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Background: Conventional cytotoxic agents and pazopanib are approved for advanced soft tissue sarcomas but have low response rates and modest survival benefits. Recently, immune checkpoint inhibitors have shown clinically meaningful activity. The combination of pazopanib and immunotherapy has shown synergism in various other malig- nancies but has not been fully explored in advanced soft tissue sarcomas. Case presentation: A 63 year old woman with metastatic undifferentiated pleomorphic sarcoma progressed after two lines of palliative combination chemotherapy—doxorubicin with olaratumab, and gemcitabine with docetaxel. In view of significant symptoms, she was treated with pazopanib in combination with pembrolizumab. She had remarkable radiological and clinical improvement, with a manageable toxicity profile and an ongoing response at ten months of therapy. Conclusions: Undifferentiated pleomorphic sarcoma is an immunologically active subtype of soft tissue sarcoma, which is particularly amenable to immune checkpoint inhibitors. Pazopanib with immune checkpoint inhibitors is a well-tolerated, yet hitherto underexplored combination that may offer significant clinical benefit in advanced sarco - mas—this finding warrants further evaluation in clinical trials. Keywords: Pembrolizumab, Undifferentiated pleomorphic sarcoma, Pazopanib, Immunotherapy Background was approved by (US FDA) United States Food and Drug The outcomes in metastatic soft tissue sarcoma (mSTS) Administration in second line in non-adipocytic STS . remain dismal even though various drugs have been Subsequently trabectedin and eribulin were approved in added in treatment arsenal during this decade. Conven- second line in L-sarcomas (liposarcoma and leiomyo- tional cytotoxic agents like doxorubicin, ifosfamide and sarcoma). This was followed by accelerated approval for gemcitabine/docetaxel have modest activity and signifi - olaratumab in first line after it showed unprecedented cant toxicities associated with their use. Pazopanib was improvement in overall survival of 11.8 months in a small the first targeted therapy that broke the dormancy in phase 2 trial . However, the ANNOUNCE trial pre- the landscape of mSTS based upon PALETTE trial and sented recently in American Society of Clinical Oncology (ASCO) 2019 meeting in abstract form showed lack of benefit and thereafter its FDA approval has been revoked *Correspondence: firstname.lastname@example.org . Department of Medical Oncology, Dr B.R.A. Institute Rotary Cancer Immune checkpoint inhibitors have shown promis- Hospital, All India Institute of Medical Sciences, New Delhi, India ing results in many other tumors apart from sarcoma Full list of author information is available at the end of the article © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Arora et al. Clin Sarcoma Res (2020) 10:10 Page 2 of 6 (melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin’s lymphoma etc.) and are thus being explored in advanced STS. A multicenter phase 2 trial (SARC-028) evaluating pembrolizumab in advanced STS showed an overall response rate of 40% (4/10) in patients with undifferentiated pleomorphic sarcoma (UPS) but was ineffective in leiomyosarcoma (0/10) and moderately effective in liposarcoma (2/10) . Subsequently George et al. showed the ineffectiveness of nivolumab in uter - ine leiomyosarcoma (LMS) . The PEMBROSARC trial tested pembrolizumab in combination with metronomic cyclophosphamide for patients with LMS, UPS and other sarcomas . None of the sixteen UPS patients in this report had a response to pembrolizumab. Fig. 1 Histology photomicrograph of the excised right thigh Based upon the available data (which show some- soft tissue mass showing a malignant mesenchymal tumor with what conflicting results), liposarcoma and undifferenti - markedly pleomorphic spindle to bizarre cells exhibiting marked ated pleomorphic sarcoma are probably the sarcomas in nuclear pleomorphism, coarse chromatin and abundant eosinophilic cytoplasm (H&E, 200x) which immunotherapy should be explored. Herein we present the case of a 63 year old patient with metastatic undifferentiated pleomorphic sarcoma who failed two membrane antigen, Alk-1, HMB45, Melan-A, CK18, lines of therapy but had a remarkable response with anti- CK19, P63, ER, CD10, CK5/6, CK-HMW. She presented programmed death protein-1 (anti-PD-1) antibody