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The Oncologist, Vol. 10, No. 4, 282-291, April 2005; doi:10.1634/theoncologist.10-4-282
© 2005 AlphaMed Press

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Three Emerging New Drugs for NSCLC: Pemetrexed, Bortezomib, and Cetuximab

Sarita Dubey, Joan H. Schiller

University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, USA

Correspondence: Joan H. Schiller, M.D., K4/548, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA. Telephone: 608-263-5389; Fax: 608-265-8131; e-mail: jhschill{at}facstaff.wisc.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the targets of new biologic anticancer drugs.
  2. Interpret pharmacodynamic characteristics of drugs and apply this information in clinical use.
  3. Identify approved indications for the use of these new drugs.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 
Despite advances made in cytotoxic chemotherapy, the prognosis for patients with non-small cell lung cancer (NSCLC) continues to be poor. New, more effective drugs must be identified and developed to improve the outcome of these patients. Three drugs with promising activity in NSCLC are pemetrexed (Alimta®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com), bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA, http://www.mlnm.com), and cetuximab (Erbitux®; ImClone Systems, Inc., New York, NY, http://www.imclone.com). Pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase, enzymes necessary for purine and pyrimidine synthesis, thus causing cell-cycle arrest in the S phase. Bortezomib, a proteasome inhibitor, interferes with the cytosolic protein degradation machinery, namely the ubiquitin-proteasome complex, causing breakdown of cell-cycle regulators and cell-cycle arrest. Cetuximab is a chimeric mouse-human antibody that inhibits ligand-dependent activation of the epidermal growth factor receptor, resulting in receptor internalization and inhibition of downstream pathways that, in turn, causes cell growth and progression. All three drugs are approved for different tumor types, and studies defining their role in NSCLC are under way.

Key Words. Lung cancer • Pemetrexed • Bortezomib • Cetuximab


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 
Lung cancer continues to be the leading cause of cancer-related deaths in the U.S., with approximately 160,000 estimated deaths in the year 2004 [1]. The median survival time of patients with stage IV disease treated with standard chemotherapy regimens is approximately 8–11 months [2, 3]. The addition of a third drug to the standard chemotherapy doublet offers no therapeutic benefit and results in increased toxicity [4, 5]. In the relapsed setting, the median survival time with single-agent therapy is approximately 5–7 months, and time to progression is merely 8–10 weeks [6, 7]. The need for new agents is obvious.

Pemetrexed (Alimta®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com), bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA, http://www.mlnm.com), and cetuximab (Erbitux®; ImClone Systems, Inc., New York, NY, http://www.imclone.com) are three novel agents that are biologically distinct from one other and have approved indications in different malignancies. All three have promising antitumor activity in non-small cell lung cancer (NSCLC) in preclinical models and in early-phase NSCLC trials. In this review, we address their development in NSCLC.


   PEMETREXED
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 
Mechanism of Action
Pemetrexed is a multitargeted antifolate drug that targets the enzymes thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT) [8]. TS converts deoxyuridine monophosphate to deoxythymidine monophosphate during pyrimidine synthesis, GARFT is involved in purine synthesis, and DHFR produces tetrahydrofolate during folate metabolism. Even though pemetrexed resembles fluorouracil, by inhibiting TS, and methotrexate, by inhibiting DHFR, by virtue of GARFT inhibition, it overcomes TS resistance. Thus, by targeting different enzymes, pemetrexed affects the synthesis of substrates necessary for cell growth and division and causes cell-cycle arrest by accumulation of cells in the S phase [9]. Pemetrexed is transported in the cell as a reduced folate and is converted to its active polyglutamate form by folylpolyglutamate synthase [10]. Decreased activity of folylpolyglutamate synthase and decreased folate transportation across the cell lead to resistance to pemetrexed [11].

