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Adjuvant temozolomide prolongs OS, PFS in certain patients with anaplastic glioma
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CHICAGO — Twelve cycles of adjuvant temozolomide extended OS and PFS among patients with newly diagnosed anaplastic glioma without 1p/19q co-deletion, according to early results from the phase 3 CATNON trial presented at the ASCO Annual Meeting.
“Anaplastic glioma is an orphan disease, with 1,250 to 1,500 patients diagnosed each year in the United States,” Martin J. van den Bent, MD, professor of neuro-oncology at Erasmus MC Cancer Institute in Rotterdam, the Netherlands, said during a press conference. “So, it took the collaboration of many cooperative groups to enroll the number of patients required for the study.”
Patients with anaplastic glioma and 1p/19q co-deletion benefit from chemotherapy, but its efficacy in patients without the 1p/19q co-deletion had not been established.
Van den Bent and colleagues screened 1,407 adults from 12 countries with newly diagnosed WHO grade 3 glioma to evaluate the use of chemotherapy with temozolomide. From that cohort, they enrolled 748 patients determined not to have 1p/19q co-deletion.
All patients received 59.4 Gy radiation in 33 fractions. Using a 2 x 2 factorial design, van den Bent and colleagues randomly assigned patients to one of four arms: radiation alone (arm 1); radiation concurrently with 75 mg/m2 temozolomide (arm 2); radiation followed by 12 cycles of 150 mg/m2 to 200 mg/m2 adjuvant temozolomide on days 1 to 5 of each week for 4 weeks (arm 3); or radiation with concurrent temozolomide plus 12 cycles of adjuvant temozolomide (arm 4).
Although the trial was designed to evaluate the use of concurrent and adjuvant chemotherapy, follow-up on the use of concurrent chemotherapy continues.
In total, 373 patients received adjuvant temozolomide (arms 3 and 4) and 372 patients did not.
OS served as the study’s primary endpoint.
After a median follow-up of 27 months, researchers conducted an interim analysis based on 221 events (41% of planned events).
Results showed adjuvant temozolomide reduced risk for mortality (HR = 0.67; 95% CI, 0.51-0.88). Patients who received adjuvant temozolomide achieved longer median OS (not reached vs. 41.1 months) and were more likely to survive 5 years (55.9% vs. 44.1%).
Adjuvant temozolomide also significantly prolonged PFS (42.8 months vs. 19 months; HR = 0.58; 95% CI, 0.47-0.72).
“We did not expect anything to come out of this interim analysis, because usually these trials take a long time to produce a positive result,” van den Bent said. “We were completely taken by surprise when the independent data monitoring committee that looked into the data recommended the release of the data. We had at no point in time anticipated this outcome.”
Seventy-four percent of patients were evaluated for MGMT promoter methylation status, and 42% had methylated MGMT. Methylated MGMT appeared prognostic for OS (HR = 0.54; 95% CI, 0.38-0.77). However, researchers could not determine whether methylated MGMT predicted benefit from adjuvant temozolomide.
“We know now that temozolomide given after radiation therapy improves survival in this disease,” van den Bent said. “Because of this, this trial has become a practice-changing trial. These findings should expand treatment choices and change the way we treat patients with this rare form of brain cancer.”
Final data from the study are expected in 2020, according to researchers. – by Alexandra Todak
Reference:
van den Bent MJ, et al. Abstract LBA2000. Presented at: ASCO Annual Meeting; June 3-7, 2016.
Disclosure: Schering Plough/Merck Sharpe & Dohme provided funding for the study and provided temozolomide. Van den Bent reports consultant/advisory roles with, as well as honoraria or research funding from, AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Celldex, Merck, Novocure and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Andrew B. Lassman, MD
This trial was conducted through the publically funded cooperative group mechanism, not a pharmaceutical industry-sponsored trial, and this demonstrates the value and retained importance of the cooperative group system in the conduct of practice-changing trials.
Anaplastic gliomas are a slightly less aggressive variety of glioblastoma, the most common type of primary brain tumor in adults. We previously had level-one evidence that patients with glioblastomas benefit from temozolomide. Until now, we did not have the same type of evidence for anaplastic gliomas, particularly those thought to be relatively insensitive to chemotherapy because they lack a particular biomarker called 1p19q co-deletion. This phase 3 trial proved that adjuvant temozolomide given after radiotherapy prolongs survival in anaplastic gliomas that do not harbor 1p19q co-deletion.
Because the data are not yet mature enough, we still do not know whether patients, in addition to benefitting from adjuvant temozolomide after the radiation ends, also benefit from concurrent temozolomide plus radiotherapy. We will have to wait for these results.
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Don S. Dizon, MD, FACP
This illustrates very nicely the theme of this years meeting: collective wisdom. Even more than that, it illustrates that even within a rare tumor type, and while using standard chemotherapy it is very important that we still can select patients most likely to benefit from treatment. At the same time, we can spare patients toxicities from a therapy from which they are unlikely to benefit.
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