A New Option for Glioblastoma Multiforme Treatment: Regorafenib

Glioblastoma is the most common malignant brain tumor in adults. GBM, GBM-IV, glioblastoma multiforme , or grade 4. brain tumor are other names. For newly diagnosed glioblastoma, standard treatment is maximal cancerous tissue removal through brain tumor surgery followed by temozolomide chemotherapy and adjuvant chemoradiotherapy. Despite this, median overall survival is less than 24 months, and recurrence is inevitable.

Treatment after recurrence is unclear and has weak effectiveness. A synthetic nitrosourea-class DNA -alkylating agent, lomustine, has been widely used in recurrent glioblastoma in phase 2 and 3 clinical trials.

Glioblastoma has intense angiogenesis (new blood vessel formation), among the most vascular tumors. Through VEGF receptor signaling, bevacizumab is an antibody suppressing new blood vessel formation; for progressive or recurrent glioblastoma, it is FDA approved. However, alone or with chemotherapy, bevacizumab has not prolonged overall survival in first- or second-line glioblastoma treatment.

For recurrent glioblastoma, lomustine + bevacizumab versus lomustine alone was tested in trial 26101, a phase 3 study. Adding bevacizumab improved progression-free but not overall survival.

Although highly vascular, glioblastoma rapidly develops resistance to the anti-angiogenic drug bevacizumab, with resistance prompting research into other vascular-targeted agents. One was regorafenib .

Note: Regorafenib targets tumor angiogenesis (VEGFR1-3 and TIE2), oncogenesis (TIT, RET, RAF1, and BRAF genes), the tumor microenvironment (platelet-derived growth factor receptor [PDGFR]), and fibroblast growth. It is an oral tyrosine kinase inhibitor cancer drug. Regorafenib (Stivarga) is approved by the United States FDA and European Medicines Agency (EMA) as monotherapy for metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma (liver cancer).

Preclinical studies showed antitumor activity against glioblastoma. With lapatinib, it also acted against human glioblastoma cells. A phase 1 trial suggested benefit with cetuximab in advanced cancers, including a glioblastoma patient. Based on these features and preclinical results, the randomized comparative multicenter REGOMA phase 2 trial assessed efficacy and safety in recurrent glioblastoma. The primary endpoint analysis, with 78 deaths, was performed on 7 July 2017 and presented on 8 September 2017 at the European Society for Medical Oncology (ESMO) congress. On 3 December 2018, Lancet Oncology published final results.

REGOMA Phase-2 Trial Design

• This randomized multicenter open-label phase-2 study involved 10 Italian centers.
• After glioblastoma surgery and adjuvant chemoradiotherapy, patients with recurrence were randomized 1:1 equally to daily 160 mg regorafenib in each 4-week cycle for 3 weeks, or lomustine 110 mg/m2 every 6 weeks. Treatment continued until progression, death, or unacceptable adverse effects.
• Overall survival was the primary endpoint.

Study Results

• Between November 2015 and February 2017, 124 were screened and 119 eligible for randomization (59 regorafenib, 60 lomustine).
• Median follow-up was 15.4 months.
• Of 119 patients, 99 (% 83) had died at analysis (% 71 of the regorafenib group and % 95 of lomustine).
• Overall survival was 7.4 months with regorafenib and 5.6 months with lomustine.
• Regorafenib reduced mortality risk by % 50 compared with lomustine.
• At month 12., % 38.9 receiving regorafenib versus % 15 receiving lomustine were alive.
• Serious (grade 3-4) adverse effects occurred in 59 regorafenib patients, affecting 33 (% 56), and in 60 lomustine patients, affecting 24 (% 40).
• The most common serious regorafenib effects (grade 3 or 4) were hand-foot skin reaction, increased lipase, and elevated blood bilirubin. For lomustine, they were low platelet, lymphocyte, and neutrophil counts. No treatment-related death occurred.

Conclusion

In REGOMA, oral regorafenib showed an overall survival advantage in recurrent glioblastoma multiforme. It may be a new potential treatment and should be investigated in an adequately powered phase III trial.