pem- to our center at this point for further management and brolizumab in combination with the multitargeted small in view of metastatic disease, was advised doxorubicin- molecule tyrosine kinase inhibitor pazopanib. based chemotherapy. After discussion of the encouraging results from the phase 2 trial conducted by Tap et al. with Case presentation the patient, the platelet derived growth factor receptor A 63 year old woman with no known comorbidities, alpha antibody olaratumab was also added . However, was evaluated in September 2017 for complaints of an response assessment done after 4 cycles of doxorubicin insidious onset, gradually progressive painless swelling and olaratumab showed progressive disease and she was in the posterior aspect of right thigh. Magnetic reso- then switched to gemcitabine and docetaxel regimen. nance imaging scan revealed a well-defined, lobulated She received 8 cycles of gemcitabine/docetaxel and had soft tissue lesion in posterior subcutaneous compart- reduction in number and size of lung nodules, sugges- ment of the right knee joint. She underwent excision tive of partial response (Fig. 2a, b). Chemotherapy was biopsy of the primary lesion at a local hospital and his- stopped in view of unacceptable toxicity and she was kept topathology was suggestive of undifferentiated pleomor - on follow-up. After 3 months of treatment-free interval, phic sarcoma, with 14–15 mitoses per high power field, she developed progressively worsening cough. A CT scan no necrosis and FNCLCC grade II (Fig. 1). Subsequently of the chest was done, which revealed disease progression whole body 18-fluorodeoxyglucose positron emission (Fig. 2c, d). Biopsy blocks were reviewed for expression tomography with computed tomography (FDG PET- of programmed death ligand-1 (PD-L1) by IHC using CT) scan showed metabolically active soft tissue mass in the Ventana PD-L1 assay (SP263), which was positive, musculofascial plane of right lower thigh with FDG-avid with a tumor cell score of 25 percent (Fig. 3). She was right inguinal and external iliac lymph nodes, and mul- then started on pazopanib 800 mg daily along with anti- tiple small bilateral lung nodules suspicious for metas- PD-1 antibody pembrolizumab pembrolizumab (200 mg tases. In view of residual disease, she underwent wide every 3 weeks). She had grade 2 infusion reaction with local excision of the primary tumor along with right ilio- second dose of pembrolizumab, grade 2 immune-related inguinal lymph node dissection. The tumor measured hypothyroidism and grade 2 hypertension. There was sig - 8 × 5 × 5 cm, with all peripheral margins being negative. nificant improvement in her cough within one month of 10 out of 19 inguinal lymph nodes and 11 out of 22 pelvic therapy and response evaluation done after 3 months of lymph nodes showed metastatic tumor with extracapsu- therapy showed regression of lung metastases (Fig. 2e, lar extension. On immunohistochemistry (IHC), tumor f ). Same combination was continued with no unmanage- cells had a Ki-67 of 40%, and were positive for desmin, able adverse effects, and a repeat evaluation done after while being negative for SMA, S-100, CD34, CD99, Bcl2, 9 months of treatment showed further disease regression MDM2, Desmin, H-caldesmon, cytokeratin, epithelial A rora et al. Clin Sarcoma Res (2020) 10:10 Page 3 of 6 Fig. 2 Axial (a) and coronal (b) fused positron emission tomography—computed tomography (PET-CT ) images showing 18-fluorodeoxyglucose (18-FDG) avid soft tissue nodule in the left lung upper lobe (green arrows) after completion of gemcitabine-docetaxel chemotherapy. CT scan images (c, d) in lung window showing progression of nodules in left lung upper lobe (red arrows) after 3 months of watchful waiting. 18-FDG PET-CT scan images showing reduction in size with resolution of metabolic activity of lung nodules after 3 months (e, f) (blue arrows) and 9 months (g, h) (white arrows) of treatment with pembrolizumab + pazopanib Arora et al. Clin Sarcoma Res (2020) 10:10 Page 4 of 6 were seen primarily in patients with alveolar soft part sarcoma (54.5%) while none of the 5 patients with UPS had an objective response. However, there have been concerns about the tolerability of such drug combina- tions. For instance, the combination of nivolumab and sunitinib for advanced RCC was associated with grade 3/4 adverse events in 82% and treatment discontinuation in 39% patients