Benefit of Bevacizumab in Glioblastoma Under Discussion

Zosia Chustecka

February 19, 2014

The clinical benefit of adding bevacizumab (Avastin, Genentech/Roche) to standard therapy for newly diagnosed glioblastoma is being discussed again with the publication of 2 clinical trials in the February 20 issue of the New England Journal of Medicine.

Because of some contrasting results, the US Food and Drug Administration (FDA) has reportedly been asked to review the 2 studies.

At present, the FDA approval for bevacizumab is for use as monotherapy in recurrent glioblastoma, whereas these studies cover its use in newly diagnosed glioblastoma, which could be a new indication for the drug. Japan has recently approved both indications, but Europe has not approved either.

Results from these 2 pivotal studies — the Avastin in Glioblastoma (AVAglio) trial and the Radiation Therapy Oncology Group (RTOG) 0825 trial — were presented at the annual meeting of the American Society of Clinical Oncology in June 2013, and triggered a heated debate, as reported in detail at the time.

Both of the trials were similar in design, with bevacizumab being added to best standard therapy (radiation and temozolomide).

Both had similar primary outcomes, showing a 3- to 4-month prolongation of progression-free survival (from around 6 to 7 months with standard therapy to 10 months with the addition of bevacizumab), but no significant effect on overall survival (around 16 months).

However, the 2 trials showed "strikingly different" quality-of-life data, Howard Fine, MD, from the New York University Cancer Institute in New York City, commented at the meeting. He was not involved in either trial, and acted as a discussant.

"RTOG showed worsened patient-reported symptom burden and worsening neurocognitive function with bevacizumab. By contrast, the AVAglio trial showed the exact opposite — improved quality of life, prolonged Karnofsky Performance Scale scores, and reduced doses of steroids," he said.

Now, writing in an accompanying editorial, Dr. Fine says that subtle differences between the 2 trials could have influenced these data, but "the true reason for the difference remains an enigma."

This discrepancy is neither trivial nor academic. Dr. Howard Fine

"This discrepancy is neither trivial nor academic," he states.

"If bevacizumab is associated with an increase in and maintenance of quality of life and performance status, then a strong argument can be made for its use as part of the initial treatment of glioblastoma regardless of its effects on survival," he writes.

"By contrast, if bevacizumab is associated with worsening neurocognitive function, then its use as part of initial therapy cannot be widely advocated, especially in light of its questionable effects on survival," he adds.

Dr. Fine says the investigators of both trials need to share their raw data with each other and with independent investigators (including the FDA) to try to resolve the question of true effects of bevacizumab on quality of life and neurocognitive function.

He also suggests that further trials are needed, and indeed are ongoing, as there is "still much to learn," especially about how and when the drug should be used "in this population of patients for whom so few treatment options currently exist."

"Despite its limitations, bevacizumab remains the single most important therapeutic agent for glioblastoma since temozolomide," Dr. Fine comments.

Japan Alone at This Point

Japan is the first, and so far only, country to approve the use of bevacizumab in newly diagnosed glioblastoma in combination with radiotherapy and temozolomide chemotherapy. The drug is also approved for use as monotherapy for recurrent glioblastoma, and certain other types of high-grade glioma after previous therapy.

The Japanese approval was based on the AVAglio study, the phase 2 BRAIN study, and a Japanese phase 2 study (JO22506).

Ryo Nishikawa, MD, professor and chair of neuro-oncology and neurosurgery at the Comprehensive Cancer Center, International Medical Center at Saitama Medical University, in Japan, and an investigator on the AVAglio trial, has told Medscape Medical News that usually approval is based on overall survival, but the "situation in glioblastoma is a bit different."

"Because survival in glioblastoma is quite limited, 3 or 4 months of progression-free survival is significant for patients," Dr. Nishikawa said.

Roche (which markets the drug outside the United States) says it has filed for front-line use of bevacizumab in glioblastoma in the European Union and in Switzerland. Genentech, which markets it in the United States, says it is discussing the data with regulatory authorities.

AVAglio Results Support Upfront Use

Lead investigator of the AVAglio study, Olivier Chinot, MD, head of the Neuro-oncology Department at University Hospital Timone, Marseille, France, believes that the data from this study support use of bevacizumab in the upfront setting.

He highlighted the magnitude of the progression-free survival increase (from 6.2 to 10.6 months; P < .001), which he noted "was reinforced by independent review of imaging," and also the maintenance of clinical measures such as functional status and quality of life. However, he also noted the increase in adverse events.

Dr. Chinot told Medscape Medical News that his message to clinicians is that the addition of bevacizumab to radiation and temozolomide does not produce a new standard of treatment, but it "represents a real option to be discussed with patients."

"Considering the documented activity of bevacizumab and my personal experience in patients with glioblastoma, I really think that bevacizumab is the first active drug that we have since temozolomide for patients with malignant glioma, and so access to this drug is of major importance," Dr. Chinot said.

"It is difficult to anticipate the European Medicines Agency decision, particularly with the lack of overall survival benefit," he said, but he is hopeful for approval.

At present, bevacizumab is not approved for use in glioblastoma in the European Union, but as the drug is marketed for other cancers, including colon and lung, there is some use of it off-label. However, this use is irregular and very variable across countries; some centers and patients have access, others do not, he said.

Much work is still needed in order to try to identify the patients that benefit most from bevacizumab, Dr. Chinot said. This is also seen in other cancer types, with experience showing that "the benefit of bevacizumab is very heterogenous."

Another expert approached by Medscape Medical News, Henry Friedman, MD, from the Duke University Medical Center in Durham, North Carolina, agrees. He also believes that the AVAglio study supports the use of bevacizumab in newly diagnosed glioblastoma because of the increase seen in progression-free survival, and also because the quality of life was maintained and a reduction in steroid use was reported.

He added: "I have grave concerns about the statistical analysis used in the RTOG 0825 study."

In an editorial he cowrote recently in CNS Oncology (2014;3[1]:1-3), he said the results from the 2 trials were "so different and confusing" that it led Max Wallace, executive director of the Accelerate Brain Cancer Cure advocacy group, to ask for an FDA review of both trials, which is now eagerly awaited.

The subject of bevacizumab in glioblastoma has inflamed "strong passions" as experts argue over the interpretation of the data, but there are several basic facts that are immutable, Dr. Friedman and colleague Annick Desjardins, MD, write in their editorial.

"Bevacizumab works in the treatment of recurrent glioblastoma," they state. (Dr. Friedman headed the phase 2 trial that led to the 2009 FDA accelerated approval for use in recurrent disease). However, not all patients benefit, and at present there is no way to identify those who might, they add.

It also increases progression-free survival in newly diagnosed disease, but it may or may not enhance or worsen quality of life and neurocognition in these patients, they continue.

"In our opinion, it will enhance survival in specific cohorts of newly diagnosed and recurrent glioblastoma patients," they predict.

Dr. Friedman said his center uses bevacizumab in patients with recurrent glioblastoma and that they also use the drug in newly diagnosed patients who are participating in clinical trials and those with bulky residual disease after surgery, in whom it is used off-label.

RTOG 0825 Does Not Support Upfront Use

However, the principal investigator of the other trial, Mark Gilbert, MD, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, said that the RTOG 0825 results do not support the use of bevacizumab upfront in glioblastoma.

Although the RTOG 0825 trial showed a similar improvement in progression-free survival (from 7.3 to 10.7 months), in this study the difference did not "reach the prespecified improvement target," the researchers comment.

"Even though the P value was .007, it did not reach our predetermined definition of significance," Dr. Gilbert explained at the ASCO meeting. "We decided that we would weight it more toward overall survival," he said. Therefore, the researchers chose a P value of .05 for statistical significance and then divided it between the 2 coprimary outcomes, setting a P value of .046 for overall survival and .004 for progression-free survival — which adds up to .05.

Toxicity was higher in the bevacizumab treatment group, with modest increases seen in the rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia, the researchers note.

In addition, the bevacizumab treatment group showed, over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function.

Dr. Gilbert and colleagues comment that the AVAglio study restricted patient-reported outcomes primarily to health-related quality-of-life measures, "whereas we also collected measures of symptom burden and interference and the results of objective tests of neurocognitive function."

"These assessments consistently showed that patients receiving bevacizumab, as compared with placebo, had greater deterioration in scores on objective tests of neurocognitive function as well as in perceived cognitive function, suggesting either unrecognized tumor progression or bevacizumab-related neurotoxicity," Dr. Gilbert and colleagues write.

At the ASCO meeting, Dr. Gilbert elaborated further on these findings. More patients free of progression on imaging showed a decline in these functional domains, he said. "Put in the context of the prolongation of progression-free survival, that made the difference. Not only did we not hit the progression-free survival target that was prespecified, we also saw that, over time, a portion of the patients who were progression-free on bevacizumab did not maintain their overall function status."

However, Dr. Chinot commented that, because of the way the assessments were made, there is a hypothesis that the degradation of quality of life and neurocognition reported may be related to an unrecognized progression of the disease. He pointed out that the degradation is reported mainly at one time point, was not continuously observed, which is surprising, and it has never been reported before: "As far as I am aware, never observed in clinical practice by clinicians, despite some experience in the recurrent setting."

The RTOG researchers are adamant in their conclusions. In a press release issued by the American College of Radiation, which administers the RTOG, Dr. Gilbert said: "'The relevant result is that upfront use of bevacizumab is not indicated."

