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 when participating in the study, 20 patients received local treatment, 5 of which 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.

Reference

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

Comments are closed.