Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas

Despite optimal therapy with surgery, radiotherapy, and chemotherapy, the prognosis of malignant gliomas remains poor. Patients with glioblastoma (GBM) have a median survival of approximately 9 to 15 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months.¹ Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks.² There is a need for more effective, novel forms of therapy.

Human cancers, including malignant gliomas, result from aberrations in cell signaling. Specific inhibitors of tyrosine kinases and signaling pathways have demonstrated therapeutic efficacy in an increasing number of cancers. Recently, there has been growing interest in the use of these targeted molecular agents for the treatment of malignant gliomas.³ The major molecular abnormalities in GBM are amplification of the epidermal growth factor receptor (EGFR) and inactivation of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene.^4,5 EGFR is amplified in 40 to 50%, and overexpressed in >60% of GBMs.^4,5 Approximately 40% of tumors with EGFR amplification have a constitutively active mutation (EGFR vIII).⁴ Approximately 40 to 50% of GBMs have PTEN deletions or mutations.⁴ These molecular abnormalities result in overactivity of the Ras/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways, resulting in tumor proliferation, angiogenesis, and inhibition of apoptosis.

Studies with single-agent mTOR and EGFR inhibitors have shown only limited activity in malignant gliomas with response rates of 10 to 15% or less, and no significant prolongation of survival.^3,5–8 These results are not surprising given the complexity of the molecular derangements in malignant gliomas and the presence of redundant signaling pathways. In a recent study correlating response to EGFR inhibitors and tumor genotype, GBMs expressing the EGFRvIII mutation and intact PTEN were found to have an increased response rate.⁸ This suggests that tumors with loss of PTEN and activation of the PI3K/Akt/mTOR pathway were unlikely to respond to EGFR inhibitors alone. It is possible that combinations of targeted molecular agents inhibiting complementary molecular pathways may have greater therapeutic efficacy.^3,9 In this pilot study, we reviewed our experience with the combination of EGFR inhibitors gefitinib and erlotinib with the mTOR inhibitor sirolimus in a heavily pretreated group of patients with recurrent malignant gliomas.

Methods.

We performed a retrospective review of 28 consecutive patients with a histologic diagnosis of malignant gliomas and radiographic documentation of recurrent disease treated between October 2004 and December 2005. All patients had prior treatment with radiotherapy, baseline MRI within 2 weeks of initiating therapy on stable dose of corticosteroids for ≥5 days, age 18 years and older, Karnofsky Performance Status ≥50, absolute neutrophil count ≥1,500/mm³, platelets ≥100,000/mm³, normal renal and liver function, and no prior therapy with EGFR or mTOR inhibitors. There was no limit on the number of prior therapies. Because gefitinib (IRESSA), erlotinib (Tarceva), and sirolimus (Rapamune) are all cytochrome P-450 3A4 substrates, patients could not be on enzyme-inducing antiepileptic drugs for at least 10 days before beginning therapy. The endpoints were evaluation of toxicity, progression-free survival at 6 months (6M-PFS), and response as determined by the MacDonald et al. criteria.¹⁰ Patients were treated with either gefitinib 500 mg or erlotinib 150 mg orally once daily in combination with sirolimus. Sirolimus was administered at a dose of 6 mg orally the first day followed by 4 mg orally once daily thereafter. Both medications were given continuously every day in 28-day cycles. Complete blood counts, liver function tests, lipid profile, and sirolimus levels were obtained every 2 weeks. The sirolimus dose was adjusted to ensure that trough drug levels were in the mid to high therapeutic range. Neuroimaging studies were obtained every 8 weeks. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (CTC Version 3.0).

Results.

We studied 28 patients (16 men and 12 women) (table) The median age was 56 years (range 34 to 87) and median Karnofsky Performance Status was 60 (range 50 to 90). There were 22 GBMs and six anaplastic gliomas (AGs). Overall, patients had a median treatment for two prior relapses (range one to six). The six AG patients were especially heavily pretreated with a median treatment for three prior relapses (range three to six). Nine patients received gefitinib and 17 patients received erlotinib. All patients received sirolimus.

The regimen was generally well tolerated. Twenty-three patients (82%) developed an erythematous maculopapular rash. These were generally grades I and II; one patient developed a grade III rash that required discontinuation of treatment after 1 week. Seventeen patients (61%) developed grade I or II diarrhea, which was usually well controlled with loperamide. Eight patients (29%) developed mucositis. Although these were generally grade I or II, the majority of these patients required a reduction in the dose of sirolimus. Most patients experienced mild fatigue. There were no grade II or greater hematologic toxicities. Two patients developed grade III infections. No patient required treatment for hyperlipidemia. All patients receiving concomitant warfarin for venous thromboembolic disease had significant elevation of the international normalized ratio (INR) requiring reduction in the dose of warfarin.

Of the 26 patients assessable for response, five (19%) (four GBMs, one AG) had a partial response (figure) and 14 (50%) (nine GBMs, five AGs) had stable disease at the 2-month restaging MRI. Among the nine patients who received gefitinib, five had stable disease and one had a partial response. These results are comparable to those for patients who received erlotinib. Of the 23 patients assessable for the primary endpoint of 6M-PFS, six were progression free (26%). The 6M-PFS for GBM patients alone was 25%. The median time-to tumor-progression (TTP) was 12 weeks (range 4 to >44).

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Figure. (A, B) Axial T1-weighted MRI with gadolinium of 57-year-old man with recurrent right parietal glioblastoma treated with surgery, radiation therapy with concomitant and adjuvant temozolomide, reoperation and carmustine. (C, D) Follow-up MRI after 8 weeks of therapy with erlotinib and rapamycin showing partial response.

Discussion.

The combination of EGFR and mTOR inhibitors was reasonably well tolerated in this heavily pretreated group of recurrent malignant gliomas patients with poor performance status (median Karnofsky Performance Status 60). The major complications of rash, diarrhea, and mucositis were predictable from prior studies of the individual agents,^3,5–8 but the severity of the rash and mucositis appeared to be greater with the combination. The ability of the majority of patients to tolerate these combinations of drugs is encouraging because toxicities have been problematic in several other ongoing trials involving EGFR and mTOR inhibitors. In those studies, significant dose reductions were required, potentially reducing drug exposure and decreasing the efficacy of the treatment. In patients on this combination receiving warfarin, the INR should be carefully monitored because a significant reduction of the warfarin dose was inevitably required.

Although this was a pilot study, there was suggestion of activity with a 19% response rate overall and a 6M-PFS of 25% in GBM patients. A retrospective review of eight consecutive negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS for GBM of 15% and 31% for AGs.² Direct comparison with these endpoints is not possible because this was a small, retrospective study with potential for selection bias. However, the results appear encouraging because the patients in this study were fairly heavily pretreated and had a generally poor performance status. These preliminary results await confirmation by several ongoing multicenter trials evaluating the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Many of these studies will attempt to correlate tumor genotype with response and perhaps allow the subset of patients who are most likely to benefit from this therapeutic strategy to be identified.