Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial

Wilky, Breelyn A.; Trucco, Matteo; Subhawong, Ty K.; Florou, Vaia; Park, Wungki; Kwon, Deukwoo; Wieder, Eric; Kolonias, Despina; Rosenberg, Andrew E.; Kerr, Darcy A.; Sfakianaki, Efrosyni; Foley, Mark K.; Merchan, Jaime R.; Komanduri, Krishna V.; Trent, Jonathan C.

doi:10.1016/s1470-2045(19)30153-6

Cited by 296 publications

(291 citation statements)

References 29 publications

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“…Anti‐VEGF TKIs are the most active agents historically for ASPS, although recent studies have demonstrated remarkable activity of ICIs in this subtype . We conducted a phase II trial of combined axitinib and pembrolizumab for advanced soft tissue sarcomas, which produced objective responses in 54.5% of the 11 evaluable patients with ASPS, greater than would be expected with either axitinib monotherapy or single agent PD‐1 blockade . While other sarcoma subtypes including HGUPS and dedifferentiated liposarcomas have previously been reported to respond to pembrolizumab monotherapy, we observed limited activity in these subtypes, with some patients demonstrating more rapid progression of disease with combination axitinib/pembrolizumab.…”

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 91%

“…Our group has also identified worse outcomes with an elevated baseline neutrophil‐lymphocyte ratio (NLR) in sarcomas treated with immune checkpoint blockade . Increased NLR has been associated with inferior responses to immune checkpoint blockade in a variety of solid tumors, and has been associated with worsened recurrence‐free survival and development of metastases in surgically resected sarcomas .…”

Section: Biomarkers Of Response To Immune Checkpoint Inhibitorsmentioning

confidence: 92%

“…These outcomes are consistent with those observed from checkpoint inhibitors in other trials of solid tumors with unselected patients. However, meaningful and durable responses to checkpoint blockade have been observed in certain subtypes including HGUPS, dedifferentiated liposarcoma, ASPS, clear cell sarcoma, and cutaneous angiosarcomas …”

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

“…One intriguing possibility would be to consider pretreatment of these tumors with strategies aimed at promoting immunogenicity and T‐cell influx, or potentially in combination with agents reprogramming the TME prior to T‐cell collection and expansion. We previously treated a patient with refractory synovial sarcoma who had received prior NY‐ESO‐1 engineered TCRs with response several years previously with a combination of the VEGF receptor TKI axitinib plus pembrolizumab . While synovial sarcomas rarely respond to either CTLA‐4 or PD‐1 monotherapy, this patient achieved stable disease on axitinib/pembrolizumab for 32 weeks.…”

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

“…However, meaningful and durable responses to checkpoint blockade have been observed in certain subtypes including HGUPS, dedifferentiated liposarcoma, ASPS, clear cell sarcoma, and cutaneous angiosarcomas. 22,[36][37][38][39][40] In many cases, sarcomas epitomize the most challenging obstacles to overcome in facilitating an immune response. While understanding of the sarcoma immune TME is limited, available data suggest that sarcomas are likely to be cold tumors, with relatively infrequent expression of PD-L1, low mutational burden, and suppressive immune infiltrates consisting of suppressive macrophages and myeloid derived suppressor cells (MDSCs), rather than exhausted CD8 + T cells.…”

Section: The Immune E Va S I On C a Sc Adementioning

confidence: 99%

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Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

167

113

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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.

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Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 91%

Section: Biomarkers Of Response To Immune Checkpoint Inhibitorsmentioning

confidence: 92%

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

Section: The Immune E Va S I On C a Sc Adementioning

confidence: 99%

See 3 more Smart Citations

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

167

113

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Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma

et al. 2020

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IMPORTANCE Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes. OBJECTIVE To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas. DESIGN, SETTING, AND PARTICIPANTS This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma. INTERVENTIONS Two dose levels of doxorubicin (45 and 75 mg/m 2) were tested for safety in combination with pembrolizumab. MAIN OUTCOMES AND MEASURES Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines. RESULTS A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed. CONCLUSIONS AND RELEVANCE In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

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The diagnosis, classification, and treatment of sarcoma in this era of artificial intelligence and immunotherapy

Crombé

Roulleau‐Dugage

Italiano

2022

Cancer Communications

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Soft-tissue sarcomas (STS) represent a group of rare and heterogeneous tumors associated with several challenges, including incorrect or late diagnosis, the lack of clinical expertise, and limited therapeutic options. Digital pathology and radiomics represent transformative technologies that appear promising for improving the accuracy of cancer diagnosis, characterization and monitoring.Herein, we review the potential role of the application of digital pathology and radiomics in managing patients with STS. We have particularly described the main results and the limits of the studies using radiomics to refine diagnosis or predict the outcome of patients with soft-tissue sarcomas. We also discussed the current limitation of implementing radiomics in routine settings.Standard management approaches for STS have not improved since the early 1970s. Immunotherapy has revolutionized cancer treatment; nonetheless, immuno-oncology agents have not yet been approved for patients with STS. However, several lines of evidence indicate that immunotherapy may represent an efficient therapeutic strategy for this group of diseases. Thus, we emphasized the remarkable potential of immunotherapy in sarcoma treatment by focusing on recent data regarding the immune landscape of these tumors. We have particularly emphasized the fact that the development of immunotherapy for sarcomas is not an aspect of histology (except for alveolar soft-part sarcoma) but rather that of the tumor microenvironment. Future studies investigating immunotherapy strategies in sarcomas should incorporate at least the presence of tertiary lymphoid structures as a stratification factor in their design, besides

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Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial

Cited by 296 publications

References 29 publications

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma

The diagnosis, classification, and treatment of sarcoma in this era of artificial intelligence and immunotherapy

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