With more than 200 histological subtypes, the landscape of sarcoma management is rapidly evolving. Recent developments are ushering in the age of personalized medicine in the management of sarcomas leading to exciting new avenues for previously refractory disease. We hereby describe the current ongoings in bone and soft tissue sarcomas that are changing the landscape of treatment of this rare disease
There is a long-standing debate on the optimum management of Ewing sarcoma (ES) family of tumors with VIDE regimen followed by autologous stem cell transplant (ASCT) being preferred in European setting and VAC/IE being followed in America. The EURO EWING 2012 trial is an international, multi-centre, phase III open-label randomized controlled trial conducted to establish the standard regimen of chemotherapy for newly diagnosed ES family of tumors . The trial had factorial design and participants were randomized at time of entry (R1) and following local control therapy (R2) and the primary outcome of Event-free survival (EFS) along with secondary outcomes of overall survival (OS) and toxicity were measured. The VIDE (Vincristine, Ifosfamide, Doxorubicin and Etoposide) regimen followed by VAI or VAC (Vincristine, Actinomycin-D, Cyclophosphamide or Ifosfamide) consolidation was compared to compressed VDC/IE induction and IE/VC consolidation. 640 patients were analyzed between 2013 and 2019 with median follow up duration of 1.7 years. The Hazard Ratios (HRs) were 0.70 (95% CI 0.51-0.95) for EFS and 0.64 (95% CI 0.42-0.96) in favor of VDC/IE arm and this treatment effect was consistent across all baseline stratification parameters. Hence, VDC/IE chemotherapy has been found superior in terms of both EFS and OS without significant difference in toxicity. However, the role of ASCT still remains in question following VAC/IE induction and it would be more prudent to compare compressed VAC/IE-only regime and VIDE/ASCT in further trials.
The optimal treatment regimen for recurrent/refractory ES remains unknown till date, and the recurrent and primary refractory Ewing Sarcoma (rEEcur trial) is attempting to fulfil this unmet need. The second interim assessment of this international randomized controlled trial has recently been reported. While the first interim assessment revealed that gemcitabine docetaxel was a less effective treatment regimen as compared to topotecan/cyclophosphamide, temozolomide/irinotecan (IT) and high dose ifosfamide therapy , the current assessment revealed that IT was inferior to the other two therapy arms . Among the total 366 recruited patients, 118 patients received IT with response rates of 20%, and this combination regime was inferior to the two remaining regimens in terms of OS, Progression-free Survival (PFS) and Overall Response (OR). The remaining two treatment arms continue to recruit patients so as to generate more robust evidence regarding the standard of care treatment in recurrent and refractory Ewing Sarcoma patients.
Following promising preclinical results in models of Ewing sarcoma and osteosarcoma on pharmacological MET signaling and aberrant angiogenesis inhibition, the Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE) trial was conducted by Italiano et al . It was a multicentre, single-arm, two-stage phase 2 trial in patients with advanced Ewing Sarcoma or osteosarcoma. 90 patients recruited between 2015 to 2018 and received cabozantinib (60mg or 40mg/m2 in children). 6-month objective response was attained in 26% and 12% patients of Ewing sarcoma and osteosarcoma respectively and 33% osteosarcoma patients had 6-month non-progression of disease. The side effect profile was tolerable with notable grade 3 and 4 toxicities being hypophosphatemia and transaminitis. The results of this trial have provided a potential therapeutic option in the setting of advanced Ewing sarcoma and osteosarcoma and warrant further investigation. We await the availability of cabozantinib in India so as to utilize this novel drug among our patient population.
The EPAZ study examined the possibility of pazopanib having comparable efficacy to doxorubicin in first-line treatment of advanced inoperable soft tissue sarcomas (STS) . This study was based on the premise that about 40% STS patients are aged 60 years or older and are vulnerable to serious complications with standard chemotherapy. This was a non-inferiority phase 2 randomized controlled trial (RCT) which included patients aged 60 years or older to be randomized to first-line pazopanib or doxorubicin. Non-inferiority was assumed for PFS if the upper limit of HR was less than 1.8 and neutropenia and febrile neutropenia were included as key secondary endpoints. 81 and 39 patients received pazopanib and doxorubicin respectively, and pazopanib was found non-inferior to doxorubicin in terms of PFS and OS. Moreover, grade 4 laboratory or clinical neutropenia (0% versus 56.4%) and febrile neutropenia (0% versus 10.3%) significantly favored pazopanib over doxorubicin. However, it is still premature to change the clinical practice based on a phase 2 RCT performed in a limited sample size. This is reminiscent of the optimism around olaratumab leading to its accelerated approval based on phase Ib/II trial results which were later negated in the phase 3 ANNOUNCE trial [6,7]. Nevertheless, the result of the EPAZ study are notable, and pazopanib can be used as first line treatment based on the clinical scenario.
The combination of pazopanib to preoperative chemoradiotherapy was investigated in the joint Children’s Oncology Group and NRG Oncology multi-centre randomized open label phase 2 trial (ARST 1321) among children and adults with newly diagnosed trunk extremity STS . Pazopanib was administered with ifosfamide and doxorubicin with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Among the 81 participants, 58% patients in the pazopanib group and 22% in the control group attained 90% pathological response. The number of grade 3 and 4 toxicities were similar in pediatric and adult patients, suggesting the feasibility of the combination of pazopanib and neoadjuvant chemoradiotherapy in both age groups. Longer follow-up is required to provide survival outcome differences between the two groups and its correlation with pathological response rates.
