An Overview of the REGAL Trial and Anti-VEGF Therapies in Recurrent Glioblastoma


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Annick Desjardins, MD, FRCPC

"Despite its negative findings, the REGAL trial still teaches us a lot about the use of anti-VEGF therapies in recurrent glioblastoma patients."

—Annick Desjardins, MD, FRCPC

As published in the Journal of Clinical Oncology by Batchelor and colleagues1 and reviewed in a recent issue of The ASCO Post (November 15, 2013, page 106), the REGAL trial was a randomized, phase III, placebo-controlled, partially blinded trial evaluating the efficacy of cediranib, an investigational oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine (CeeNu) vs lomustine monotherapy in patients with first recurrence of glioblastoma. The primary endpoint was progression-free survival.

In total, 325 patients with a median age of 54 years were included in this international study. Progression-free survival was not significantly different for either cediranib alone or cediranib in combination with lomustine vs lomustine with placebo. More grade 3 or higher adverse events occurred in the combination arm of cediranib with lomustine (80%) compared to the cediranib monotherapy arm (61%) and the lomustine arm (61%).

Anti-VEGF Therapies and Recurrent Gliomas

Since vascular proliferation is a histopathologic hallmark of glioblastoma and levels of overexpression of VEGF in malignant glioma correlate directly with tumor vascularity and grade and inversely with prognosis, anti-VEGF therapies have emerged as therapies of choice in malignant gliomas.2-5 Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, was granted accelerated approval by the U.S. Food and Drug Administration for the treatment of recurrent glioblastoma in May 2009 on the basis of radiographic response rate and quality-of-life data.6,7 Since then, multiple anti-VEGF agents have been tested.8-10

As demonstrated with other VEGF-directed therapies, Batchelor and colleagues found a response rate of 28% to 38% in the cediranib-containing arms, which is similar to the 28.2% to 37.8% objective response rates observed with bevacizumab in the BRAIN study.6 Comparatively, no imaging improvement was obtained in the lomustine with placebo arm, which is also consistent with the minimal radiographic response rate expected with chemotherapy monotherapy in this patient population.11

Furthermore, as also observed in other clinical trials evaluating anti-VEGF therapies for recurrent glioblastoma patients, corticosteroid usage was reduced at the time of progression compared to baseline for patients on the cediranib-containing arms vs the lomustine-alone arm.6,10 Also, patients on the cediranib arms showed a slower deterioration of their neurologic status compared with patients on the lomustine arm. The steroid-sparing effect of anti-VEGF therapies has been observed in a multitude of clinical trials evaluating recurrent glioblastoma patients, as has the ability of such treatments to delay neurologic deterioration.6,10

Concerns and Questions

The REGAL trial did not meet its primary endpoint of prolongation of progession-free survival, and unfortunately, the concern will remain that the reduction in the dose of cediranib in the combination arm from 30 mg to 20 mg due to toxicity seen in a metastatic lung carcinoma trial12 might be in part responsible for the negative results seen in this study.

Furthermore, overall survival was evaluated as a secondary endpoint and also showed an absence of benefit for the cediranib arms compared to lomustine, with a median overall survival of 8.0, 9.4, and 9.8 months for the cediranib monotherapy arm, cediranib plus lomustine arm, and lomustine arm, respectively. The lack of overall survival benefit might be secondary to a high number of patients receiving bevacizumab at the time of progression on trial, including 51% of patients on the cediranib plus lomustine arm and on the lomustine arm and 27% of patients on the cediranib monotherapy arm. Despite overall survival being recognized as the ultimate standard for demonstration of efficacy, the widespread use of bevacizumab at the time of recurrence in the United States has made it almost impossible to truly evaluate in this country the survival advantage of patients exposed to anti-VEGF therapies vs those never exposed to anti-VEGF therapies.

The REGAL trial, like other clinical trials in this setting, has failed to identify good predictors of response to anti-VEGF therapies. The ability to rapidly identify patient subgroups benefiting or not from anti-VEGF therapies remains elusive in this patient population, but remains an area of active research.

Further Considerations

Despite the fact that the REGAL study failed to reach its primary objective, this study and another contemporary study reported by Wick and colleagues13 have highlighted the observation that lomustine monotherapy produces an improved median and 6-month progression-free survival compared to what was observed in historical controls with recurrent glioblastoma.

As mentioned by the authors, the REGAL trial was limited to patients at first recurrence, whereas the historical series included patients treated at multiple recurrences. The results support the use of lomustine monotherapy in recurrent glioblastoma patients, but also raise an important recurring issue in neuro-oncology—ie, that the improvement in progression-free and overall survival of glioblastoma patients compared to historical controls is not due to the emergence of new and very active therapies, but to an improvement in our understanding and use of new supportive care interventions.

Conclusions

Despite its negative findings, the REGAL trial still teaches us a lot about the use of anti-VEGF therapies in recurrent glioblastoma patients. It confirms the positive response rates of other anti-VEGF therapies, as well as their ability to decrease the length of time patients are exposed to corticosteroids and thus potentially decrease the extent of side effects induced by corticosteroids. It also confirms the prolongation of time before neurologic decline offered by anti-VEGF therapies, and thus, an improvement in the severity of the physical and emotional burden the disease causes not only on patients, but also on caregivers. However, the ability to identify subgroups of patients experiencing the greatest benefit from anti-VEGF therapies remains extremely limited.

Finally, this multi-institutional group should be commended for enrolling—in a little less than 1 year—325 glioblastoma patients at first recurrence, prior to any exposure to anti-VEGF therapies. ■

Disclosure: Dr. Desjardins reported no potential conflicts of interest for cediranib. She serves on an advisory board for Genentech/Roche.

References

1. Batchelor TT, et al: Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31:3212-3218, 2013.

2. Chaudhry IH, et al: Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 39:409-415, 2001.

3. Ke LD, et al: The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin Cancer Res 6:2562-2572, 2000.

4. Plate KH, et al: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845-848, 1992.

5. Samoto K, et al: Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55:1189-1193, 1995.

6. Friedman HS, et al: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733-4740, 2009.

7. Kreisl TN, et al: Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740-745, 2009.

8. de Groot JF, et al: Phase II study of aflibercept in recurrent malignant glioma. J Clin Oncol 29:2689-2695, 2011.

9. Schiff D, et al: Phase II study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma (rGBM) [abstract]. J Clin Oncol 28(15 suppl):182s, 2010.

10. Wen PY, et al: Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB) [abstract]. J Clin Oncol 28(15 suppl):181s, 2010.

11. Wong ET, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999.

12. Goss GD, et al: Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer. J Clin Oncol 28:49-55, 2010.

13. Wick W, et al: Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28:1168-1174, 2010.



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