Molecular Targeted Agents in Non–Small-Cell Lung Cancer

Molecular Targeted Agents in Non–Small-Cell Lung Cancer Alan B. Sandler Abstract Although advances in chemotherapy have provided some improvement in overall survival for patients with advanced non–small-cell lung cancer (NSCLC), outcomes remain poor. Several targeted therapies for lung cancer are in development, and it is hoped that these new approaches will continue to improve survival for patients with advanced NSCLC. These new therapies are targeted specifically to the molecular pathways and processes that characterize tumor growth and progression, including uncontrolled cell growth, invasion, metastasis, angiogenesis, and resistance to apoptosis. Some molecules, such as protein kinase C and the epidermal growth factor receptor–tyrosine kinase, play central roles in cellular activity and are involved in many of the different signaling pathways underlying malignant transformation. Other molecules are dedicated to a specific process, such as the role of vascular endothelial growth factor in angiogenesis. New approaches use a variety of technologies to target these molecules, including small-molecule inhibitors, antibodies, and antisense oligonucleotides, among others. Many of these therapies are currently being tested alone or in combination with each other and with standard treatments for a variety of tumors. This article summarizes data on treatment of NSCLC with some of the agents that are the furthest along in clinical development. It is possible to envision a future in which a combination of therapies treat lung cancer on multiple fronts, significantly enhancing tumor responses and improving survival beyond current expectations. Clinical Lung Cancer, Vol. 5, Suppl. 1, S22-S28, 2003

Key words: Epidermal growth factor receptor–tyrosine kinase, Gefitinib, Targeted therapies

Introduction

emerged during the past decade, including paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan, and trials indicate single-agent activity that is possibly superior to cisplatin alone (Table 1). Phase II/III trials of cisplatin- or carboplatin-based combination chemotherapy demonstrate improved survival outcomes compared with single-agent cisplatin or carboplatin.1,3-6,11,13,14 However, in 3 phase III trials (Southwest Oncology Group [SWOG] 9509, SWOG 9308, and Eastern Cooperative Oncology Group [ECOG] 1594) comparing different cisplatin-based combinations of the new chemotherapy agent, no combination regimen showed markedly superior response rates or survival compared with any of the other treatment arms.7-9 Furthermore, the response rates in all treatment arms of these large trials were approximately 20%-28%, comparable to the rates previously observed with single-agent therapy.7-9 Although the newer agents may offer a slight improvement over platinum-based therapy alone, clinical trial data suggest that the treatment of advanced NSCLC has reached an efficacy ceiling (Figure 1).15 The efficacy of chemotherapy regimens is limited in part by the dosage restrictions necessitated by the toxicity associated with these agents. Rather than attempting to further refine current cytotoxic therapy combinations, new treatment modalities are needed to improve outcomes without significantly increasing toxicity. Recent advances in targeted therapy represent a paradigm

Non–small-cell lung cancer (NSCLC) is one of the most often-diagnosed cancer in the United States and is the leading cause of cancer death.1 The majority of lung cancers (approximately 80%, or 135,000 cases diagnosed annually) are NSCLC, and many of these (40%) present as advanced, metastatic disease.2 Platinum-based chemotherapy has been the standard of treatment for advanced NSCLC, providing measurable, although modest, benefits (Table 1).2-15 Cisplatin-based chemotherapy improves median survival by an average of 1.5 months and relieves symptoms in approximately 70% of symptomatic patients with stage III/IV NSCLC, thereby positively affecting quality of life, despite the associated toxic side effects.1 Several new agents for the treatment of advanced cancers have Vanderbilt-Ingram Cancer Center, Department of Medicine, Division of Hematology/Oncology, Vanderbilt University, School of Medicine, Nashville, TN Submitted: May 1, 2003; Revised: Jul 21, 2003; Accepted: Jul 23, 2003 Address for correspondence: Alan B. Sandler, MD, Vanderbilt-Ingram Cancer Center, Vanderbilt, University School of Medicine, 777 Preston Research Building, Nashville, TN 37232-6307 Fax: 615-343-7602; e-mail: [email protected]

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Clinical Lung Cancer Vol 5 • Suppl 1 September 2003

Survival and Response Rates of Different Chemotherapy Regimens in Clinical Trials2-15 Median Tumor 1-Year Chemotherapy Survival Response Survival Agent(s) (Months) Rate

Cisplatin Alone

10%-20%

28%

6-8

Monotherapy: Newer Agents Paclitaxel

26%

41%

8.5

Docetaxel

26%

52%

9.7

Vinorelbine

20%

24%

7.6

Gemcitabine

21%

39%

9.7

Irinotecan

23%

41%

8.1

Figure 1 Overall Survival of Patients with Stage IV Non–Small-Cell Lung Cancer by Treatment Group in ECOG 1594 100 Probability of Survival (%)

Table 1

Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplatin/Docetaxel Carboplatin/Paclitaxel

80 60 40 20 0 5

10

15

20

25

30

Time (Months)

Combination Therapy: Phase II Trials

There was no difference in survival between the different chemotherapy regimens in this large, randomized, phase III trial.9,15 Abbreviation: ECOG = Eastern Cooperative Oncology Group Source: Schiller JH et al. Plenary session presented at the Annual Meeting of the American Society of Clinical Oncology; May 22, 2000; New Orleans, LA. Reprinted with permission from the American Society of Clinical Oncology.