enrolled in one study . In contrast to these findings, the combination of avelumab and axitinib was well tolerated and had comparable adverse events (including grade 3 and 4 adverse events) when compared to a VEGF TKI (sunitinib) alone in the JAVELIN Renal 101 trial . As the patient was in significant distress due to persis - Fig. 3 Immunohistochemistry for anti-programmed death ligand-1 tent cough, and monotherapy with pazopanib and pem- antibody showing membranous positivity in tumor cells ( Ventana brolizumab is associated with modest objective response SP263 assay) rates (6 and 23%, respectively), we considered combing the two agents in her case. Given the need to achieve a rapid tumor response, and evidence for the combination (Fig. 2 g, h). Thus far, she has completed ten months of therapy resulting in meaningful results with acceptable this combination therapy and continues to be in good toxicity, we were enticed to offer it to our patient after a general condition. discussion of the potential risks and benefits. She has tol - erated the dual therapy well and has had no grade 3 or 4 adverse effects. Although each agent’s individual contri - Discussion and conclusions bution to the good response observed in this patient can Vascular endothelial growth factor (VEGF) has been only be confirmed or refuted in a randomized trial, the implicated not only in tumor angiogenesis and metasta- improvement was most likely attributable to the immune ses, but also plays a crucial role in maintaining an immu- checkpoint inhibitor since objective responses with sin- nosuppressive tumor microenvironment. VEGF-VEGF gle agent pazopanib are uncommon and typically not receptor interactions have been shown to upregulate well-sustained . Interestingly, the durable response intratumoral regulatory T cells (Tregs), myeloid derived achieved in our patient is in contrast to the poor response suppressor cells (MDSCs), and tumor-associated mac- rate (only 1 minor response in 5 patients with UPS) seen rophages, while suppressing T cell function and inter- in the trial by Wilky and colleagues . The explana - fering with differentiation and activation of dendritic tion may lie in the expression of PD-L1, or the fact that in cells . VEGF receptor inhibitors, apart from their fun- contrast to axitinib, pazopanib inhibits multiple kinases damental mechanism of inhibiting angiogenesis, have that play a pivotal role in the tumor microenvironment been shown to modulate the intratumoral cytokines and and immune response . thereby infiltration by immune effector and suppres - In contrast to immunologically active tumors like mela- sor cells . The positive immunomodulatory activity noma, the tumor microenvironment in soft tissue sarco- of VEGF receptor tyrosine kinase inhibitors (TKIs) like mas is considered immunologically quiescent. Sarcoma sunitinib, pazopanib and axitinib in the tumor microen- tumor cells have poor antigenicity and easily escape vironment underlies the proposition of combining them recognition by tumor infiltrating immune effector cells. with immune checkpoint inhibitors to increase the thera- However, undifferentiated pleomorphic sarcomas have peutic responsiveness of the latter . Such combina- high tumor mutation burden and may provide protein tions were initially explored in the setting of advanced targets for immunotherapy. Extremity and trunk UPS renal cell carcinoma (RCC) and have yielded positive biopsy samples have been shown to have an infiltrate of results . In a single arm, phase 2 trial, VEGF TKI axi- immune cells at baseline, and this infiltration by CD3, tinib plus pembrolizumab was studied in 33 patients with CD4, CD8 and FOXP3 positive cells is further enhanced advanced sarcoma who had progressed after or declined by radiation therapy . The possible mechanisms may standard chemotherapy or targeted therapy . Not- include radiation induced increased antigenic expres- withstanding the limitations of cross-trial compari- sion, release of pro-inflammatory cytokines that recruit son, progression free survival at 6 months in this series immune cells, promotion of antigen cross-presentation compared favorably to the results obtained with mono- and increased death receptor expression in tumors . therapy with either agent. However, objective responses A rora et al. Clin Sarcoma Res (2020) 10:10 Page 5 of 6 Abbreviations In the SARC028 trial, only 3 out of 70 