Preclinical Studies
Pemetrexed has demonstrated antitumor activity in a variety of solid tumor cell lines. For example, response rates of 25% in NSCLC and 32% in colorectal cancer cell lines have been reported [12, 13]. Pemetrexed was active even in methotrexate and ralitrexed-resistant (Tomudex®; AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com) cell lines that had TS amplification. Additive or synergistic effects were obtained when pemetrexed was combined with other cytotoxic agents, including 5-fluorouracil, gemcitabine (Gemzar®; Eli Lilly and Company), cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), paclitaxel (Taxol®; Bristol-Myers Squibb), doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com), oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York, NY, http://www.sanofi-synthelabo.us), and irinotecan (Camptosar®; Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) [14, 15]. Sequencing of drugs by administering pemetrexed prior to 5-fluorouracil and gemcitabine produced the highest response [14, 16].

Clinical Studies

Phase I Studies

Single-Agent Studies Several phase I studies of single-agent pemetrexed have evaluated different dosing schedules. In one study, 25 patients were treated with pemetrexed administered over 10 minutes weekly for 4 weeks out of every 6 [17]. In a second trial, pemetrexed was administered for 5 days every 3 weeks [18]. Reversible neutropenia was the dose-limiting toxicity (DLT) in both of those studies. No major responses were seen.

A third phase I study administered pemetrexed once every 21 days [19]. The maximum-tolerated dose (MTD) was defined as 600 mg/m2 based on hematologic toxicities, which included neutropenia and thrombocytopenia. Nonhematologic toxicities included fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible transaminitis. Partial responses were seen in two patients with pancreatic cancer and in two patients with colorectal cancer.

Since pemetrexed is metabolized by the kidney, a phase I study evaluated the safety of pemetrexed in patients with altered renal function [20]. Patients were stratified in cohorts based on creatinine clearance. DLTs again involved myelosuppression. That study demonstrated that, for those with moderate renal dysfunction, with a creatinine clearance of 40 mg/ml or more, pemetrexed can be administered at a dose of 500 mg/m2 every 3 weeks.

Combination Studies Adjei et al. conducted a phase I combination study evaluating two separate schedules of pemetrexed and gemcitabine [21]. All patients received gemcitabine on days 1 and 8 of a 21-day cycle. Thirty-five patients in cohort 1 received pemetrexed on day 1 and 21 patients in cohort 2 received pemetrexed on day 8. The DLT was neutropenia. The MTDs were 1,000 mg/m2 gemcitabine and 500 mg/m2 pemetrexed in cohort 1 and 1,250 mg/m2 gemcitabine and 500 mg/m2 pemetrexed in cohort 2. Partial responses were seen in seven patients with various malignancies in cohort 1 and in six patients in cohort 2. That study demonstrated that the regimen of gemcitabine on days 1 and 8 and pemetrexed on day 8 is active and is the better tolerated regimen.

Phase I studies have shown that combinations of pemetrexed with cisplatin or docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) are feasible [22, 23]. DLTs with those combinations, as expected, were hematologic. A response rate of 11% in head and neck cancer patients was seen with the docetaxel combination, whereas a response rate of 27% was seen with the cisplatin combination in patients with head and neck cancers and pleural mesothelioma.

Phase II Studies
The encouraging activity shown by pemetrexed in phase I trials led to phase II NSCLC studies. In all studies, pemetrexed was administered once every 21 days as recommended by the phase I studies.

Single-Agent Studies In relapsed NSCLC, a single-agent, phase II study was conducted with pemetrexed at a dose of 500 mg/m2 every 21 days [24]. Of the 81 patients, 45 had received prior platinum therapy. Patients in each arm had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0 or 1. Response rates and median survival times were 4.5% and 6.4 months in the platinum-treated group and 14% and 4.0 months in the nonplatinum-treated group. The principal toxicity was myelosuppression, with grade 3/4 neutropenia occurring in 35% of patients.

Two single-agent, phase II studies were conducted in untreated NSCLC patients [25, 26]. In the first study, 59 patients received pemetrexed at a dose of 500 mg/m2 every 21 days. Thirty-two patients had performance status scores of 2, indicating that this was a relatively poor prognosis group of patients. The overall response rate and median survival time were 15.8% and 7.2 months, respectively. In the second study, 33 patients were treated with pemetrexed at a dose of 600 mg/m2 every 3 weeks. Only one patient had a performance status score of 2. The response rate seen in that study was higher, at 23%. Toxicities were similar in the two studies, with grade 3 and 4 neutropenia in approximately 40% of patients. More than one third of the patients had grade 3 or 4 rashes. Pretreatment with dexamethasone (Decadron®; Merck and Co., Inc., Whitehouse Station, NJ, http://www.merck.com) during subsequent cycles prevented the recurrence of rash.

