Addition of temozolomide to vincristine, irinotecan may improve outcomes in relapsed rhabdomyosarcoma
CHICAGO — The addition of temozolomide to vincristine and irinotecan may improve outcomes among children and adults with relapsed or refractory rhabdomyosarcoma, according to results of a randomized phase 2 study presented at ASCO Annual Meeting.
“We observed a nearly significant PFS benefit, and a large and significant OS benefit, with the [temozolomide] regimen,” Anne Sophie Defachelles, MD, pediatric oncologist at Centre Oscar Lambret in Lille, France, said during her presentation. “The efficacy of the combination of temozolomide with vincristine and irinotecan was sufficient to accept excess toxicity.”
Although the combination of vincristine and irinotecan has demonstrated activity among patients with relapsed rhabdomyosarcoma, outcomes for these patients remain poor.
Defachelles and colleagues hypothesized that the addition of temozolomide could confer benefit due to its different resistance mechanisms and distinct toxicity profile.
The international, open-label VIT-0910 trial included 120 patients (median age, 11 years; range, 0.75-46) with relapsed or refractory rhabdomyosarcoma.
Investigators recruited patients from 37 European centers between March 2012 and April 2018. The majority (89%) had relapsed rhabdomyosarcoma.
The study initially followed a Simon’s optimal two-stage design, with a total of 80 patients whose randomization was stratified by disease status (relapsed vs. refractory) and country.
In October 2015, after an analysis of the first 80 patients, the independent data monitoring committee recommended an additional 40 patients — only with relapsed disease — be recruited. Randomization of these patients controlled for prior radiotherapy, staging (locoregional vs. metastatic) and country.
In 2018, another amendment prior to the final analysis allowed for comparison of the randomized groups, with adjustments for predefined confounding factors.
Researchers assigned half (n = 60) of enrolled patients to vincristine 1.5 mg/m2 on day 1 and day 8, and irinotecan 50 mg/m2 and temozolomide 125 mg/m2 on days 1 through 5. The temozolomide dose increased to 150 mg/m2 beginning in the second treatment cycle for patients who did not experience grade 2 or higher toxicity.
The other 60 patients received vincristine and irinotecan alone.
Treatment continued in 21-day cycles until disease progression or unacceptable toxicity.
Centrally reviewed objective response rate after two cycles — based on WHO response criteria for primary lesions and RECIST 1.1 criteria for metastatic sites — served as the primary endpoint.
Secondary endpoints included PFS, OS and adverse events.
Researchers reported a higher ORR among temozolomide-treated patients in both the overall study population (44% vs. 31%; adjusted OR = 0.5; 95% CI, 0.22-1.12) and the subgroup of patients at relapse (47% vs. 33%; adjusted OR = 0.53; 95% IC, 0.23-1.22), but the differences did not reach statistical significance.
Results showed a slight improvement in PFS with temozolomide (median, 4.7 months vs. 3.2 months; HR = 0.68; 95% CI, 0.46-1.01) but, again, the difference did not reach statistical significance.
However, researchers reported a statistically significant and clinically meaningful improvement in OS among patients assigned temozolomide (median, 15 months vs. 10.3 months; adjusted HR = 0.55; 95% CI, 0.35-0.84).
Toxicity was significantly higher in the temozolomide group. However, most adverse events were manageable, Defachelles said.
Patients assigned temozolomide more frequently experienced grade 3 or higher adverse events (all events, 98% vs. 78%; treatment-related events, 93% vs. 69%) or serious adverse events (all events, 48% vs. 43%; treatment-related events, 38% vs. 19%). However, only hematologic toxicity was significantly higher in the vincristine group (81% vs. 59%; OR = 1.36; 95% CI, 1.06-1.76).
Temozolomide plus vincristine and irinotecan is now standard treatment in Europe for relapsed rhabdomyosarcoma, Defachelles said. – by Mark Leiser
Defachelles AS, et al. Abstract 10000. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Defachelles reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.