necessary preclinical data in support of a clinical trial utilizing this treatment strategy.

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“…2 Conventional chemotherapy benefits patients with advanced STS with objective response rates from 15 to 25% with drugs such as doxorubicin, ifosfamide, and dacarbazine. A current paradigm shift favors pathological subtype-specific chemotherapy regimen, 3 and recent drug approvals were linked with specific sarcoma subtypes, such as trabectedin for leiomyosarcomas and liposarcomas, first described in sarcoma patients, whose tumor regressed after an infection 10 or after local injections of streptococcal broth cultures. 11 Similar to melanoma or kidney cancer, cases of spontaneous regression were reported in patients with sarcoma.…”

Section: Introductionmentioning

confidence: 99%

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

et al. 2017

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Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery. PDL1 expression was heterogeneous across the samples. PDL1-high samples (41%) were more frequently leiomyosarcomas and liposarcomas, and showed more frequently a complex genetic profile and a high-risk CINSARC signature. No correlation existed with other clinicopathological features such as tumor site, depth, and pathological tumor grade and size. In multivariate prognostic analysis, the PDL1-high class was associated with shorter MFS, independently of the pathological type and the CINSARC signature. Analysis of correlations with biological factors suggested the existence in tumors of the PDL1-high class of a strong and efficient cytotoxic T-cell response, however associated with some degree of T-cell exhaustion and negative regulation. In conclusion, we show that PDL1 expression refines the prediction of metastatic relapse in operated localized STS, and that PD1/PDL1 blockade holds potential to improve patient survival by reactivating inhibited T cells to increase the antitumor immune in PDL1-high tumors.

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Contemporary Therapy for Advanced Soft-Tissue Sarcomas in Adults

Abstract: The biological features of each sarcoma subtype are associated with specific sensitivity patterns to chemotherapy, and despite their rarity, future trials will need to emphasize specific histologic subtypes (many with well-defined genetic alterations) to best fit diagnosis to therapy.

Cited by 21 publications

References 65 publications

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

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