Combination Studies Based upon the single-agent activity of pemetrexed in NSCLC, combination studies were conducted with cisplatin, carboplatin (Paraplatin®; Bristol-Myers Squibb), and gemcitabine, with encouraging response rates and survival times. In two front-line phase II studies, a total of 67 patients were treated with pemetrexed and cisplatin on day 1 of a 21-day cycle [27, 28]. Patients with performance status scores of 0–2 were included. The partial response rate was similar in both studies (45%), and the median survival times were 9 and 11 months. Grade 3–4 neutropenia was observed at frequencies of 35% and 59% in the two trials, and grade 3 nausea was observed in 6% of the patients in both studies. In order to improve the toxicity profile, the combination of pemetrexed and carboplatin was explored [29]. Fifty patients were treated with carboplatin (to an area under the concentration-time curve [AUC] of 6) and pemetrexed (500 mg/m2) on day 1. The partial response rate was 28% and the median survival time was 14 months. Thus, the carboplatin combination appeared to have similar activity to the cisplatin combination with lower incidences of grade 3/4 neutropenia (34%) and grade 3 nausea (2%).

A phase II study of the pemetrexed/gemcitabine combination adopted the schedule recommended by the phase I study of Adjei et al., in which gemcitabine on days 1 and 8 and pemetrexed on day 8 was the better tolerated regimen [30]. Even though the partial response rate was lower, at 15.5%, the median survival time of 10.1 months compared favorably with those of platinum combinations without the platinum-associated toxicities.

Phase III Studies
Following the encouraging phase II results, two randomized phase III studies were done in patients with thoracic malignancies, which led to U.S. Food and Drug Administration (FDA) approval (Table 1Go). The first study was a randomized comparison between cisplatin and a combination of cisplatin and pemetrexed in patients with unresectable malignant mesothelioma [31]. Four hundred fifty-six patients were randomized to receive cisplatin at a dose of 75 mg/m2 or cisplatin at the same dose with pemetrexed at a dose of 500 mg/m2 once every 21 days. Three deaths were observed in the first 43 patients randomized to the pemetrexed arm. Because of the excessive toxicity associated with high homocysteine and methylmalonic acid levels in other pemetrexed studies, a protocol amendment requiring B12 and folate supplementation for all subsequently treated patients was made.


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  		Table 1. Pemetrexed phase III trials
 
The combination of pemetrexed and cisplatin proved to be superior to single-agent cisplatin. The response rates and median survival times were 41% and 12.1 months in the combination arm and 17% and 9.3 months in the cisplatin arm. The median survival time of supplemented patients in the combination arm was 13.3 months, versus 10.0 months for patients in the cisplatin arm (p = .051). Thus, supplementation did not compromise the activity of the regimen.

The only phase III trial of pemetrexed in NSCLC was a survival comparison between pemetrexed and docetaxel in relapsed NSCLC [32]. Until that trial, docetaxel was the only FDA-approved cytotoxic chemotherapy for the second-line treatment of NSCLC. In this noninferiority study, both pemetrexed and docetaxel were given on day 1 of a 21-day cycle. Patients in both arms were premedicated with dexamethasone. Patients in the pemetrexed arm also received folate and B12 supplementation. Seventy-five percent of the patients in both arms had ECOG performance status scores of 2. Response rates were 9.1% and 8.8%, and median survival times were 8.3 and 7.9 months in the pemetrexed and docetaxel arms, respectively. The docetaxel arm had higher incidences of grade 3 and 4 neutropenia (40% versus 5%), neutropenic fever (13% versus 2%), and neuropathy (8% versus 3%) than the pemetrexed arm. Thus, pemetrexed produced similar results and was better tolerated than docetaxel in the treatment of patients with pretreated NSCLC, leading to the FDA approval of pemetrexed in relapsed NSCLC.

