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The Oncologist, Vol. 5, No. 2, 144-151, April 2000
© 2000 AlphaMed Press

Promising New Drugs and Combinations

Temozolomide, a Novel Alkylating Agent with Activity in the Central Nervous System, May Improve the Treatment of Advanced Metastatic Melanoma

Sanjiv S. Agarwala, John M. Kirkwood

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

Correspondence: Sanjiv S. Agarwala, M.D., Associate Director, Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412-648-6507; Fax: 412-648-6579; e-mail: agarwalass{at}msx.upmc.edu

Abstract

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.

Key Words. Antineoplastic agents • Alkylating • Central nervous system • Drug therapy • Imidazoles • Melanoma • Neoplasm metastasis • Pharmacokinetics

Introduction

Temozolomide (TMZ; TemodarTM [TemodalTM in the United Kingdom and Europe], Schering-Plough Corporation; Kenilworth, NJ) is a novel oral alkylating agent that has demonstrated efficacy in the treatment of a variety of solid tumors, including primary malignant brain tumors and metastatic melanoma [1-7]. TMZ has certain advantages over many existing alkylating agents because of its unique chemical structure and pharmacokinetic properties [8, 9]. Because of its small molecular weight, TMZ efficiently crosses the blood-brain barrier [10]. Thus, TMZ is effective against primary brain tumors and, for this reason, TMZ is also being actively investigated for the treatment of secondary central nervous system (CNS) malignancies, particularly in patients with metastatic melanoma. In addition, TMZ can be administered orally without dietary restrictions, and essentially 100% of the orally administered dose enters the blood stream. TMZ is also associated with a low incidence of severe adverse events. Unlike nitrosoureas and other alkylating agents that chemically cross-link the DNA and are associated with severe, dose-limiting, cumulative hematologic toxicity, TMZ is associated with generally mild, noncumulative myelosuppression.

TMZ has been extensively investigated for the treatment of high-grade gliomas, including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), and for the treatment of metastatic melanoma. Based on the results of a phase II trial in patients with recurrent AA [4], the United States Food and Drug Administration (FDA) recently granted TMZ accelerated approval for the treatment of refractory AA in adult patients at first relapse with disease progression on a nitrosourea and procarbazine-containing regimen. A phase IV trial is under way to confirm the efficacy of TMZ in patients with refractory AA. TMZ has not yet been approved in the United States for the treatment of GBM, because the Oncologic Drugs Advisory Committee (ODAC) did not accept six-month progression-free survival as an adequate clinical end point in the pivotal trial. However, TMZ is currently licensed in Europe for the treatment of any refractory high-grade glioma. Studies are also currently ongoing to demonstrate the efficacy of TMZ as first-line chemotherapy in patients with newly diagnosed high-grade gliomas. Despite a number of studies demonstrating activity, TMZ has not been granted approval in the United States or Europe for the treatment of metastatic melanoma. These studies include a randomized, phase III trial [11] demonstrating that TMZ is at least as active as dacarbazine (DTIC), which is the only chemotherapy agent currently licensed by the FDA for the treatment of melanoma. The ODAC indicated that demonstrating equivalence to DTIC was not sufficient to recommend approval in the United States. TMZ has been approved in Australia for use in metastatic melanoma. The major potential advantage of TMZ over DTIC is that TMZ is able to penetrate the CNS and may be effective against CNS metastases. Although both drugs are converted to the same active compound (i.e., 5-(3-dimethyl-1-triazenyl) imidazole-4-carboxamide [MTIC]), DTIC is only metabolized in the liver, whereas TMZ is able to cross into the CNS, where it is spontaneously hydrolyzed to the active metabolite. This review will summarize the clinical pharmacology of TMZ, review the data in recurrent glioma, and discuss the potential of TMZ in the treatment of advanced metastatic melanoma.

Chemical Structure and Mechanism of Action

TMZ belongs to a new class of alkylating agents known as imidazotetrazines. These compounds contain an imidazole ring and are structurally and functionally similar to DTIC, which is a member of the triazene subgroup [9]. TMZ was first synthesized by Stevens and coworkers in 1984 [8], and they were the first to demonstrate that TMZ has anticancer activity [8, 12]. TMZ is a small molecule with a molecular weight of 194 daltons and is, therefore, readily absorbed in the digestive tract and, because it is lipophilic, it is able to cross the blood-brain barrier. TMZ is robustly stable at the acidic pH of the stomach. However, once in contact with the slightly basic pH of the blood and tissues, TMZ spontaneously undergoes hydrolysis to the active metabolite MTIC, which rapidly breaks down to form the reactive methyldiazonium ion (Fig. 1Go) [9]. Penetration of TMZ into the CNS has been studied in rats and rhesus monkeys, and these studies have shown that the levels of drug in the brain and cerebrospinal fluid are approximately 30% to 40% of the plasma concentration [10]. The metabolite MTIC, however, does not effectively penetrate the CNS.



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  		Figure 1. Metabolism of temozolomide in aqueous solution. Reprinted with permission [9].

 
The methyldiazonium ion formed by the breakdown of MTIC primarily methylates guanine residues in the DNA molecule, resulting in the formation of O6- and N7-methylguanine. The formation of O6-methylguanine is primarily responsible for the cytotoxic effects of TMZ and DTIC. When DNA mismatch repair enzymes attempt to excise O6-methylguanine, they generate single- and double-strand breaks in the DNA, leading to activation of apoptotic pathways. N7-methylguanine is comparatively less cytotoxic because the nucleotide excision repair pathway can successfully excise these adducts without damaging the DNA. TMZ does not result in chemical cross-linking of the DNA strands. Thus, it is less toxic to the hematopoietic progenitor cells in the bone marrow than are the nitrosoureas (i.e., carmustine, lomustine), platinum compounds, and procarbazine, which do cross-link the DNA.

Clinical Pharmacology

TMZ is rapidly absorbed after oral administration, and the bioavailability is approximately 100%. The absorption of TMZ is only minimally affected by food. Absorption is reduced by only approximately 9% when taken with food, and this is not a clinically significant effect [13]. However, to reduce potential for nausea and vomiting, it is recommended that patients take TMZ at least 1 h before a meal or, preferably, at bedtime.

Phase I and II clinical studies have determined the maximum tolerated dose to be 1,000 mg/m2 divided over five days in each 28-day cycle [1-6]. TMZ is generally well tolerated at these dose levels. The most common nonhematologic adverse events are nausea, vomiting, headache, fatigue, and constipation. These events are generally mild to moderate in severity, and nausea and vomiting are readily controlled with standard antiemetics. With regard to hematologic toxicities, the incidence of grade 3/4 neutropenia and thrombocytopenia is generally lower than 10%, and fewer than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Myelosuppression is generally not cumulative and seldom results in discontinuation of treatment.

Based on the favorable toxicity profile observed in early clinical trials, subsequent studies have investigated doses of 150 mg/m2/day x 5 days for patients who had previously been treated with cytotoxic chemotherapy (total dose = 750 mg/m2 per cycle), with a planned increase to 200 mg/m2/day if no major myelosuppression was evident on day 22 of the 28-day cycle. For previously untreated patients, the initial dose is typically 200 mg/m2/day x 5 days (total dose = 1,000 mg/m2 per cycle). A continuous oral dosing schedule has also been investigated in a phase I trial [14]. Administration of 75 mg/m2/day for six to seven weeks was well tolerated and resulted in a twofold increase in drug exposure over four weeks compared with the five-day every 28 days schedule. This regimen produced a 33% objective response rate among 24 patients with varying tumor types, including 17 patients with gliomas. The continuous daily regimen lends itself to potential combination with fractionated radiation therapy.

The pharmacokinetics of TMZ after administration at 150 and 200 mg/m2 on a five-day schedule have been evaluated in humans (Table 1Go) [15]. The data indicate that TMZ is rapidly absorbed and eliminated. The mean time to maximal plasma concentration was less than 1 h, and the mean terminal elimination half-life was approximately 1.8 h. The maximum plasma concentration was 7.75 and 10.7 µg/ml at the 150 and 200 mg/m2 doses, respectively. Figure 2Go [16] shows the plasma concentration curve after oral administration of a single dose of TMZ ranging from 100 to 250 mg/m2. Nearly all of the administered dose was eliminated within 8 h. Because of its rapid elimination and its mechanism of action, TMZ has a reduced risk of causing cumulative hematologic toxicity. The mean plasma area under the curve of TMZ after oral administration was 22.6 and 29.7 µg•h/ml after a dose of 150 and 200 mg/m2, respectively. These pharmacokinetic characteristics have been evaluated in a number of clinical studies and are consistent among studies and in different patient subgroups, including pediatric patients [5, 17-20].


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  		Table 1. Single-dose pharmacokinetics of temozolomide
 


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  		Figure 2. Plasma concentration versus time curve after oral administration of a single dose of temozolomide (TMZ). From data on file [16].

 
Cellular Resistance Mechanisms

Several cellular mechanisms of resistance to alkylating agents have been identified. These include defects in DNA mismatch repair, increased excision repair, and increased enzymatic removal of alkyl groups. One of the key enzymes responsible for removing methyl groups from O6-methylguanine is O6-alkylguanine transferase (AGT), also known as O6-methylguanine methyltransferase. Overexpression of AGT can lead to resistance to the cytotoxic effects of MTIC. However, TMZ is able to deplete the levels of AGT in various cell types, thus reducing the potential for drug resistance [21-23]. A potential advantage of continuous low-dose administration of TMZ may be the more sustained depletion of AGT that can be achieved using this schedule.

Two studies have investigated the relationship between cellular AGT levels and response to TMZ and have yielded disparate results [7, 24]. Middleton et al. [7] reported that among 33 melanoma patients in whom pretreatment AGT level and clinical response could be correlated, the AGT level was not predictive of response to TMZ. In contrast, Friedman et al. [24] reported that among newly diagnosed patients with high-grade gliomas, those patients with fewer than 20% AGT-staining cells had a substantially higher response rate compared with patients with greater than 20% AGT-positive cells (76% versus 27%). Among 25 patients with fewer than 20% AGT-positive cells, there were three patients with a complete response, 12 patients with a partial response, and four patients with stable disease. This is compared with only one partial response and two patients with stable disease among 11 patients with greater than 20% AGT-positive cells. This study suggests that lower expression of AGT correlates with improved response to TMZ.

Pivotal Data in Patients with Recurrent High-Grade Glioma

TMZ has demonstrated activity in patients with recurrent AA and GBM. The pivotal phase II trial in patients with recurrent AA enrolled 162 patients at 15 United States sites and 17 international sites [25]. Eligible patients had histologically confirmed AA or anaplastic oligoastrocytoma and had failed initial therapy, which could have included surgery, radiation therapy, and chemotherapy. Patients could have received only one prior chemotherapy regimen that included a nitrosourea. Eligible patients were required to have a good Karnofsky performance status (i.e., >=70) and a life expectancy of at least 12 weeks. All patients received TMZ at a dose of 150 to 200 mg/m2/day x 5 days every 28 days until disease progression, for a maximum of two years. This is the largest trial ever conducted in this patient population, and it was well designed with rigorously defined prospective criteria for determining response and progression using gadolinium-enhanced magnetic resonance imaging. The patient's neurologic status and corticosteroid use were also considered by the investigators when determining response and progression, and responses were confirmed by central neuroradiology review of the magnetic resonance imaging scans. The primary clinical end points were six-month progression-free survival (PFS), overall survival, and response rate.

In this trial, TMZ produced a six-month PFS rate of 46% in the intent-to-treat population. The six-month overall survival rate was 75%, with a median overall survival of 13.6 months (Table 2Go) [4]. This compares very favorably with published studies; expected median survival for patients with recurrent AA is only six to nine months [26-31]. The number of responding patients in this trial was also very encouraging. The 62% overall response rate is superior to most response rates reported in the literature [26], and a substantial number (8%) of patients achieved a complete response. Within the total patient population in this trial, 54 patients were deemed to have refractory disease, having failed treatment with procarbazine, vincristine, and lomustine (PCV regimen), which is the standard first-line therapy for AA. Within this subgroup the six-month PFS rate was 45%, the six-month overall survival rate was 74% with a median of 15.9 months, and 59% of patients responded to TMZ (Table 2Go).


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  		Table 2. Efficacy summary in patients with anaplastic glioma
 
TMZ was well tolerated in this trial. Nausea, vomiting, headache, fatigue, and constipation were the most commonly reported adverse events. The majority of nonhematologic adverse events were mild to moderate in severity (World Health Organization [WHO] grade 1 or 2). Only 7% of treated patients developed thrombocytopenia (6% grade 3/4), and only 2% of treated patients developed grade 3/4 neutropenia and leukopenia. Myelosuppression was generally not cumulative and resulted in discontinuation of treatment in only five patients. The majority (93%) of patients received more than one treatment cycle, and 50% of patients received five cycles. Very few dose reductions or treatment delays were required in this trial because of toxicity. Dose reductions occurred in only 4% of cycles, mainly for hematologic toxicity. Treatment delays due to hematologic toxicity occurred in 28% of cycles. Based upon the results of this trial, the FDA approved the use of TMZ in patients with refractory AA in first relapse.