The combination of doxorubicin and pembrolizumab was examined as an effective treatment option in advanced sarcomas . Pollack et al conducted this nonrandomized phase 1/2 trial with 37 patients comprising of leiomyosarcoma (n=11) among other histological subtypes. The overall response in the phase 1 cohort was 19% and 13% in the phase 2 cohort. 12-week and 24-week PFS rates were 81% and 73% respectively with median PFS of 8.1 months and median OS 27.6 months. Interestingly, the PD-L1 status was not associated with PFS or OS and durable responses were documented even in dedifferentiated liposarcoma and chondrosarcomas. The study has generated some questions on its 3+3 design, subtherapeutic dosage of doxorubicin in phase 1 (45mg/m2) , and the influence of different heterogeneous subtypes having differing responses to the therapy. Follow-up studies may throw more light on the role of this treatment combination in more resistant tumor subtypes such as chondrosarcomas.
Another new study examining immunotherapy in advanced STS has attempted to convert the cold tumor environment into an inflamed one utilizing combination therapy . The double inhibition of sunitinib (angiogenesis inhibitor) and nivolumab (PD-1 inhibitor) was administered in this phase Ib/II single-arm trial. Phase Ib established two dose levels; level -1 comprised of sunitinib 37.5mg in the first 14 days as induction and then 25 mg with nivolumab 3mg/kg while level 1 of dosing comprised of sunitinib 37.5mg on the same schedule. The 6-month progression-free survival rate (PFR) was 48% (95% CI 41-55%) with a manageable toxicity profile suggesting the activity of this scheme of treatment in advanced STS.
Recent times have seen newer treatment approvals in advanced sarcomas. The indication profile of pomalidomide was expanded to include AIDS-related and HIV-negative Kaposi Sarcoma based on results of the Study 12-C-0047 . This open-label, single-arm trial on 28 patients found overall response rate (ORR) of 67% (95% CI 41-87%) and 80% (95% CI 44-98%) in HIV-positive and negative patients respectively with 5mg pomalidomide on days 1 through 21 in 28-day cycles. The approval of the oral targeted EZH2 inhibitor tazemetostat in advanced epithelioid sarcoma (ES) with loss of INI1 or SMARCB1 opens a new therapeutic window for this rare and aggressive disease . The open-label phase 2 basket study included 62 ES patients and found 15% ORR, and 26% disease control at 32 weeks. Tazemetostat was tolerated well and produced a median PFS of 5.5 months (95% CI 3.4-5.9) and median OS of 19 months (95% CI 11.0-not estimable), demonstrating a potential to improve outcomes in advanced epithelioid sarcoma patients. The phase Ib/III trial combining doxorubicin and tazemetostat in first-line treatment of advanced ES is ongoing and could be a game-changer in the field of personalized medicine.
There is ongoing research on the immunogenic potential of alveolar soft part sarcoma (ASPS) owing possibly to MSH alterations, TFE3 mediated antigen presentation and the immunogenic epitopes presented on the ASPL-TFE3 fusion protein. The Connective Tissue Oncology Society (CTOS) meeting of 2018 saw encouraging results with atezolizumab in advanced ASPS which led to 42% ORR . In CTOS meeting of 2020, worldwide registry retrospective data was presented on the role of checkpoint inhibitors for ASPS showing ORR of 47.6% and median PFS of 10.9 months . In this retrospective data by Hindi et al, pembrolizumab and atezolizumab were received by 23% and 19% patients respectively, while nivolumab was given in 13% as monotherapy. The recent phase 2 trial by Kawai et al (OSCAR trial) on nivolumab in unresectable clear cell sarcoma and ASPS has found median PFS of 4.1 months (95% CI 1.8-8.9) and 6 months (95% CI 3.7-9.3) in CCS and ASPS respectively . However, the response rates to immunotherapy were 7% and 0% for ASPS and CCS respectively. These results suggest that nivolumab may not be the optimum immune checkpoint inhibitor of potential use in ASPS, although head-to-head studies between particular inhibitors are lacking.
The novel concept of adoptive cellular therapy is under exploration in the domain of sarcomas with trials underway in synovial sarcoma. NY-ESO-1 and MAGE-A4 are expressed in around 70-80% cases of synovial sarcomas and genetically engineered specific peptide enhanced affinity receptor (SPEAR) T-cells are being used to target the overexpressed tumor antigens . Results of these studies presented at CTOS 2020 produced interesting outcomes, with documented responses in approximately 50% of the patients, lasting more than 12 months in 20% . Cohorts with high NY-ESO-1 expression had ORR of 50% and 27% with high and low lymphodepletion regimens respectively. MAGE-A4 based therapy had a greater incidence of cytokine release syndrome (88%) and produced ORR of 44% with median PFS of 20.4 weeks (95% CI 6-80.1). It was found that high target expression was required to produce favorable responses which may limit its routine applicability to therapy. The caveat for its reproducibility in Indian population is the low prevalence of HLA-A*02 among our patients which is a prerequisite for this engineered T-cell receptor therapy .
These newer studies throw light on the aspects which can be improved in the Indian setting. Availability of newer therapies such as cabozantinib and tazemetostat in India would provide alternative options for advanced sarcomas. The absence of HLA-A*02 in the Indian population currently renders our patients ineligible for adoptive cell therapies for sarcomas. We anticipate more such research in the future that would target and benefit our population to improve outcomes in patients of sarcomas.
Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni