“In a disease in which most patients at an advanced stage are incurable – with 5-year survival rates of less than 30% – we are seeing promising results from early studies,” says Professor Uta Dirksen from University Hospital Essen, Germany commenting on some data presented at the ESMO Virtual Congress 2020.
In a phase I study in adult and paediatric patients with recurrent/refractory Ewing sarcoma, the anti-ETS agent TK216 combined with vincristine led to a clinical benefit rate of 64% (Abstract 1620O). At the recommended phase II dose (200 mg/m2/day), 2 out of 15 (13%) patients achieved a complete response and 5 (33%) experienced stable disease.
“Conventional combined-modality treatment reduces tumour burden but fails to eradicate residual cancer cells and improvements with novel agents have so far not been seen. Novel therapies with a different mechanism of action from conventional chemotherapy, such as TK216, are required to eliminate dormant and chemoresistant cells.” Haematological toxicity, fatigue and vincristine-related neurotoxicity were reported in the trial.
Modest antitumour activity was reported in the phase II REGOBONE study of the receptor tyrosine kinase inhibitor regorafenib versus placebo in 41 patients with metastatic/relapsed Ewing Sarcoma (Abstract LBA68). Non-progression rate at 8 weeks– the primary endpoint – was 57% with regorafenib versus 8% with placebo, and median PFS was 11.4 months versus 3.9 months, respectively. In the regorafenib group, 5 patients had a partial response (PR; 22%) and 11 (48%) had stable disease, and the safety findings were as expected.
Another study (phase Ib) reported that a combination of trabectedin – a chemotherapy agent that binds to the minor groove of DNA – and the PD-L1 inhibitor durvalumab was associated with tumour shrinkage in 43% of patients with unresectable or metastatic pre-treated soft tissue sarcoma (Abstract LBA67). One PR was reported, leading to an objective response rate of 7.1% and 6-month progression-free rate of 29%. The main drug-related grade 1–2 adverse events (AEs) were nausea (15.1%) and fatigue (11.3%). Notably, two fatal AEs occurred. Dirksen cautions that the clinical relevance of the results remains to be determined. “The data presented do not appear to demonstrate an advantage of the combination over the already good responses reported with trabectedin monotherapy in the literature,” she says. She also suggests that the importance of the toxicity profile will depend on the setting. “Quality of life is paramount in the palliative setting, so nausea and fatigue may be problematic. However, should a treatment provide a curative approach, then a greater degree of toxicity may be more acceptable to the patient.”
According to the expert, the responses from these studies in a small group of heavily pre-treated patients with sarcoma are encouraging. However, other trials are now needed to confirm these results in larger patient cohorts.
In terms of further improving the treatment of sarcoma, Dirksen thinks that one focus should be to bring these types of drugs to the first-line setting. “However, a major barrier is the lack of availability of new treatments for our young patients,” she adds. “Drug development and testing of new agents is fostered in adult cancers and the lack of trials in children – where rare, highly aggressive malignancies occur – is very frustrating. Importantly, data from trials in adults do not necessarily predict outcomes in children or adolescents. The main concern in children relates to the late effects of treatment. However, given the poor prognosis of disseminated and relapsed Ewing sarcoma, the prevention of late effects is unfortunately currently not an issue. As the course of disease in young patients differs from adult cancer, there is an urgent need to test the efficacy and safety of new treatments in parallel in children,” she concludes.
Abstracts and sessions details
-
Ludwig JA et al. Phase I study of TK216, a novel anti-ETS agent for Ewing sarcoma. ESMO Virtual Congress 2020, Abstract 1620O
Proffered Paper – Sarcoma, 20.09.2020, h. 16:20 – 18:00, Channel 1
-
Toulmonde M, et al. Tramune, a phase Ib study combining trabectedin and durvalumab, results of the expansion cohort in patients with advanced pretreated soft tissue sarcomas. ESMO Virtual Congress 2020, Abstract LBA67
Proffered Paper – Sarcoma, 20.09.2020, h. 16:20 – 18:00, Channel 1
-
Duffaud F, et al. Results of the randomized, placebo (PL-) controlled phase II study evaluating the efficacy and safety of regorafenib (Reg) in patients (pts) with metastatic relapsed Ewing Sarcoma (ES), on behalf of the French Sarcoma Group (FSG) and Unicancer. ESMO Virtual Congress 2020, Abstract LBA68
Proffered Paper – Sarcoma, 20.09.2020, h. 16:20 – 18:00, Channel 1