A similar, large, well-designed, phase II trial was conducted in patients with recurrent GBM and demonstrated a significant improvement in six-month PFS compared with procarbazine [32]. Moreover, this trial demonstrated that TMZ was well tolerated, prolonged the time to clinical worsening, and was associated with improved quality of life compared with procarbazine. Both of these trials in patients with recurrent high-grade gliomas demonstrated that TMZ is active and produces response rates comparable to other currently available chemotherapy agents. Therefore, TMZ may provide a meaningful clinical benefit to patients with recurrent high-grade gliomas.

Treatment of Advanced Metastatic Melanoma

Patients with advanced (i.e., stage IV) metastatic melanoma also have few available treatment options. The five-year survival rate for these patients is less than 5%, and median survival is in the range of six to nine months. Current treatment options include systemic single-agent chemotherapy with agents such as DTIC, cisplatin, and nitrosoureas; combination chemotherapy; systemic therapy with biologic agents, particularly interleukin 2 (IL-2); and combinations of chemotherapy and biologic agents (i.e., biochemotherapy). Single-agent chemotherapy produces response rates of approximately 20%, with few, if any, long-term remissions. Historically, DTIC has produced response rates of 15% to 25%, with median response durations of five to six months, but less than 5% of responses are complete [33]. As is the case with most chemotherapy agents, responses are generally not durable. Combination chemotherapy produces higher response rates but no improvement in survival compared with single-agent chemotherapy, despite the added toxicity and cost [34]. Dacarbazine has remained the mainstay of many combination chemotherapy regimens, including the popular Dartmouth regimen, consisting of DTIC, cisplatin, carmustine, and tamoxifen. However, a recent Eastern Cooperative Oncology Group randomized trial has demonstrated that the Dartmouth regimen was not significantly more effective than single-agent DTIC and was associated with significantly greater toxicity [34]. Therefore, despite more than 20 years of research, DTIC remains the standard against which all new chemotherapy agents are compared. Single-agent, high-dose IL-2 produces sustained remission in a small subset of patients (5% to 10%) [35], but toxicity is considerable. Biochemotherapy is a promising approach with encouraging results in phase II studies [36-39], but a survival benefit has not been confirmed by ongoing randomized trials [40, 41].

The failure of current biochemotherapy regimens, which can produce objective tumor responses in upwards of 50% of treated patients, is often a result of CNS relapse. Several patients apparently "cured" by high-dose IL-2 therapy have suffered isolated CNS relapse [35]. The majority of patients with advanced metastatic disease will eventually die of either respiratory failure or brain metastases. Therefore, any agent that can effectively penetrate the CNS with activity in melanoma could provide a major advance in the treatment of this disease. TMZ appears to be a candidate for just such an agent. It has demonstrated activity against melanoma and is able to penetrate the CNS; therefore, TMZ could be an exciting new alternative to DTIC, which is ineffective against CNS metastases.

The activity of TMZ in metastatic melanoma was first established in several phase I/II studies conducted by the Cancer Research Campaign [5-7]. Subsequently a large, multicenter, randomized, phase III, pivotal trial was conducted by European investigators to prospectively compare the efficacy of TMZ with that of DTIC [11]. This trial enrolled 305 patients with advanced metastatic melanoma who were randomized to receive oral TMZ (200 mg/m2 x 5 days, every 28 days) or intravenous DTIC (250 mg/m2 x 5 days, every 21 days). Eligible patients were older than 18 years of age and were previously untreated for metastatic disease. Patients with brain metastases were excluded. The primary efficacy end point was overall survival, and secondary end points included PFS, response rate, and quality of life. Patients were stratified before randomization based on important prognostic factors, including gender, WHO performance status, and site(s) of metastatic disease. Treatment groups were well balanced with respect to age, WHO performance status, sites of metastases, and time from initial diagnosis to diagnosis of metastatic disease. Of note, the proportion of patients with liver metastases was equal between treatment groups (33% in the TMZ arm versus 34% in the DTIC arm).

As shown in Table 3Go [42], TMZ compared favorably with DTIC in this trial. Response rates were similar, and TMZ demonstrated a slight but not statistically significant progression-free and overall survival advantage. These results suggest that TMZ is at least as effective as DTIC in this patient population. The toxicity profiles of the two drugs were also nearly identical. Both treatments were well tolerated. The most common adverse events were nausea (52%), vomiting (34%), pain (34%), constipation (30%), headache (22%), and fatigue (20%). Most of these adverse events were mild to moderate (WHO grade 1 to 2) and manageable. Thrombocytopenia occurred in 9% of patients in both groups, and grade 3/4 thrombocytopenia occurred in 7% of TMZ-treated patients and in 8% of DTIC-treated patients. Myelosuppression resulted in discontinuation in 3% of TMZ-treated patients compared with 5% of DTIC-treated patients. Of interest was that TMZ demonstrated an advantage in terms of improved quality of life. At week 24, a larger proportion (86% versus 38%) of patients in the TMZ arm had maintained or improved scores for physical functioning and global quality of life (77% versus 38%) compared with the DTIC arm.


