mTOR inhibition in glioblastoma: requiem for a dream?

See the article by Chinnaiyan et al, pp. 666–673.

Important recent advances in the understanding of the molecular derangements that drive gliomagenesis have had minimal impact on the development of efficacious therapeutic agents that extend survival beyond what is achieved by conventional chemoradiotherapy.¹ The tumor suppressor gene phosphatase and tensin homolog negatively regulates the Akt/protein kinase B (PKB) signaling pathway; mutation of this gene and subsequent inactivation of its function is observed commonly in glioblastoma (GBM).² Increased activity of the Akt/PKB signaling pathway leads to activation of mammalian target of rapamycin (mTOR), which is a critical step for cell-cycle progression. Mammalian target of rapamycin functions in 2 distinct multiprotein complexes defined by association either with RAPTOR (regulatory associated protein of mTOR complex 1 [mTORC1]) or RICTOR (rapamycin-insensitive companion of mTOR complex 2 [mTORC2]). The function of mTORC1 is to regulate cell size and growth in response to nutrient levels, while mTORC2 modulates both the cytoskeleton and Akt activation.^3,4 These specific pathways have also been associated with a poor prognosis in GBM.⁵ Although several previous studies evaluating mTOR inhibition in GBM have furnished disappointing results,^6,7 there remains a strong rationale for developing strategies that target the mTOR pathway in this disease.

In the randomized phase II clinical trial of everolimus (mTORC1 inhibitor) in GBM by Chinnaiyan et al,⁸ a total of 171 patients were randomized to receive either standard therapy (concurrent chemoradiation with temozolomide) or standard therapy combined with daily everolimus (10 mg) during concurrent chemoradiation and adjuvant temozolomide. After the median follow-up time of 27.7 months (range, 0.1 to 36.7 mo), the median progression-free survival, the primary endpoint, for the control arm was 10.2 months (95% CI: 7.5–13.8 mo) compared with 8.2 months (95% CI: 6.5–10.6 mo) for patients randomized to receive everolimus. Alarmingly, the experimental therapy reduced median overall survival by 4.7 months. Furthermore, the use of everolimus in the first-line setting for GBM was unexpectedly toxic. The incidence of serious adverse events was significantly higher in the experimental arm (grades 3–5 toxicities 80% experimental vs 42.3% control), and grade 5 adverse events attributed to protocol treatment occurred in 1 patient in the control arm compared with 4 in the experimental arm (respiratory failure and infections). Of the patients in the control arm, 77.1% received adjuvant temozolomide, while only 60.2% in the experimental arm went on to receive adjuvant chemotherapy. Did everolimus toxicity during concurrent therapy contribute to the diminished use of adjuvant temozolomide in the experimental arm and did this impact unfavorably on survival and the observation that hypermethylation of O⁶-methylguanine-DNA methyltransferase conferred a survival advantage in the control arm but surprisingly did not affect survival in the everolimus group (hazard ratio = 1.48; P = 0.20)?

Although a number of trials have tested mTOR inhibitors in newly diagnosed GBM, this is the largest and only randomized study evaluating everolimus in the first-line setting for this disease. In this trial, surprisingly, the control arm had a significantly better survival than the experimental arm. This unexpected observation is unusual and remains unexplained but serves as a poignant reminder of the value of a control arm as opposed to the use of historical controls and single-arm phase II studies for the evaluation of therapies for newly diagnosed GBM. Although the baseline characteristics and post-progression therapies administered were generally balanced in both groups, apparent differences between control and experimental arms in age (control arm, 60.2% below age of 60 vs experimental arm, 43.2%) and, following progression, the higher rate of surgical resection (21.2% control vs. 12.7% experimental) and use of chemotherapy (38.5% control vs 27.3% experimental) may have had bearing on the remarkable survival observed in the control arm. While survival in the experimental arm was in an acceptable range, it was inferior to survival in the control group, and this observation raises the concern that the increased and serious toxicities associated with everolimus compromised survival. This randomized trial was initiated on the basis of a phase I study that suggested that everolimus could be combined safely with standard initial therapy for GBM.⁹ Perhaps the use of a 2-stage study design¹⁰ in the randomized phase II trial and oversight by an independent data monitoring committee might have identified the deleterious effects of this agent earlier and reduced potential harm.

The limited capacity of mTOR inhibitors such as everolimus to cross the blood–brain barrier and compensatory Akt activation as a result of unregulated mTORC2 signaling perhaps presaged the failure of these agents in the clinic. The inhibition of mTORC1 as a part of the multimodality treatment of GBM is not likely to be investigated further due to the negative result of this study and the unacceptable toxicities observed. However, this is not the end of the road for mTOR inhibition. Unlike everolimus, mTORC1/mTORC2 dual inhibitors inhibit all of the kinase-dependent functions of mTORC1 and mTORC2 and therefore block the feedback activation of phosphatidylinositol-3 kinase (PI3K)/Akt signaling. Ongoing clinical trials targeting dual mTOR should clarify the role of dual mTOR inhibition in the treatment of GBM.

The design of this phase II trial, incorporating randomization with an appropriate control arm, enabled a reliable and accurate assessment of the efficacy and toxicity of an mTOR inhibitor that has been under evaluation in GBM for approximately a decade. The results, while disappointing, highlight the importance of good trial design in neuro-oncology. In addition to the value of a control arm, the risks of drug-related toxicities on outcome have been demonstrated. This trial did not incorporate meaningful biomarkers, an omission that had minimal consequences, as the experimental agent was ineffective. However, PI3K-mTOR-Akt retains its interest as an area for therapeutic intervention and future studies that target this, and related signaling cascades should include appropriate molecular biomarkers that might predict response.

Funding

None.

Conflict of interest statement. None declared.