ASCO 2013 Impressions

Presentations regarding the use of Avastin in glioblastoma (GBM) were prominent in the Central Nervous System Cancer and Plenary Session during this years. ASCO annual meeting, with the focus being the newly diagnosed GBM treatment setting.

The eagerly anticipated results from the large, randomized, double blind, Phase III trial of Avastin in newly diagnosed glioblastoma, in combination with the standard of care chemotherapy (temozolamide; TMZ) and radiotherapy (RT), versus TMZ/RT alone (RTOG 0825; Gilbert MR, 2013) were presented during the Plenary Session on Sunday, June 2. Results from a similar trial funded by Roche, AVAglio, were presented during the Central Nervous System Cancers oral abstract session on Saturday 1st June, and were also discussed during the Plenary Session discussion of the RTOG 0825 results.

Both trials showed that the addition of Avastin to TMZ/RT does not confer an overall survival (OS) advantage over the standard of care; in the RTOG 0825 trial, median OS in the Avastin arm was 16.1 months, compared to 15.7 months in the control arm (P = 0.21). At the same time however, there was a progression-free survival (PFS) advantage in the Avastin arm of both trials; in the RTOG 0825 trial (PFS in the Avastin arm was 10.7 month, compared to 7.2 months in the placebo arm; P = 0.007), this did not meet the pre-specified improvement, and thus the trial can be considered to be a negative trial. Similarly, in the AVAglio trial MOS in the bevacizumab arm was 16.8 months (compared to 16.7 months in the placebo arm; P = 0.099), and PFS was 10.6 and 6.2 months in the two arms respectively (P < 0.0001) (Wick W, 2013). Importantly, the two trials differ only in terms of the dosing schedule.

The results were disappointing, as there is dire need for new, more effective therapies for this underserved disease, where OS for the vast majority of patients is measured in months, rather than in years. With Avastin having gained conditional approval in the recurrent GBM treatment setting, as a monotherapy based on impressive results in a series of Phase II trials, there was hope that this could be replicated in the newly diagnosed GBM setting.

The reasons behind the failure of Avastin/TMZ/RT to improve OS compared to TMZ/RT are not clear. Crossover between the two treatment arms is the obvious factor; other possibilities were also discussed, including the lack of a biomarker to predict response to aid patient selection, suboptimal drug delivery to every part of the tumor and the possibility of VEGF not having a central role in angiogenesis in GBM.

This is reminiscent of the Avastin trials in the front line setting in other oncology indications, most notably in breast (CaB) and non-squamous non-small-cell lung cancer (NSQ-NSCL). Notably, Avastin's FDA conditional approval in CaB was revoked in 2011, after Avastin failed to confirm an OS benefit. In NSQ-NSCLC, questions regarding the efficacy of Avastin in terms of OS persist, with a large Phase III trial showing an OS benefit, and one not. The added significant hematologic toxicity observed with Avastin/chemotherapy combinations, together with the lack of a clear OS signal has led to oncologists questioning the risk/benefit ratio of such therapies in NSQ-NSCLC. The RTOG 0825 and AVAglio trials have not been able to escape this historical pattern, and physician skepticism regarding the front line use of Avastin will persist.

Additionally, both trials investigated the impact of adding Avastin in first-line treatment to quality of life (QOL), and in the case of RTOG 8025, to patients cognitive function (CF) among other measures. In the case of the RTOG 0825 trial, enrolled patients could volunteer to participate in the QOL and CF test parallel study, while in the AVAglio trial, all patients were required to complete the QOL questionnaires. Notably, RTOG 0825 reported significantly declining motor dysfunction, communication deficit and cognitive function of patients who had not progression while on Avastin over time compared to patients in the placebo arm, raising serious doubts regarding the risk/benefit ratio of the Avastin/TMZ/RT therapy in the newly diagnosed GBM patient population. Of note, RTOG 0825 also looked at the overall symptom burden of patients and found that this measure increased in the Avastin arm of the trial with time, correlating well with the less stable overall QOL (Armstrong TS, 2013; Wefel JF, 2013).

In a disease such as GBM, improvements in OS rather than PFS are of outmost importance for treating physicians, regulatory authorities and patients. Furthermore, it is vital for a therapy to palliate symptoms and improve the QOL of patients. This is particularly important in oncology indications with a short OS, where patients are more likely to opt not to receive therapy if the risk of deteriorations of QOL is high, without a clear and significant chance for improved survival. In addition, in GBM, disease progression is often associated with a sharp decline in QOL and CF. Therefore, the advantage a therapy has by extending PFS is lost if it causes further decline in QOL and/or CF.

Interestingly however, the AVAglio trial did not see this deterioration of QOL with Avastin compared to the control arm (Henriksson R, 2013). Indeed the AVAglio trial reported statistically significant QOL benefits with Avastin, and similar deterioration of QOL with time compared to the control arm in progression-free patients. Again, several possibilities have been proposed for this difference; small patient numbers included in the analysis, different analysis methodologies, inclusion of patients with non-evident disease progression, as well as the volunteer nature of inclusion in the QOL/CF study in the RTOG 8025 trial. The questions posed by RTOG 8025 however persist, causing oncologists to doubt the value of adding Avastin to the first-line standard of care therapy.

Despite the dearth of therapies for newly diagnosed GBM and the short survival of these patients, a statistically significant improved PFS is not going to be enough for Avastin to gain a line extension in this treatment setting. The lack of an OS benefit and the questions around the impact of this therapy to QOL and CF call for further research in order to clarify the position of Avastin in the treatment pathway of GBM, the patient population most likely to benefit from Avastin and the treatment modality to be used in combination with Avastin (i.e. should it be used as a monotherapy or in combination with chemotherapy [and which chemotherapy should be used]). Importantly, the questions around the impact in the QOL and CF of patients need to be addressed for treating physicians to embrace Avastin as a valuable treatment option in the newly diagnosed GBM treatment setting, let alone considering Avastin/TMZ/RT the new standard of care.

Orestis Mavroudis-Chocholis, Ph. D., is a business insights analyst with the Oncology team at Decision Resources.

a. Armstrong TS, et al. Comparative impact of treatment on patient outcomes (PROs) in patients with glioblastoma (GBM) enrolled in RTOG 0825. Journal of Clinical Oncology. 2013;31(suppl; abstr 2003).
b. Gilbert MR, et al. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). Journal of Clinical Oncology. 2013;31(suppl; abstr 1).
c. Henriksson R, et al. Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). Journal of Clinical Oncology. 2013;31(suppl; abstr 2005).
d. Wefel JF, et al. Neurocognitive function (NCF) outcomes in patients with glioblastoma (GBM) enrolled in RTOG 0825. Journal of Clinical Oncology. 2013;31(suppl; abstr 2004).
e. Wick W, et al. Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM). Journal of Clinical Oncology. 2013;31(suppl; abstr 2002).

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