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  		Table 3. Efficacy summary in patients with advanced metastatic melanoma
 
Treatment and Prevention of Brain Metastases

Although the phase III trial described above did not evaluate the efficacy of TMZ in patients with brain metastases, this remains an important question and one that is currently being addressed. Based on the clinical pharmacology of TMZ, it has been suggested that TMZ may be effective in the prevention and treatment of brain metastases. The levels of TMZ in the cerebrospinal fluid have been evaluated in a single melanoma patient following administration of TMZ at a dose of 150 mg/m2/day for five consecutive days. This study showed that the mean concentration of TMZ in the cerebrospinal fluid was approximately 30% of the plasma concentration on day 1 and day 5 [43]. These findings are consistent with previously published preclinical studies [10]. Therefore, TMZ would be expected to be more effective than DTIC in patients with brain metastases and may have a role in the prevention of brain metastases. A recent report of a retrospective case review has provided preliminary support for this supposition. Summers et al. [44] have reported that among 40 patients with advanced melanoma treated with TMZ (n = 19) or DTIC (n = 21), the incidence of CNS relapse was lower in patients treated with TMZ. Two of 19 (10%) patients treated with TMZ developed CNS metastasis compared with 8 of 21 (38%) patients treated with DTIC. A multicenter, international, phase II trial of TMZ in melanoma patients with brain metastases before radiation therapy has also recently been completed and the data will be available soon.

Future Directions

The question remains how to incorporate TMZ into the current treatment strategies for metastatic melanoma. One attractive option is to combine it with other agents that have demonstrated efficacy in this disease. Several combination regimens have been investigated in phase I trials. We have reported a phase I trial of TMZ in combination with interferon alfa-2b in patients with previously untreated metastatic melanoma [45]. The preliminary report of this trial demonstrated that 750 mg/m2 TMZ over five days plus interferon alfa-2b (5 to 10 million IU/m2 subcutaneously three times per week) was well tolerated. Dose-limiting hematologic toxicity resulted in dose reductions in only 3 of 43 cycles; reversible hematologic toxicity resulted in dose delays in 18 of 43 cycles. A phase I trial of TMZ in combination with cisplatin has also been reported [46]. The rationale for this combination is based on the demonstrated single-agent activity of each of these drugs in melanoma, as well as the observation that cisplatin can inactivate AGT; subtherapeutic concentrations of cisplatin can increase the sensitivity of leukemic blasts to TMZ [46]. This study established the maximum tolerated dose of cisplatin at 75 mg/m2 on day 1 of each 28-day cycle with TMZ (200 mg/m2/day x 5 days). Cisplatin did not alter the pharmacokinetics of TMZ or alter its toxicity profile. No efficacy data were reported. These preliminary studies have established that TMZ can be combined with other chemotherapy agents and with biologic agents without increasing toxicity.

TMZ is also currently being investigated in a number of phase II biochemotherapy protocols in which TMZ is being substituted for DTIC. The Cytokine Working Group is conducting a phase II study of TMZ in combination with radiation therapy for patients with brain metastases. A trial has also been proposed to investigate whether the low-dose daily regimen of TMZ can prevent CNS relapse in patients who have been definitively treated for melanoma brain metastases with surgical excision or radiosurgery.

Conclusion

TMZ has demonstrated efficacy in patients with recurrent high-grade gliomas and appears to be at least equivalent in efficacy to DTIC for the treatment of advanced-stage melanoma, in which it may be effective in the treatment and prevention of brain metastases. TMZ is a convenient, orally bioavailable alkylating agent with excellent tolerability that may be useful as an alternative to DTIC either as a single agent or as part of combination regimens, including biochemotherapy regimens, for the treatment of metastatic melanoma. Its ease and convenience of administration make TMZ an attractive alternative to DTIC for patients with metastatic melanoma in whom palliation is a reasonable goal. Further study of this important new agent is warranted to determine the most effective application in the treatment of metastatic melanoma and other solid tumors.

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Received January 25, 2000; accepted for publication March 14, 2000.


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