MONTREAL – Bevacizumab-containing regimens continued to show efficacy against glioblastoma in recent reports of phase II trial results, but the trials' designs have come under fire by some neuro-oncologists.
Investigators from Duke University, Durham, N.C., reported at the meeting that adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls.
In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7 months with irinotecan), but the difference was not significant.
In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.
Newly Diagnosed in Duke Study
The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university's brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.
Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m
In the second phase of the trial, 113 patients went on to receive 6–12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m
The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi: 10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.
Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.
A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.
Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.
For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.
RTOG Trial in Recurrent GBM
The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75–100 mg/m
The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.
“The primary objectives were met,” he reported. “We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target.”
Trials' Protocols Criticized
Both study designs were challenged at the meeting.
Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.
“It's flatly outrageous. It should not have been done,” Dr. van den Bent elaborated in an interview after the session. “What I find very disturbing is they did a very big study of 120 patients … but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference.”