Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial
Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline.
Methods
In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743.
Findings
From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 [95% CI 0·48–1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 [95% CI 0·46–0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 [95% CI 0·03–0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 [95% CI 0·25–0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure.
Interpretation
Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib.
Funding
Bayer HealthCare.
Introduction
Soft tissue sarcomas are heterogeneous malignant tumours of mesenchymal origin, including four major histological groups: liposarcoma (20% of all soft tissue sarcomas), leiomyosarcoma (about 20%), synovial sarcoma (about 6%), and other sarcomas.1 Approximately 13 000 cases of soft tissue sarcomas are diagnosed annually in the USA, about 4600 in France, and about 3200 in the UK.2 Surgery, often with adjuvant radiation therapy for larger tumours, is the mainstay of treatment. Despite primary combined modality therapy, at least 40% of patients develop recurrent or metastatic disease. The standard of care for metastatic disease for decades has been anthracycline plus or minus ifosfamide.2, 3
Beyond doxorubicin-based chemotherapy, a few approved treatment options are available: ifosfamide,4 dacarbazine,3 trabectedin,5 pazopanib (for non-adipocytic sarcomas),6 and eribuline in adipocytic sarcomas.7 Other regimens such as gemcitabine plus dacarbazine,8 or gemcitabine plus docetaxel 9 also have activity, shown in randomised phase 2 trials. However, the overall survival of patients at metastatic stage remains poor with a median of approximately 18 months10 and thus metastatic soft tissue sarcoma management still represents an unmet medical need.
Research in context
Evidence before this study
We searched PubMed for clinical trials published in English from Jan 1, 2005, to June 1, 2016 that assess the activity of regorafenib in patients with advanced soft tissue and bone sarcoma (excluding gastrointestinal stromal tumours) who were previously treated with doxorubicin or other anthracycline-based chemotherapy. We used the search terms “sarcoma”, “chemotherapy”, “tyrosine kinase inhibitor”, and “regorafenib”. To our knowledge, no previous trial has been published in this population assessing the activity of regorafenib. The efficacy of pazopanib, another multikinase inhibitor, is well established in this clinical setting. One large, international, placebo-controlled, double-blind, randomised, phase 3 trial, without crossover, has shown progression-free survival improvement with pazopanib but without statistically significant improvement of overall survival.
Added value of the study
The present study showed that patients with leiomyosarcomas, synovial sarcomas, and other sarcomas treated with regorafenib had longer progression-free survival compared with patients with the same type of sarcoma who were treated with placebo. However, patients with liposarcoma treated with regorafenib had no difference in progression-free survival compared with patients with liposarcoma treated with placebo.
Implications of all the evidence
Regorafenib warrants further clinical exploration in non-adipocytic soft tissue sarcomas. Three other phase 2 trials are still recruiting in USA and France: in patients with angiosarcoma (NCT02048722); in patients with refractory liposarcomas, osteogenic sarcomas, and Ewing and Ewing-like sarcomas (NCT02048371); and in patients with osteosarcomas, chondrosarcomas, Ewing sarcomas, and chordomas (NCT02389244). Until we know more about mechanisms of resistance, we do not recommend any further trials assessing the activity of regorafenib in unselected patients with liposarcoma.
Angiogenesis inhibition and VEGFR2 inhibitors were identified as active strategies for the treatment of metastatic soft tissue sarcomas.6 In an international phase 3 trial,6 patients with non-adipocytic sarcomas treated with pazopanib were reported to have longer progression-free survival compared with patients treated with placebo. However, pazopanib did not improve the overall survival in this trial, and alternative options are needed.6 Regorafenib is an orally bioavailable multikinase inhibitor targeting tumour cells, vasculature, and the tumour microenvironment. It binds to and inhibits VEGFR1, VEGFR2, and VEGFR3, and tumour cell signalling kinases (RET, KIT, PDGFR, and Raf). In a phase 1 trial, one of the three patients with a response had an advanced osteosarcoma.11 Regorafenib showed efficacy and manageable toxicity in the treatment of refractory colorectal cancers and gastrointestinal stromal tumour in three phase 3 trials,12, 13, 14 leading to its approval in many countries worldwide.