Vitamin Supplementation Elevated homocysteine levels are the most sensitive indicators of folate and vitamin B12 deficiency and correlate with pemetrexed-induced toxicity [33, 34]. Vitamin supplementation with folic acid and B12 has been shown to reduce pemetrexed-related toxicities without compromising clinical benefit [31, 35]. Hence, supplementation with both vitamin B12 and folate is recommended. A useful guideline is to use folic acid at a dose of 350–1,000 µg/day orally and B12 at a dose of 1,000 µg intramuscularly every 9 weeks. Both supplements should be started 1–2 weeks prior to chemotherapy and continued until discontinuation of therapy.


   BORTEZOMIB
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
 Bortezomib
Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 
Mechanism of Action
Cellular proteins are degraded by the ubiquitin-proteasome complex [36]. Protein substrates that need to be degraded are marked by ubiquitin, a smaller cytosolic protein. Ubiquitin-marked proteins are presented to the 26S proteasome complex, which consists of a 20S proteasome, 19S proteasome, and multiple ATPases and peptidases. The ubiquitin-proteasome pathway is responsible for the proteolysis of cellular proteins, including those involved in cell-cycle regulation, such as the cyclin-dependent kinases (CDKs) and their inhibitors (CDKIs) [37]. Proteasomes are also required for the maintenance of NF{kappa}B by degrading its inhibitor I{kappa}B. NF{kappa}B is an important regulator of transcription for certain genes and adhesion molecules involved in the cellular inflammatory response and tumor growth.

Bortezomib is a proteasome inhibitor. By inhibiting proteasomes, bortezomib increases the levels of the CDKI p21 and causes G2-M cell-cycle arrest and, subsequently, apoptosis of tumor cells [38]. In addition to disrupting the proteasome pathway, bortezomib has antitumor effects through a variety of other mechanisms. For example, bortezomib inhibits vascular endothelial growth factor (VEGF) secretion in the bone marrow, inhibits VEGF-mediated caveolin phosphorylation, and decreases caveolin expression [39]. Caveolae are vesicular invaginations of the cell membrane that contain proteins called caveolins. Caveolin-1 is important for interleukin-6 and insulin-like growth factor-I-dependent growth and VEGF-dependent migration of multiple myeloma cells. Bortezomib also causes cell death by the generation of reactive oxygen species, which can be blocked by antioxidants [40].

Preclinical Studies
Bortezomib has demonstrated antitumor activity in preclinical models by a variety of mechanisms. By increasing the levels of the CDKI p21 and cyclins A and B, bortezomib treatment in NSCLC cell lines resulted in cell-cycle arrest in the G2-M phase [41, 42]. Of note, the proapoptotic gene p53 increased the activity of bortezomib: cell lines with mutant p53 exhibited a sixfold greater resistance to bortezomib. In mice models, bortezomib caused regression of squamous cell cancers through inhibition of NF{kappa}B and a decrease in angiogenesis [43].

In preclinical models, proteasome inhibition and cell death were observed 24 hours after initiating treatment and increased at 48–72 hours. This observation provided strong pharmacodynamic rationale for twice-weekly dosing of the drug.

Clinical Studies

Phase I Studies

Single-Agent Studies Given that the duration of proteasome inhibition is 48–72 hours, all clinical studies have used a regimen of bortezomib administered on days 1, 4, 8, and 11. Two phase I trials tested a schedule of twice-weekly drug administration for 4 weeks followed by 2 weeks of rest [44, 45]. The first study, which was conducted in patients with refractory hematologic malignancies, defined the MTD as 1.04 mg/m2. One complete response and decreases in paraprotein levels in eight others were observed. Toxicities in both studies included thrombocytopenia and nonmyeloid toxicities, such as anorexia, fatigue, electrolyte disturbances, and nausea. A third phase I study, conducted in a variety of solid tumors, administered bortezomib on days 1, 4, 8, and 11 of a 21-day cycle [46]. Forty-three patients were treated on this schedule. The DLTs were diarrhea and sensory neuropathy. No hematologic toxicities were observed. One major response was seen in an NSCLC patient. All the phase I studies demonstrated a dose-related proteasome inhibition, with the return of proteasome activity to baseline prior to the next infusion. The mean elimination half-life of bortezomib was 9–15 hours.

