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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
Reference:
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.
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The primary objective of this study was to evaluate response rate after two cycles of vincristine plus irinotecan with or without temozolomide. The study was well-designed with centrally reviewed response using 3-D volumetric assessment of the primary tumor, while REECIST 1.1 was used for metastatic sites.
All patients had measurable disease. This was an all-comers study but the majority (76%) were in first relapse.
Importantly, local control could be offered relatively early in this study; 43% of patients assigned vincristine-irinotecan and 36% of those assigned vincristine-irinotecan plus temozolomide went on to receive local control before progression.
The statistical analysis is important because both arms of the study were powered to compare against a null hypothesis. The initial null hypothesis was a response rate less than 20%. Then more patients were added to compare against a new null hypothesis of a response rate greater than 35%.
The response rate after two cycles among relapsed patients was 33% with vincristine-irinotecan and 47% with vincristine-irinotecan plus temozolomide, statistically better than the 35% efficacy bar established a priori (P = .045). However, caution must be taken when comparing the two populations against each other, as this is not how the study was initially powered.
One of the more intriguing observations about this study is that the potential of adding temozolomide could have a PFS or OS benefit. However, it is important to remember that the study was not sufficiently powered for these assessments to be considered definitive. Other variables may have factored into outcomes, such as differences in local control, tumor burden or number of recurrences. OS and PFS were secondary objectives that should be considered exploratory in nature. They are very interesting but they are not yet definitive.
So what is the role of temozolomide in rhabdomyosarcoma? We know the drug probably has limited single-agent activity in this setting, although it has not been thoroughly studied as a single agent. There has been reported activity in small trials that combined temozolomide, irinotecan and vincristine, although most patients had not had prior irinotecan.
Importantly, in the recently published Children’s Oncology Group (COG) ARSTO8P1 study of patients with newly diagnosed metastatic rhabdomyosarcoma, 71 patients received temozolomide with vincristine and irinotecan in six of their 18 cycles of therapy, and there was no improvement in outcomes among these patients compared with historical controls.
So what conclusions can be made from this study? The response rate was numerically higher for vincristine, irinotecan and temozolomide in relapsed rhabdomyosarcoma, but it came at a cost with a modest increase in hematologic toxicity.
The exploratory data that suggest improved outcomes are very intriguing but need to be confirmed. It is a little uncertain regarding how to reconcile the role of temozolomide in general for people with this disease — particularly high-risk patients, as the highest-risk patients did not seem to benefit from the addition of temozolomide in the recently published COG study. Having said that, that is a tough [group of patients to treat] and we have not identified other agents that can improve outcomes for those patients.
It also is uncertain how the data from this study should be applied to patients — like many in the United States — who receive irinotecan upfront. If these patients relapse, do you go back and treat with temozolomide and irinotecan, or do you move on to something they haven’t seen yet? For patients with rhabdomyosarcoma who do not receive irinotecan as part of their standard therapy, this does seem like a potentially attractive option for recurrent disease.
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