To determine the activity of regorafenib in patients with metastatic soft tissue sarcomas, we did a double-blind, placebo-controlled, phase 2 trial assessing the efficacy and safety of regorafenib in patients previously treated with doxorubicin or other anthracycline-based chemotherapy.
Section snippets
Study design
REGOSARC was a double-blind, placebo-controlled, multicentre, randomised phase 2 trial assessing the activity and safety of regorafenib in the following four cohorts in France and Austria: liposarcomas, leiomyosarcomas, synovial sarcomas, and other sarcomas. We amended the study protocol on Oct 7, 2015, to add a new cohort comprising those with non-adipocytic sarcomas who received pazopanib. The enrolment in this last cohort is still ongoing. Within each cohort, patients were randomly assigned
Results
From Aug 5, 2013, to Nov 26, 2014, 220 patients were screened and 182 were randomly assigned to one of four cohorts (table 1; figure 1). Baseline characteristics were well balanced in both groups in each cohort, nevertheless there were more grade 3 leiomyosarcomas and synovial sarcomas in the regorafenib group compared with placebo (table 1). The liposarcoma cohort was prematurely closed after enrolment of 43 [86%] patients of the 50 planned patients because the required number of events was
Discussion
The results of this trial show significant anti-tumour activity of regorafenib in patients with non-adipocytic advanced soft tissue sarcomas who previously received anthracycline. This trial was not designed to measure the effect on overall survival, because crossover was allowed and 70 (76%) of 92 patients who were initially randomly assigned to the placebo group crossed over to the regorafenib group (appendix pp 1–4).
Our study design was extensively discussed between the study coordinators,
This systematic review evaluates reporting of patient-reported outcomes (PROs) within randomized clinical trials (RCTs) for advanced soft tissue sarcoma (STS) patients.
A systematic literature search from January 2000 – August 2022 was conducted for phase II/III RCTs evaluating systemic treatments in adult patients with advanced STS. Quality of PRO reporting was assessed using the CONSORT PRO extension.
Out of 7294 abstracts, 59 articles were included; comprising 43 RCTs. Only 15 RCTs (35%) included PROs, none as primary endpoints. Only 10 of these RCTs reported PROs, either in the primary (6/10) or secondary publication (1/10) or in both (3/10), with a median time interval of 23 months. The median CONSORT PRO adherence score was 5.5/14, with higher scores in publications focusing exclusively on PROs.
These results highlight the need for improved and more consistent PRO reporting to inform patient care in the setting of advanced STS.
To investigate the activity of regorafenib in advanced solitary fibrous tumour (SFT).
An Italian monocentric investigator-initiated exploratory single-arm Phase II trial was conducted of regorafenib in adult patients with advanced and progressive SFT, until progression or limiting toxicity. Prior treatment with antiangiogenics was allowed. Primary and secondary end-points were: overall response rate (ORR) by Choi criteria, and ORR by RECIST, progression-free survival (PFS), overall survival (OS).
From January 2016 to February 2021, 18 patients were enroled [malignant-SFT = 13; dedifferentiated-SFT (D-SFT) = 4; typical-SFT (T-SFT) = 1]. Fourteen patients were pre-treated, in 12 cases with antiangiogenics (median [m-] lines of treatment = 3). Sixteen patients were evaluable for response (one screening failure; one early discontinuation). Six/16 (35.2%) required a definitive dose reduction. ORR by Choi was 37.5% (95% CI: 15.2–64.6), with 6/16 (37.5%) partial responses (PR), 6/16 (37.5%) stable disease (SD) and 4/16 (25%) progressions; 5/6 responses occurred in patients pre-treated with antiangiogenics. No responses were detected in D-SFT. Best RECIST responses were: 1/16 (6.2%) PR, 12/16 (75%) SD, 3/16 (18.8%) progressions. At 48.4 month m-FU, m-PFS by Choi was 4.7 (inter-quartile range: 2.4–13.1) months, with 31.2% patients progression-free at 1 year.
Regorafenib showed activity in SFT, with 30% patients free-from-progression at one year. Responses were observed also in patients pretreated and refractory to another antiangiogenic agents. However, ORR and m-PFS were lower than reported with other antiangiogenics, and this was possibly due to discrepancies in the patient population and the high-rate of dose reductions.