Combination Studies Based upon its encouraging single-agent activity, bortezomib was combined with other agents in phase I studies. Bortezomib was administered on days 1, 4, 8, and 11 in combination with gemcitabine on days 1 and 8 of a 21-day cycle [47]. The MTDs were 1.0 mg/m2 bortezomib and 1,000 mg/m2 gemcitabine. DLTs seen at these doses were grade 3 thrombocytopenia and grade 3 leukopenia. One patient with NSCLC had a partial response. When combined with carboplatin and gemcitabine in a phase I NSCLC study, the MTDs were 1.0 mg/m2 for bortezomib and 1,000 mg/m2 for gemcitabine with carboplatin at an AUC of 5 [48]. Grade 3 and 4 toxicities were hematologic. Four partial and five stable disease responses were observed in the ten evaluable patients. Similarly, the combination of bortezomib and irinotecan was found feasible, without pharmacokinetic interactions or additive toxicities [49]. The MTDs were defined as 1.3 mg/m2 for bortezomib (days 1, 4, 8, and 11) and 125 mg/m2 for irinotecan (days 1 and 8) in a 21-day cycle. Two patients experienced response by Response Evaluation Criteria In Solid Tumors criteria.

Phase II Studies

Single-Agent Studies Bortezomib recently received FDA approval for the treatment of relapsed myeloma based upon the rate and duration of response in two phase II studies. Partial response rates ranged from 23%–35%, with a median duration of response of 12 months and a median overall survival time of 16 months [50, 51]. Grade 3 and 4 neutropenia and thrombocytopenia occurred less frequently than nonhematologic toxicities such as asthenia, nausea, diarrhea, anorexia, and constipation. A comprehensive review of the studies that led to accelerated approval in relapsed myeloma has been described by Kane et al. [52].

In minimally pretreated (≤1 prior chemotherapy regimens) NSCLC patients, 23 patients were treated with single-agent bortezomib at doses of 1.3–1.5 mg/m2 in 3-weekly cycles [53] (Table 2Go). One patient experienced a partial response and nine others had stable disease. The duration of response was >4 cycles in five patients. Grade 3 toxicities included nausea (three patients), sensory neuropathy (one patient), constipation (two patients), rash (one patient), and thrombocytopenia (three patients). Effects on NF{kappa}B reached a maximum 4 hours after drug administration, with recovery beginning in 24 hours. Thus, bortezomib demonstrated clinical activity in NSCLC, with a measurable effect on the biologic target.


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  		Table 2. Bortezomib phase II NSCLC trials
 

Combination Studies A recently completed randomized phase II study compared a 1.5-mg/m2 bortezomib dose with the combination of 1.3 mg/m2 of bortezomib and 75 mg/m2 of docetaxel in pretreated patients with NSCLC. Docetaxel was administered on day 1 of a 21-day cycle. Preliminary results indicate that adverse events, including nausea (59% versus 35%), fatigue (38% versus 48%), diarrhea (38% versus 29%), and neutropenia (55% versus 3%), respectively, were more common in the combination arm than in the single-agent bortezomib arm [54] (Table 2Go). An interim analysis revealed partial response rates of 10.3% in the bortezomib arm (n = 29) and 16% in the combination arm (n = 31). Although final results are pending, the study demonstrated that bortezomib has activity in pretreated patients as a single agent and may have greater activity in combination therapy with docetaxel.


   CETUXIMAB
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
Conclusion
 Disclosure of Potential...
 References
 
Mechanism of Action
Cetuximab is a monoclonal human-murine chimeric antibody against the epidermal growth factor receptor (EGFR). EGFR is overexpressed in a variety of solid tumors, including NSCLC. The binding of a ligand, such as transforming growth factor-{alpha} and EGF, triggers EGFR tyrosine kinase phosphorylation, which in turn activates cellular pathways such as the mitogen-activated protein kinase, phosphatidylinositol 3' kinase, and Akt pathways [55]. The ultimate result is cell growth and tumor progression. In NSCLC, the EGFR is important in the process of neoplastic transformation and is found at an increased level in dysplastic bronchial epithelium and invasive cancer [56]. High EGFR gene copy numbers correlate with a poor prognosis [57].