"We feel that bevacizumab remains an important therapy for patients with glioblastoma, but the results of this study do not support its front-line use. Rather, it can be reserved as a later treatment," he told reporters at a press briefing during the ASCO meeting.

Not Convinced By the Data

Discussing both the AVAglio and the RTOG 0825 studies during a "highlights of the day" session at the ASCO meeting, Christina Tsien, MD, from the University of Michigan in Ann Arbor, said: "There does not appear to be a clinical benefit from upfront treatment with bevacizumab in glioblastoma."

"I remain doubtful about the true antitumor efficacy of bevacizumab in glioblastoma," commented Deepa Subramaniam, MD, director of the brain tumor center at the Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C, who was approached to comment by Medscape Medical News. "It is certainly a very helpful drug in the symptomatic patient and does improve survival in very specific patient subsets, but I do not think we know what those subsets are, meaning we have no reliable predictive markers for benefit from bevacizumab."

"This is true of the role of bevacizumab in most other solid tumors for which it is approved," Dr. Subramanian added.

Recurrent vs Newly Diagnosed Glioblastoma

Bevacizumab is beneficial in recurrent glioblastoma, but it may be a different story in newly diagnosed disease, Dr. Fine commented in an interview with Medscape Medical News.

Glioblastoma has two quite different growth patterns, one where it is more invasive and doesn't require a lot of blood vessel growth, and another where it becomes bulky and does require blood vessel growth, he explained. So one would predict, quite rightly, that an angiogenesis inhibitor such as bevacizumab would be more effective in the second pattern of growth, and this angiogenic-driven growth is seen on tumor progression.

The benefit from bevacizumab in recurrent glioblastoma can be profound, he said. Between 25% and 50% of patients show a decrease in tumor size, and 30% to 40% show a decrease in steroid use and feel better, he said. He has several patients maintained on bevacizumab and still alive at more than 2 years after recurrence; usually survival is only 3 to 4 months. "We have never seen a drug do this," he said, adding: "it's so dramatically different from anything else we've had."

After the accelerated FDA approval for recurrent glioblastoma in 2009, there was a requirement for a phase 3 study with survival data — and the AVAglio study was to fill that requirement. However, it was conducted in newly diagnosed glioblastoma, which may not be a similar biological entity, Dr. Fine said, and to some extent "we were set up to fail."

Until recently, cancer has been treated with chemotherapy, which kills cancer cells, and the general observation was that if it works in advanced disease, then it usually works even better in the earlier stages of the disease, usually because there were fewer tumor cells in newly diagnosed disease than in recurrent advanced disease, he said. But this assumption may no longer be true for biologics that are targeting specific biological events, he said.

In fact, exposure to such a drug may even change the biology of the tumor, he said. Using bevacizumab in newly diagnosed patients could result in a more treatment-resistant recurrence. "If they've had long-term bevacizumab from the start, then when they recur, it is a nonangiogenic recurrence," which will not respond to bevacizumab, he said.

Maybe it would be better not to expose the tumor to bevacizumab too soon, and earlier on, control it with radiation and temozolomide, and save the drug for when the tumor starts to break through that control. "That's not proven, that's conjecture, but there are preclinical data to suggest that it is true, and that could be one of the explanations to suggest why we see such a profound effect of bevacizumab in the recurrent setting but don't necessarily see such a profound effect when we see it in newly diagnosed disease," Dr. Fine said.

But he added that there are also other explanations. One of the simplest explanations for why there was no overall survival advantage is the crossover design of the study, where patients in the placebo group were offered bevacizumab on tumor progression, and "a good many received it."

It is because bevacizumab is so important in recurrent glioblastoma that there is "a lot of emotion" in the discussions now going on about the just-published trials in newly diagnosed glioblastoma, when the efficacy of the drug is being questioned, Dr. Fine said. "We don't want to throw the baby out with the bathwater," he said. Asked if the current situation is reminiscent of the situation for bevacizumab in breast cancer, where the indication was given an accelerated approval after phase 2 trials and then the approval was withdrawn after phase 3 trials, Dr. Fine said, No... I think this situation is entirely different." Bevacizumab is dramatically effective in recurrent glioblastoma, for which there is little other option, and this wasn't seen in breast cancer, where it was used in combinations, and also there are many other drugs available for breast cancer.

"I can't believe that bevacizumab would not remain available for glioblastoma, especially given the lack of other options," Dr. Fine said.

The AVAglio trial was supported by Roche. The RTOG 0825 trial was supported by a grant from the National Cancer Institute and an unrestricted educational grant from Genentech. Dr. Fine has disclosed no relevant financial relationships.

N Engl J Med. 2014;370:699-708, 709-722, 764-765. RTOG 0825 abstract, AVAglio abstract, Editorial


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