biopsy samples mSTS: Metastatic soft tissue sarcoma; US FDA: United States Food and with advanced sarcoma were positive for PD-L1 expres- Drug Administration; ASCO: American Society of Clinical Oncology; LMS: sion at 1% threshold—all 3 cases were UPS. Although Leiomyosarcoma; UPS: Undifferentiated pleomorphic sarcoma; anti-PD1: Anti-programmed death protein-1; FNCLCC: Fédération Nationale des Centres responses to pembrolizumab were seen even in the de Lutte Contre Le Cancer; FDG PET-CT: 18-fluorodeoxyglucose positron emis- absence of PD-L1 expression, 2 evaluable patients with sion tomography with computed tomography; IHC: Immunohistochemistry; PD-L1 expressing tumors achieved partial response or PD-L1: Programmed death ligand-1; VEGF: Vascular endothelial growth factor; Tregs: Regulatory T cells; MDSCs: Myeloid derived suppressor cells; TKI: Tyrosine complete response. The authors concluded that UPS kinase inhibitor; RCC : Renal cell carcinoma. fits the model of an inflamed tumor, with potential ben - efit from single agent anti-PD-1 antibodies. We may Acknowledgements Not applicable extrapolate these findings to suggest that patients with PD-L1 expressing UPS represent the most likely subset Authors’ contributions to benefit from anti-PD-1 antibodies. This biomarker SA: Conception and design, analysis and interpretation of the data, drafting of the manuscript, final approval of the manuscript. SR: Conception and design, analysis may allow better patient selection for consider- analysis and interpretation of the data, critical revision of the manuscript, ation of immune checkpoint inhibitors. Outcomes from final approval of the manuscript. SAS: Analysis and interpretation of the data, the expansion cohort of SARC 028 trial including total final approval of the manuscript. AB: Analysis and interpretation of the data, final approval of the manuscript. MS: Analysis and interpretation of the data, 40 patients with UPS have now been reported and have final approval of the manuscript. All authors read and approved the final shown encouraging results. In these patients who failed manuscript. one or more prior lines of therapy, pembrolizumab Funding showed an overall response rate of 23% (9/40)—2 com- No external funding, apart from the support of the authors’ institution, was plete responses and 7 partial responses . 75% of available for this study. the responders had tumors positive for PD-L1 expres- Availability of data and materials sion. The immune-related toxicities were predictable All data generated or analyzed during this study are included in this published and manageable in most cases. Based on these positive article. outcomes, an open label, randomized phase 2 trial to Ethics approval and consent to participate assess the response to neoadjuvant nivolumab (anti- Formal ethics approval was not required owing to the retrospective, PD-1) alone or in combination with ipilimumab (anti- observational,and anonymous nature of this case report. CTLA-4) with or without concurrent radiotherapy Consent for publication in patients with surgically resectable dedifferentiated Written informed consent was obtained from the patient for publication of liposarcoma and undifferentiated pleomorphic sarcoma this case report and any accompanying images. has been designed and is currently recruiting . The Competing interests outcomes of this trial, expected in 2021, will further The authors declare that they have no competing interests. our understanding of the benefits of immunotherapy in these tumor subtypes. Considered together, these Author details Department of Medical Oncology, Dr B.R.A. Institute Rotary Cancer Hospital, data indicate that undifferentiated pleomorphic sar - All India Institute of Medical Sciences, New Delhi, India. Department coma is an immunologically active subtype of soft tis- of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India. sue sarcoma, which is particularly amenable to immune Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. Department of Ophthalmology, Lady Hardinge Medical College, New checkpoint inhibitors. Clinical trials with inclusion of Delhi, India. biomarkers such as PD-L1 expression may help identify patients most likely to benefit from immunotherapy. 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Clinical Sarcoma Research – Springer Journals
Published: Jul 9, 2020
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