Cetuximab competes with ligands for receptor binding, causing receptor internalization and preventing ligand-mediated receptor tyrosine kinase phosphorylation. This results in downstream events such as the upregulation of p27KIP1, a decrease of CDK2, cyclin A, and cyclin E, and cell-cycle arrest in G1 [58, 59].

Preclinical Studies
Cetuximab has shown significant antitumor activity in preclinical models. Cetuximab caused EGFR antagonism and tumor regression in A431, an EGFR-positive cell line, by competing for ligand binding on the EGFR [58, 60]. In GEO colon cancer cell lines, cetuximab inhibited tumor growth by a dose-dependent inhibition of VEGF production [61]. Synergistic activity was seen in combination with VEGF antisense oligonucleotide in this model. Cetuximab also augmented the tumor response to radiation in mice models [62]. It is hypothesized that the antiangiogenic effect of cetuximab increased the radiosensitivity of these tumors. These preclinical models illustrated the activity of cetuximab as a single agent and in combination with other agents, paving the way for further investigation.

Clinical Studies

Phase I Studies

Single-Agent Studies Two pharmacokinetic studies of a single dose of cetuximab were conducted in patients with solid tumors, with doses ranging from 50–500 mg/m2 weekly [63, 64]. Below 250 mg/m2, cetuximab was rapidly cleared. Between the doses of 250 and 400 mg/m2, the plasma half-life was 71–75 hours, supporting a weekly dosing regimen. Pre- and post-treatment biopsies demonstrated a biological effect of cetuximab on EGFR signal transduction in tumor and skin [63]. The majority of patients developed skin rashes, most of which were grade 1–2. In an ongoing study, patients with EFGR-overexpressing advanced malignancies were treated with either a single dose or multiple weekly doses of cetuximab [65]. The doses used were 5, 29, 50, and 100 mg/m2. Two patients with head and neck cancers had minor responses. Toxicities consisted primarily of fever, nausea, and fatigue.

Combination Studies In a multicenter phase I trial, patients with EGFR-expressing tumors were treated with cetuximab as a single dose (n = 13), multiple weekly dose (n = 17), or multiple weekly dose with cisplatin (n = 22, head and neck cancer or NSCLC only) [66]. As in other phase I studies, dose-dependent pharmacokinetics were seen. No difference in clearance was observed between the 250 and 400 mg/m2 doses, implying saturation of clearance at this level. Cisplatin did not alter the pharmacokinetics of cetuximab. Only one of the 52 patients developed antibodies to cetuximab. Mild rash, fever, transaminitis, and nausea were reported. Grade 3 toxicities in the combination arm consisted of diarrhea, epiglottitis, dyspnea, and anaphylaxis. The MTD was not reached. At the 200-mg/m2 dose level, saturation of clearance was observed, which correlated with a >50% receptor saturation, establishing the optimal biological dose of approximately 200 mg/m2 as the recommended phase II dose. Two patients with head and neck cancers achieved partial responses.

Phase II Studies
Single-agent and combination phase II studies of cetuximab were conducted in NSCLC (Table 3Go). In those studies, cetuximab was administered at a starting dose of 400 mg/m2 followed by 250 mg/m2/week.


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  		Table 3. Cetuximab phase II NSCLC trials
 

Single-Agent Studies Interim results of a single-agent, phase II study in recurrent NSCLC have been reported, with 29 EGFR-positive patients showing a partial response rate of 7% and a stable disease rate of 17% [67]. The mean number of cycles received was three. Grade 3 or higher toxicities included rash, cellulitis, fatigue, nausea, and vomiting. That study is ongoing.

