This phase 1 study sought to determine the MTD of erlotinib and characterize its pharmacokinetics alone and when combined with temozolomide in the presence and absence of EIAEDs.
Mild to moderate rash, fatigue, and diarrhea were the most common adverse events with erlotinib monotherapy in patients not taking an EIAED. Grade 3 rash with 250 mg/day was the main DLT, and based on these data, the MTD and recommended phase 2 dose of erlotinib with or without temozolomide is 200 mg/day (). When erlotinib was administered alone with EIAEDs, similar adverse events were reported, but DLT was observed at a higher dose (at least 500 mg). This is because EIAEDs reduced exposure to single-agent erlotinib. The MTD was not reached in patients receiving EIAEDs and erlotinib alone because the trial was stopped, as a higher dose (650 mg) had been reached in a parallel study by the NABTC. When temozolomide was given with erlotinib, the MTD was 450 mg/day. Based on these data, a dose of 450 mg/day is recommended for phase 2 trials in patients receiving erlotinib with temozolomide and EIAEDs, and a dose of 650 mg/day is recommended for patients receiving erlotinib alone with EIAEDS, based on the NABTC trial ().
Recommended phase 2 dose of erlotinib
The adverse events observed in this study were similar to those in a phase 1 trial of erlotinib monotherapy in patients with various solid tumors: Mild to moderate rash and diarrhea were the most common adverse events, and diarrhea was dose limiting at 200 mg/day (Hidalgo et al., 2001
). Rash is a common adverse event with all HER1/EGFR small-molecule tyrosine kinase inhibitors (Baselga et al., 2002; Herbst et al., 2005
) and anti-HER1/EGFR monoclonal antibodies (Baselga et al., 2000
). Although the exact etiology of this rash is unclear, it is likely to be associated with HER1/EGFR inhibition in the skin (Hidalgo et al., 2001
). A similar safety profile has been reported in other phase 1/2 studies with erlotinib or gefitinib monotherapy (alone or combined with EIAEDs) in glioma. The most frequent adverse events were mild to moderate rash and diarrhea (Lieberman et al., 2004; Raizer et al., 2004; Rich et al., 2004; Uhm et al., 2004; Vogelbaum et al., 2004; Yung et al., 2004
In this study, a total of eight patients had a PR, one on erlotinib not on an EIAED, five on erlotinib plus EIAEDs, and two on erlotinib combined with temozolomide (one with EIAEDs). Six patients had a PFS of six months or longer, four of whom also had a PR. This study was not designed to assess efficacy, but these preliminary data are encouraging and indicate that this combination is worthy of further study. Data from two phase 2 studies of erlotinib in glioma also suggest activity. In the first study, patients with recurrent, pretreated GBM who were not taking EIAEDs received erlotinib monotherapy at 150 mg/day. Of the 16 patients enrolled to date, four had a PR, one a mixed response, and four SD for more than three months. Enrollment is continuing (Vogelbaum et al., 2004
). In the second study, GBM patients with measurable disease at first relapse received a starting dose of 150 mg/day (no EIAEDs) or 300 mg/day (with EIAEDs). Doses were increased until DLT or to 200 mg/day in the no-EIAED group and 500 mg/day in the EIAED group. Preliminary analysis of 47 patients showed one CR, two PRs, and 18 SDs. The median duration of response was 15.6 weeks and median time to progression eight weeks. Eight patients (17%) were progression free at 24 weeks (Yung et al., 2004
In contrast, response data from study of erlotinib monotherapy at 150 mg/day in 45 patients with recurrent malignant gliomas who were not on EIAEDs (30 patients with GBM and 15 with anaplastic gliomas) were less encouraging. Four of the patients with GBM had SD, and the median PFS for all GBM patients was 12 weeks. For patients with anaplastic gliomas, PFS was 8.6 weeks, with one partial responder (unconfirmed) and two patients with SD (Raizer et al., 2004
). Response was limited in this monotherapy study as compared with others, possibly because of differences in the treatment regimen or patient population in terms of factors like prior therapy and disease type. Further studies are needed to determine accurately the efficacy of different regimens in different patient groups.
Several studies are complete or ongoing with gefitinib, another HER1/EGFR inhibitor, in patients with glioma. In one phase 2 trial (Rich et al., 2004
), 53 patients with GBM at first relapse receiving gefitinib at 500, 750, or 1000 mg/day and EIAEDs failed to show objective tumor responses or improved survival when compared with historical data (Wong et al., 1999
). In another trial, patients with recurrent GBM, recurrent anaplastic glioma, or unresectable benign or malignant meningioma who received gefitinib at 500 mg/day without EIAEDs, or up to 1500 mg/day with EIAEDS, failed to show an increase in time to disease progression compared with historical controls (Lieberman et al., 2004
). A phase 2 trial of patients with newly diagnosed, stable GBM who received gefitinib (500 mg/day, or escalated to 1000 mg/day in patients receiving dexamethasone and/or EIAEDs) did not show an improvement in overall PFS in comparison with historical controls (Uhm et al., 2004
). Finally, preliminary data from an ongoing trial with gefitinib and temozolomide, similar to the erlotinib trial in this report, show that in 28 patients there was one CR and 14 patients with SD, four of whom did not have disease progression (Prados et al., 2004
). Because of different eligibility and various treatment combinations examined in these studies, and as they are often not designed to assess response, interpretation of the relative efficacy of erlotinib and gefitinib in this setting is unclear. However, preliminary data with erlotinib may be more encouraging than with gefitinib. It is interesting to consider whether this is because of the potentially greater activity of erlotinib against the EGFRvIII mutant receptor (Iwata et al., 2002
), frequently found in GBM (Moscatello et al., 1995; Wikstrand et al., 1995
). Additional studies are needed to investigate further the efficacy of these agents in patients with malignant glioma.
The pharmacokinetic findings of this study support the recommended phase 2 dose of 200 mg/day for patients not taking an EIAED and a minimum of 450 mg/day for those taking an EIAED. At these doses (450–500 mg/day), exposure in patients receiving EIAED is expected to be approximately 50% lower than in those not receiving EIAEDs at the 200-mg/day dose. Systemic exposure and Cmax were similar in the dose ranges of 100 to 200 mg/day with erlotinib alone. A nearly twofold increase in AUC0–24 and Cmax was observed when the dose of erlotinib was increased to 250 mg/day, suggesting possible saturation of drug-clearance mechanisms.
Concomitant treatment with EIAED significantly reduced exposure to erlotinib, probably as the result of activation of cytochrome P450 enzymes responsible for the metabolism of erlotinib. A similar interaction has been reported in other studies with erlotinib (Yung et al., 2004
) and gefitinib (Chakravarti et al., 2004
). This interaction should be accounted for in future trial design.
The ratio of OSI-420 to erlotinib when coadministered with EIAED was higher than that for erlotinib alone. This was primarily because of a reduction in erlotinib level, possibly as a result of increased OSI-420 metabolism.
In contrast to the dramatic effect of coadministration with EIAEDs, only a modest pharmacokinetic interaction between erlotinib and temozolomide was observed. The nature of this interaction is paradoxical, as temozolomide tended to increase erlotinib exposure in the lower-dose groups (100–150 mg/day) not receiving EIAEDs. These effects are also more pronounced in the lower-dose groups receiving EIAEDs (). The reasons for these observations are unknown and could be attributed to the small group sizes or an imbalance in other factors that alter clearance.
In summary, erlotinib in combination with temozolomide, with or without EIAEDs, is well tolerated, and there is evidence of antitumor activity. Further investigation of this combination is warranted. Studies to evaluate the safety of erlotinib at doses higher than used in this study combined with EIAEDs are completed, and data will be reported shortly from the NABTC phase 1 trial. Phase 2 studies combining these two agents during and after radiotherapy in patients with newly diagnosed disease have begun.