Vincristine/Irinotecan Plus Temozolomide Shows Improved Efficacy in Relapsed/Refractory Rhabdomyosarcoma

According to the European Pediatric Soft Tissue Sarcoma Group, the addition of temozolomide to vincristine and irinotecan appears to be a new standard of care for adult and pediatric patients with relapsed/refractory rhabdomyosarcoma.

The efficacy of chemotherapy was improved by the addition of temozolomide (Temodar) to vincristine (Marqibo) and irinotecan (Onivyde; VIT) compared to VI alone for patients with relapsed/refractory rhabdomyosarcoma and may represent a new standard of care, according to results of a phase 2 study (NCT01355445) published in the Journal of Clinical Oncology.

The objective response rate (ORR) after 2 cycles of VIT treatment was 44% (n = 24) and 31% (n = 18) in the VI arm (n = 18; adjusted OR 0.50; 95% CI 0.22- 1.12, P = 0.09). The VIT arm also experienced better overall survival (OS) compared to VI (adjusted HR, 0.55; 95% CI, 0.35-0.84; P = 0.006. Treatment with VIT was also associated with a reduction in the risk of progression from relapse being almost statistically significant (adjusted HR 0.68; 95% CI 0.46-1.01; P=0.059) In terms of progression-free survival, investigators identified benefit with VIT versus VI (adjusted HRPFS 0.64 95% CI 0.42-0.98; P = 0.039), as well as stable and significant OS (adjusted HROS 0.59; 95% CI 0.37-0.93; P = 0.02) In addition, investigators observed more objective responses in the VIT arm (57% ; n = 33) compared to the VI arm (38%; n = 22; adjusted OR 0.40; 95% CI 0.18-0.88; 2-sided P = 0.023).

“The [European pediatric Soft Tissue Sarcoma Group] recently launched its new multi-arm, multi-stage frontline and fallback [relapsed or refractory rhabdomyosarcoma] study, and VIT will be the new standard control arm in relapsed patients. Depending on the expected combination toxicity, the experimental arms will contain a VI or VIT backbone, combined with innovative agents,” said study researchers.

This phase 2 study enrolled 120 patients randomized to the VI arm (n = 60) or the VIT arm (n = 60). Patients were treated with vincristine at a dose of 1.5 mg/m2 daily on days 1 and 8, as well as 50 mg/m2 irinotecan once daily on days 1 through 5. In addition, those in the VIT arm received temozolomide at 125 mg/m2 once daily on Days 1 through 5 and 150 mg/m2 daily from Cycle 2. Patients were treated in 21 day cycles until disease progression or unacceptable toxicity.

The researchers initially planned to use a Simon 2-phase study design to analyze 40 patients individually. After expanding the sample size to 120, a comparison between arms and correction for confounding factors was added to the statistical plan.

Patients had a median age of 11 years (range 0.75-45) and 89% of the population had relapsed disease at enrollment.

The primary endpoint of the study was ORR at 2 cycles, with the major secondary endpoints being best response, PFS, OS and adverse events.

The median follow-up was 57 months. Researchers reported that 104 patients showed disease progression or relapsed, and 91 patients died.

A total of 55 patients developed progressive disease and had to discontinue treatment early, and 13 patients discontinued due to toxicity. Researchers identified a non-significant trend in fewer early terminations due to progression and more due to toxicity in the VIT arm (P = 0.30). In addition, 16 patients received 12 or more cycles of VIT or VI.

Additional systemic therapy was administered to 17 patients after they discontinued VI or VIT and before progression, including 23% (n = 13) of those in the VIT arm and 7% (n = 4) of those in the VI arm (P = .02). Of those who had local or locoregional disease at the time of study entry, 20 patients received local treatment, 5 of whom had surgery only, 7 only radiotherapy, and 8 both; no significant differences were noted in the study groups (P = .65).

Grade 3 or greater adverse reactions occurred in 98% of patients in the VIT arm compared to 78% in the VI arm (P=0.009). In addition, 93% of patients in the VIT arm had adverse events related to study treatment, compared to 69% in the VI arm (P = 0.002). In addition, 38% of patients in the VIT arm had a significant excess of serious adverse events compared to 19% in the VI arm (P = 0.023).

Severe haematological toxicity was reported in 81% of patients in the VIT arm compared to 61% in the VI arm (P = 0.025). Grade 3 or higher adverse reactions in the VIT and VI arms, respectively, included diarrhea (24% vs. 17%; P = 0.33), as well as nausea or vomiting (26% vs. 17%; P = 0.24). Researchers reported that there were no study-related deaths.


Defachelles AS, Bogart E, Casanova M, et al. Randomized phase II trial of vincristine irinotecan with or without temozolomide, in children and adults with relapsed or refractory rhabdomyosarcoma: a European study group for pediatric soft tissue sarcoma and innovative therapies for children with cancer. J Clin Oncol. 2021;39(27):2979-2990. doi:10.1200/JCO.21.00124

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