Combination Studies In recurrent NSCLC, cetuximab has been combined with docetaxel (75 mg/m2 every 3 weeks) in patients with EGFR-positive tumors. A partial response rate of 28% and stable disease rate of 17% were reported in 47 patients [68]. The median number of cycles given was 10 and the median time to progression was 89 days. No pharmacokinetic interactions were observed between the two drugs. The most common grade 3 toxicities were fatigue (21%), infection (21%), and rash (19%). Four percent of the patients discontinued treatment due to allergic reactions. A survival analysis is ongoing.

A randomized, phase II design was used to study the combination of cisplatin and vinorelbine (Navelbine®; GlaxoSmithKline, Philadelphia, PA, http://www.gsk.com) with and without cetuximab in the first-line setting [69]. The drug regimen consisted of cisplatin at a dose of 80 mg/m2 on day 1 and vinorelbine at a dose of 25 mg/m2 on days 1 and 8. Ninety percent of the patients had EGFR-expressing tumors. Forty-three patients were enrolled in each arm. Higher frequencies of leukopenia (64% versus 51%), asthenia (17% versus 2%), infection (12% versus 5%), thrombocytopenia (7% versus 5%), acneiform rash (5% versus 0%), and diarrhea (2.4% versus 0%) were observed in the cetuximab arm. The cetuximab arm also had a higher response rate of 31.7% (95% confidence interval [CI] 17.5%–46%), versus 20% (95% CI 7.6%–32.4%), and median survival time (8.3 months versus 7.0 months). Statistical significance was not reported.

A single-arm, phase II study that combined cetuximab with carboplatin and gemcitabine showed a response rate of 22% and a median survival time of 277 days [70]. The most common cetuximab-related side effects were similar to those observed in other studies. Only one of the 35 patients suffered a grade 3 allergic reaction. The combination of carboplatin and paclitaxel, another popular NSCLC regimen, with cetuximab produced a response rate of 29% and a median overall survival time of 15.7 months in an EGFR-positive population [71]. Thus, preliminary phase II data suggest that cetuximab enhances the benefit of combination chemotherapy in chemotherapy-naive patients with NSCLC.

Rash appears to predict superior response to treatment with cetuximab. Data from trials in head and neck, colorectal, and pancreatic cancers demonstrate that patients who developed rashes with cetuximab had longer survival times. The median survival time of those with no rash was 2–4 months; patients with grade 2 rashes had a median survival time of 6–10 months and those with grade 3 rashes (with the exception of head and neck squamous cell carcinomas) had a median survival time of 10–13 months [72].

Phase III Studies
Although no randomized phase III studies in NSCLC have been reported, cetuximab has shown significant antitumor activity in head and neck and colorectal cancers. A phase III study in advanced squamous cell carcinoma of the head and neck compared radiation with radiation plus cetuximab [73]. The median survival time was significantly different in favor of the combination arm (54 months versus 28 months, p = .02). In a phase III study in relapsed colorectal cancer, cetuximab demonstrated a response rate of 18% and a median time to progression of 126 days in combination with irinotecan, compared with a response rate of 10% and a median time to progression of 45 days with cetuximab alone [74]. That study led to the FDA approval of cetuximab for recurrent colorectal cancer.

Thus, cetuximab has demonstrated antitumor activity in EGFR-expressing tumors and appears to enhance the activity of other anticancer agents, with a typical toxicity profile associated with EGFR inhibition, namely, rash and diarrhea. Given the encouraging results seen in phase II NSCLC studies, as well as in the phase III trials in head and neck and colon cancers, future trials combining cetuximab with other targeted agents or cytotoxic drugs is warranted.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
Disclosure of Potential...
 References
 
In conclusion, the advent of the targeted-therapy era in cancer therapy has led to the development of several agents with different cellular targets. Pemetrexed, bortezomib, and cetuximab are exciting new agents that have already found approved indications in relapsed NSCLC, relapsed myeloma, and relapsed colorectal cancer, respectively. Ongoing investigations in NSCLC will further identify other areas of benefit of these drugs.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
References
 
The authors indicated no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Pemetrexed
 Bortezomib
 Cetuximab
 Conclusion
 Disclosure of Potential...
 References
 

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Received October 12, 2004; accepted for publication January 3, 2005.




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