Bevacizumab Results Offer Support for Upfront Therapy

Timothy Cloughesy, MD

Director Department of Neurology,

Neurological Services, and

Neuro-Oncology Program,

Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA

Several recent clinical trials have yielded positive data that may open up new treatment options for patients with glioblastoma, the most commonly diagnosed primary brain cancer in adults, and a tumor type where the prognosis remains poor.

In 2009, the FDA approved bevacizumab (Avastin) as a single agent for use in patients with glioblastoma whose disease progresses after prior therapy. Those results were based on data that showed objective responses in 19.6% to 25.9% of patients treated in two single-arm trials, according to the National Cancer Institute. Now, new research suggests that bevacizumab could be used as a front-line therapy when given in combination with another agent.

According to the results of the phase III AVAglio trial, patients with newly diagnosed glioblastoma who received bevacizumab in combination with radiotherapy and temozolomide experienced a median improvement in progression-free survival (PFS) of 4.4 months compared with patients who received only radiotherapy, temozolomide, and a placebo.

The results were presented at the 17th Annual Scientific Meeting & Education Day of the Society for Neuro-Oncology, held in November 2012 in Washington, DC.

“So far, we’ve really only known about the benefits as a single agent in the second line,” said Timothy Cloughesy, MD, one of the authors of the study. “We’ve always been hopeful that we could bring bevacizumab upfront in treatment, and this study gives us some evidence that we might be able to do just that.”

The link between glioblastoma and the vascular endothelial growth factor (VEGF) pathway has been known for many years, Cloughesy said. However, he explained that many drugs have difficulty penetrating the blood—brain barrier, so while they may be effective in theory, they are unable to halt or slow down the progression of disease unless they can enter the brain and have an effect on the tumor.

The AVAglio study was designed to determine whether a VEGF inhibitor, specifically bevacizumab, would have an isolated effect on survival. In all, 921 patients were randomized to either the bevacizumab combination (n = 458) or the control group (n = 463). “This study was designed to really try to answer the question of whether there’s a clear benefit upfront,” Cloughesy said.

In patients who received bevacizumab plus radiotherapy and temozolomide, the median PFS was 10.6 months compared with 6.2 months in the group that received only radiotherapy and temozolomide (HR = 0.64; 95% CI, 0.55—0.74; P < .0001), according to the analysis performed by the investigators. The interim results for overall survival (OS) did not reach statistical significance (stratified HR = 0.89; 95% CI, 0.75—1.07; P = .2135). Final OS data are expected to be available in 2013, according to Genentech, the manufacturer of bevacizumab.

Selected Patient Characteristics in the AVAglio Trial

Characteristic

RT/TMZ/Pib

(n = 463)

%

RT/TMZ/BEV

(n = 458)

%

Median age, yr (range)

56.0 (18-79)

57.0 (20-84)

Gender, male

64

62

WHO PS

0

52

50

1-2

48

50

RPA class

III

16

17

IV

60

57

V

23

26

Surgical status

Biopsy

10

13

Partial resection

48

46

Complete resection

42

41

KPS

50-80

30

33

90-100

70

67

BEV indicates bevacizumab; KPS, Karnofsky performance score; Pib, placebo; PS, performance status; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide; WHO, World Health Organization.

Mixed Results for Other Agents

Cloughesy said that the key to determining the true clinical benefit of that 4.4-month improvement is whether it had any effect on the quality of life of the patients involved. In an encouraging finding, the researchers reported that patients who received the bevacizumab combination therapy maintained a median Karnofsky performance score (KPS) ≥70 for a median of nine months compared with six months in the control arm. The median duration of improved or stable status with regard to physical functioning, motor functioning, and social functioning were all longer in the combination arm than in the control arm.In addition to the positive initial results from the AVAglio trial, other drugs designed to target and treat glioblastoma have met with varying levels of success. In December, the Geron Corporation halted development of their drug GRN1005, an experimental peptide drug conjugate that was being studied in patients who developed brain metastases from breast cancer. At the 2012 San Antonio Breast Cancer Symposium in December, an independent review of a phase II study showed that there were no intracranial responses among the first 30 evaluable patients in the trial.

However, Cloughesy said that another candidate, an immunotherapy agent called rindopepimut (CDX-110), looks promising. Celldex Therapeutics, the manufacturer of rindopepimut, is currently enrolling patients with newly diagnosed glioblastoma for a phase III study.

Cloughesy said one of the reasons rindopepimut seems particularly exciting is because it targets EGFRvIII, a variant of the endothelial growth factor receptor (EGFR), which occurs in approximately 20% to 30% of patients with glioblastoma.

“It’s not present in any other part of the body, which makes it a good target,” Cloughesy said.

The results of previous trials have been promising. The phase II ACTIII trial enrolled 65 patients who received rindopepimut as well as maintenance therapy with temozolomide. In that study, the median PFS was 12.3 months (P = .0088) and the median OS was 24.6 months (P <.0001), both of which were significantly higher than historical controls.

Additionally, the study found that patients with methylated O6-methylguanine- methyltransferase enzyme (MGMT) performed significantly better when compared with those patients who had nonmethylated MGMT. The median PFS was 17.5 months in the methylated MGMT patients (n = 25) compared with 11.2 months in the nonmethylated MGMT patients (n = 40; P = .0057). The median OS was 32.3 months in the methylated patients compared with 20.9 months in the nonmethylated patients (P = .0067).

“All previous data have shown that specific populations of patients tend to do much better when they receive this vaccine,” Cloughesy said.

Chinot O, Wick W, Mason W, et al. Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: mature progression-free survival and preliminary overall survival results in AVAglio. Neuro Oncol. 2012; 14:vi101-vi105. Abstract OT-3.