In a double-blind, placebo-controlled, comparative, 1:1 randomised phase II EREMISS study, regorafenib as maintenance therapy met its primary endpoint and improved progression-free survival (PFS) in patients with non-adipocytic soft tissues sarcomas (STS), and delayed starting of a further systemic treatment.
This was associated with a non-significant trend in overall survival (OS) improvement, but this study was not designed to ensure a sufficient power for the comparison of OS according to Prof. Nicolas Penel of the Lille University and Department of Medical Oncology, Centre Oscar Lambret in Lille, France and colleagues, who published the findings on 8 April 2025 in the Annals of Oncology.
The authors wrote in the background that for most patients with advanced STS, the treatment goal is to delay disease progression and maintain the quality-of-life. Doxorubicin (or anthracycline) chemotherapy has remained the first-line standard-of-care even in 2024. Beyond that, approved options are limited with only eribulin that has marginally improved OS in patients with liposarcomas. In this context, the question of a maintenance treatment is relevant, but only few studies have explored the value of maintenance treatment in this setting.
Regorafenib is an oral multikinase inhibitor that can interfere with many oncogenic pathways, especially angiogenesis, and its activity has been demonstrated in different studies in various sarcoma subtypes, except in liposarcomas. Based on these data, the EREMISS investigators aimed to explore the benefit of maintenance treatment with regorafenib in patients with non-progressing advanced non-adipocytic STS after a first-line doxorubicin-based chemotherapy in a randomised trial.
Regorafenib 120 mg/day, 3 weeks on, 1 week off schedule was offered to patients with stable disease or partial response after 6 cycles of doxorubicin-based chemotherapy as first-line treatment for advanced disease. The primary endpoint was PFS according to RECIST v1.1 evaluated by blinded central review (BCR). Based on the following assumptions: PFS (placebo) = 4 months, expected PFS (regorafenib) = 7 months, hazard ratio (HR) 0.57, 1-sided α = 0.05 and β = 0.10, 110 events and 126 patients were required.
The study population consisted of 126 patients enrolled in 17 centres from May 2019 to November 2022. Female patients accounted for 55% of total enrolment. The median age was 58 years (range, 18-85). The most common histological subtype was leiomyosarcoma (59%). The primary objective was assessable in 122 patients (109 events).
Median PFS by BCR was 3.5 in placebo arm versus 5.6 months in regorafenib arm (HR 0.53; 95% confidence interval [CI] 0.36-0.78; p = 0.001). Median OS was 20.5 versus 27.6 months (HR 0.78; 95% CI 0.50-1.22; p = 0.28).
Despite of the reduced dose, regorafenib caused notable adverse events, which nature and frequency were in line with the well-known safety profile of regorafenib. The proportion of patients with Grade ≥ 3 adverse events was 4.8% in placebo arm versus 56.3% in regorafenib arm. The most common Grade ≥ 3 clinical adverse events in regorafenib arm were asthenia (9%), arterial hypertension (8%), and rash (8%).
The authors commented that in the present study, the subgroup analysis did not identify any difference between leiomyosarcoma, undifferentiated pleomorphic sarcoma and others, but the sample sizes were limited and other sarcomas included 14 different entities.
They concluded that this study demonstrated that maintenance treatment with regorafenib improved PFS with PFS benefit being associated with a significant delay of further line of treatment. Two avenues on how to go beyond these results are better patient selection and probably re-discussing the overall therapeutic strategy.
The study was funded by the French National Cancer Institute, patient advocacy group AMELIORE LA VIE, and Bayer HealthCare.
Reference
Penel N, Italiano A, Wallet J, et al. Regorafenib as maintenance therapy after first-line doxorubicin-based chemotherapy in advanced non-adipocytic soft tissue sarcomas patients: a double-blind randomised trial. Annals of Oncology; Published online 8 April 2025. doi: https://doi.org/10.1016/j.annonc.2025.03.024.