Synovial sarcoma (SS) is a rare and aggressive disease that accounts for 5%-10% of all soft tissue sarcomas. Although it can occur at any age, it typically affects younger adults and children, with a peak incidence in the fourth decade of life. In >95% of cases, the oncogenic driver is a translocation between chromosomes X and 18 that leads to the formation of the SS18::SSX fusion oncogenes. Early and accurate diagnosis is often a challenge; optimal outcomes are achieved by referral to a specialist center for diagnosis and management by a multidisciplinary team as soon as SS is suspected. Surgery with or without radiotherapy and/or chemotherapy can be effective in localized disease, especially in children. However, the prognosis in the advanced stages is poor, with treatment strategies that have relied heavily on traditional cytotoxic chemotherapies. Therefore, there is an unmet need for novel effective management strategies for advanced disease. An improved understanding of disease pathology and its molecular basis has paved the way for novel targeted agents and immunotherapies that are being investigated in clinical trials. This review provides an overview of the epidemiology and characteristics of SS in children and adults, as well as the patient journey from diagnosis to treatment. Current and future management strategies, focusing particularly on the potential of immunotherapies to improve clinical outcomes, are also summarized.
Vascular neoplasms account for a substantial fraction of cutaneous mesenchymal tumors, spanning from clinically indolent benign lesions to highly aggressive malignancies. These neoplasms present a distinctive challenge in terms of their diagnostic histopathology, both because of the breadth of their morphological manifestations and because of the significant histological overlap between different entities, even benign and malignant ones. The post-radiotherapy setting is particularly problematic diagnostically, insofar as radiation exposure predisposes not only to secondary angiosarcoma, but also to atypical vascular lesion, a largely benign proliferation of cutaneous blood vessels typically affecting the breast. To address these challenges, we explore the clinical, histological, and molecular features of malignant vascular neoplasia, including primary and secondary subtypes, through the comparative lens of atypical vascular lesion. In addition to highlighting the key morphological indicators of malignancy in superficial vasoformative tumors, we offer an approach that integrates clinical characteristics and molecular genetic profiling to facilitate accurate classification. With this current knowledge as our foundation, we also look ahead in an effort to frame some of the key unanswered questions regarding superficial vascular malignancies and their natural history, clinical management, and molecular underpinnings.
REGOBONE multicohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the cohort of patients with relapsed advanced or metastatic chordoma.
Patients with relapsed chordoma progressing despite 0-2 prior lines of systemic therapy, were randomised (2 : 1) to receive regorafenib (160 mg/day, 21/28 days) or placebo. Patients on placebo could cross over to receive regorafenib after centrally-confirmed progression. The primary endpoint was the progression-free rate at 6 months (PFR-6) (by RECIST 1.1). With one-sided α of 0.05, and 80% power, at least 10/24 progression-free patients at 6 months (PFR-6) were needed for success.
From March 2016 to February 2020, 27 patients were enrolled. A total of 23 patients were assessable for efficacy: 7 on placebo, 16 on regorafenib, 16 were men, median age was 66 (32-85) years. At 6 months, in the regorafenib arm, 1 patient was not assessable, 6/14 were non-progressive (PFR-6: 42.9%; one-sided 95% CI = 20.6) 3/14 discontinued regorafenib due to toxicity; and in the placebo arm, 2/5 patients were non-progressive (PFR-6: 40.0%; one-sided 95% CI = 7.6), 2 were non-assessable. Median progression-free survival was 8.2 months (95% CI 4.5-12.9 months) on regorafenib and 10.1 months (95% CI 0.8 months-non evaluable [NE]) on placebo. Median overall survival rates were 28.3 months (95% CI 14.8 months-NE) on regorafenib but not reached in placebo arm. Four placebo patients crossed over to receive regorafenib after centrally-confirmed progression. The most common grade ≥3 regorafenib-related adverse events were hand-foot skin reaction (22%), hypertension (22%), pain (22%), and diarrhoea (17%), with no toxic death.
This study failed to show any signal of benefit for regorafenib in patients with advanced/metastatic recurrent chordoma.
