Adding temozolomide to a combination of vincristine and irinotecan (VIT) improved tumor response and survival in patients with relapsed or refractory rhabdomyosarcoma in a European phase II trial.

In the trial of over 100 patients, the group who received temozolomide had a numerically improved objective response rate (ORR) after two cycles of treatment versus the group treated with vincristine and irinotecan (VI) alone (44% vs 31%, respectively) and improved overall survival (OS) as well (adjusted hazard ratio [aHR] 0.55, 95% CI 0.35-0.84), reported Anne-Sophie Defachelles, MD, of Centre Oscar Lambret in Lille, France, and colleagues.

“VIT is considered the new standard treatment in these patients … and will be the control arm in the next randomized trial,” the team wrote in the study online in the Journal of Clinical Oncology.

Rhabdomyosarcoma is a rare cancer that forms in the soft tissue and affects mostly children, although it can occur at any age. The researchers noted that for patients who relapse after initial treatment, rhabdomyosarcoma is generally refractory to treatment, with an OS rate of less than 20%, and new systemic therapies are therefore “urgently needed.”

The VIT-0910 trial by the European Paediatric Soft Tissue Sarcoma Group and the Innovative Therapies for Children with Cancer Consortium was designed to test combinations of chemotherapy in the relapsed/refractory setting.

The researchers enrolled 120 patients from 2012 to 2018 from 37 European centers — 60 in each arm. Median age was 11 years (range of 9 months to 45 years), and 89% of patients had relapsed rhabdomyosarcoma.

The trial was originally planned to compare ORR in two arms of 40 patients, but was amended to increase accrual to 120 patients to test differences in OS and progression-free survival (PFS).

Patients received 21-day cycles combining vincristine (1.5 mg/m² on days 1 and 8) and irinotecan (50 mg/m² daily from days 1 to 5) with or without temozolomide (125 mg/m² daily on days 1 to 5, and then 150 mg/m² daily starting at the second cycle), until progression or unacceptable toxicity.

With a median follow-up of 57 months, there were 104 reported disease progressions or relapses, and 91 deaths. VIT was associated with a “near significant” PFS improvement (aHR 0.68, 95% CI 0.46-1.01), the researchers noted.

Regarding relapsed patients only, the ORR after two cycles was 47% in the VIT arm and 33% in the VI arm, a non-significant edge, while the aHRs for PFS and OS were 0.68 (95% CI 0.45-1.03) and 0.57 (95% CI 0.36-0.90), respectively.

A significantly higher number of patients had grade 3 or higher adverse events in the VIT group compared with the VI group (98% vs 78%), which included a significant excess of hematological toxicity (81% vs 61%), the investigators said.

“Although toxicity was deemed manageable in the VIT arm, the increased VIT toxicity raises the question of whether it is possible to add new targeted therapy or immunotherapy to this chemotherapy backbone,” Defachelles and co-authors wrote. “Such combinations should be tested in experienced early phase centers.”

Compliments but Some Concerns by Editorialist

In an accompanying editorial, Abha A. Gupta, MD, MSc, of the Hospital for Sick Children in Toronto, praised the authors for accomplishing a randomized trial in such a rare and “enigmatic” disease, and pointed out that having data confirming whether VIT is the superior choice over VI is “relevant and impactful.”

She noted, however, that when the team amended the trial to increase accrual and formally test PFS and OS, the study committee did not change the design to account for differences in subsequent therapy and local control.

Gupta also suggested that the study may have overstated the OS benefit in the VIT arm. Defachelles and co-authors had acknowledged that one of the limitations of the study was that a higher proportion of patients received additional chemotherapy after the end of the study treatment and before progression in the VIT arm compared with the VI arm, which could confuse the interpretation of survival outcomes. The OS results, therefore, “should be interpreted with care,” the study authors wrote.

Gupta noted that a majority of patients in the trial presented with local or regional relapse, a percentage that was similar in both arms. However, twice as many patients in the VIT arm received some form of local control, either radiation and/or surgery, following disease progression.

“In this context, one cannot attribute any survival benefit to VIT chemotherapy alone,” she said. “Relapsed [rhabdomyosarcoma] can be considered an ultra-rare sarcoma, and to conduct a randomized trial in this population is a monumental feat,” Gupta concluded. “The authors again should be congratulated on this; however, the precision of trial design should not be compromised (i.e., accurate definition of endpoints), and more importantly, data interpretation not overstated.”