Effectiveness and Safety of Trabectedin and Radiotherapy for Patients With Myxoid Liposarcoma

Abstract

ImportancePreclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring.ObjectiveTo explore the effectiveness and safety of trabectedin combined with RT.Design, Setting, and ParticipantsThis international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall.InterventionsTrabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment.Main Outcomes and MeasuresThe primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response.ResultsA total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated.Conclusions and RelevanceAlthough the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…In this sense, the field is experiencing a remarkable expansion: globally, TRB is assessed in combination with ICIs (antiPD-1/PD-L1 [107][108][109][110] and/or CTLA-4 [109]), monoclonal antibodies (-mAbs) that may act as either molecular inhibitors or activators, specific inhibitors of molecular targets (PARP [51,[111][112][113], MDM2 [114], VEGF [115][116][117], CCR5 [118], m-TOR [119], IGF1-R [120], BCL2 [121], ATM/ATR [122],PPAR-γ [123], and CK-2/CLK2 [124]), recombinant proteins (shTRAIL [125]), topoisomerase inhibitors (irinotecan [126][127][128][129][130][131], topotecan [127], and camptothecin [132]), and immuno-modulatory biomolecules such as L19-mTNF [133] or dexamethasone [134], combined with propranolol [135], a β-adrenergic receptor inhibitor, or Wnt/β-catenin inhibitors [136] (PRI-724). It is combined with physical agents (hyperthermia [137] and radiation [138][139][140][141], among other strategies) as it is shown in Table 1, where it is indicated in which pathologies and cellular or murine models are applied. TRB + avelumab Anti-PD-L1 Advanced liposarcoma and leiomyosarcoma [110] TRB + nivolumab + talimogene l...…”

“…Redirects T-lymphocyte cytotoxicity to AXL-expressing cells Osteosarcoma [150] TRB + L19-mTNF Pro-inflammatory cytokine Fibrosarcoma [133] Physical agents TRB + radiotherapy Lung cancer, colon cancer [138] Advanced soft tissue sarcoma [139] Localized resectable myxoid liposarcoma [140,141] Retroperitoneal leiomyosarcoma [151] TRB + hyperthermia Osteosarcoma, liposarcoma, synovial sarcoma [137] LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [152]) and in combination with irinotecan [153,154], ATR [122,155] alone or combined with ATM [156] and PARP [157] inhibitors, anti-VEGF [158] combined with cisplatin [83,159,160], paclitaxel [158], gemcitabine [161], capecitabine [162], doxorubicin [41,163,164], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [165]).…”

The Significance of a Pathologic Complete Response in Patients With Soft Tissue Sarcoma

“…Although the study by Lansu et al does not specifically comment on the complete response rate, the addition of trabectedin to preoperative radiotherapy in the study by Sanfilippo et al did yield a 13% pCR rate, which was noted in the article by Wang et al to be associated with improved DFS and OS. In this regard, however, the studies by Sanfilippo et al and Lansu et al are somewhat difficult to compare because they used different pathologic response criteria, and the study by Sanfilippo et al used a higher radiation dose of 45 Gy in 25 fx (EQD2 [equivalent dose at 2 Gy] ~ 43.5 Gy) assuming α/β for sarcoma of 4 and time to surgery (within 8 weeks for Lansu et al and 4 weeks from last cycle of chemotherapy for Sanfilippo et al). This question is certainly worth further study, and one can envision a direct comparison of reduced-dose radiation therapy compared with reduced-dose radiation with trabectedin.…”

“…This issue of JAMA Oncology includes the results of 3 prospective clinical trials for patients with soft tissue sarcomas, Trabectedin and Radiotherapy in Soft Tissue Sarcoma (TRASTS), and a combined analysis of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9514 and 0630, that offer important insight into the clinical implications of a pathologic complete response (pCR) following neoadjuvant radiation or chemoradiation therapy. The studies also highlight the trend to design clinical trials for patients with soft tissue sarcomas in a more biologically driven fashion to better account for disease heterogeneity by comparing differences in clinical outcomes between histologic subtypes and, whenever possible, design studies tailored to 1 or a small number of histotypes with shared biologic features.…”

“…In that spirit, we would also comment on the article by Sanfilippo et al in this issue of JAMA Oncology , a prospective, phase 2 study combining trabectedin with preoperative radiotherapy for myxoid liposarcoma. This study embodies the laudable trend of multinational collaboration to facilitate the study of a histologic subtype of soft tissue sarcoma.…”