Etoposide/cisplatin

12%

32%

Docetaxel/cisplatin

35%

47%

9

Paclitaxel/cisplatin

42%

39%

10.4

Paclitaxel/carboplatin

46%

42%

9

Gemcitabine/cisplatin

47%

48%

11.1

Protein Kinase C Inhibitors

Irinotecan/cisplatin

45%

46%

10.6

ISIS 3521 (LY900003, Affinitak™)

39%

45%

10.2

25%

38%

8

28%

36%

8

Cisplatin

12%

20%

6

Vinorelbine/cisplatin

26%

36%

8

Paclitaxel/cisplatin

21%

31%

8

Gemcitabine/cisplatin

21%

36%

8

Docetaxel/cisplatin

17%

31%

7

Paclitaxel/carboplatin

15%

35%

8

One agent currently in development for the treatment of NSCLC is ISIS 3521 (LY900003, Affinitak™).19 This agent is an antisense oligonucleotide that inhibits the expression of protein kinase C-α (PKC-α), a key signal transduction molecule in the cellular proliferative response (Figure 2). Protein kinase C is a pleiotropic cellular effector that influences mitosis, differentiation, secretion, exocytosis, downregulation of receptors, apoptosis, and immune cell function. Increased expression of PKC-α has been reported for a variety of human tumors, including NSCLC. Although PKC-α is not a transforming oncogene, antisense inhibition of PKC-α reverses the malignant phenotype in tumor cell lines. ISIS 3521 hybridizes with PKC-α messenger RNA and blocks its translation into protein. ISIS 3521 has been tested in combination with chemotherapy in a multicenter phase I/II study of previously untreated patients with NSCLC.19 The trial design did not include screening for overexpression of PKC before treatment. ISIS 3521 was given by continuous infusion over 2 weeks (2 mg/kg/day), while carboplatin (area under the curve of 6) and paclitaxel (175 mg/m2 over 3 hours) were given on day 3. In a group of 48 evaluable patients, the overall response rate was 46% (complete [CR] and partial response [PR]), and 41% of patients achieved stable disease (SD). The median survival time was in excess of 1 year (19 months), with a 75% survival at 1 year. Average time to disease progression was 6.6 months. Toxicities were not significantly different from those with chemotherapy alone and included grade 3/4 neutropenia (57%) and grade 3/4 thrombocytopenia (25%), based on 53 enrolled patients. Although these results are promising, it is important to note this was a phase I/II trial involving a small, highly selected group of patients, and thus should not be overly interpreted. The effectiveness of ISIS 3521 in the treatment of patients

Vinorelbine/cisplatin

7.6

Combination Therapy: Phase III Trials SWOG 9509 Paclitaxel/carboplatin Vinorelbine/cisplatin SWOG 9308

ECOG 1594

Abbreviations: ECOG = Eastern Cooperative Oncology Group; SWOG = Southwest Oncology Group

shift in the treatment of NSCLC. Several new agents are in development that inhibit the processes underlying tumor growth and progression, such as inappropriate signal transduction, angiogenesis, or apoptosis. Farnesyltransferase inhibitors, receptor tyrosine kinase (TK) inhibitors, and monoclonal antibodies (MoAbs) can block aspects of signal transduction. Inhibitors of vascular endothelial growth factor (VEGF) and its receptor, matrix metalloproteinases (MMPs), and basic fibroblast growth factor are blockers of angiogenesis, as is the aminosterol squalamine.16 Other agents attempt to use molecules specifically expressed by tumor cells to target those cells for destruction (ie, toxin-antibody fusion protein).17,18 In addition, agents that stimulate apoptosis are also in development. This article summarizes the results of selected clinical trials that have explored the potential of these agents in the treatment of NSCLC.

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Molecular Agents in Non–Small-Cell Lung Cancer Figure 2 Signal Transduction Pathways Involving Protein Kinase C-α

Figure 3 Epidermal Growth Factor Receptor–Mediated Signal Transduction Pathways21

Hormones

Growth Factors

Cell Membrane Extracellular Domain

Ligand [TGF-α] EGFR

β

Gα

PLC

TK P

γ

P

Grb2

SOS

Ras

PKC

Intracellular Domain

TK P

Grb2

P

SOS

Ras

Raf-1 P

Raf-1

P

Other Enzyme or Adaptor

MEKK

Signaling Pathway

MEKK Cytoplasm

Gene Activation Cell Cycle Progression

MAPK

MAPK G2

Radiation or Selected Chemotherapy Agents

Transcription Factors

M

DNA Damage and Repair S

Gene Activity

Growth Arrest or Apoptosis G1

Nucleus Inhibition of Apoptosis

Proliferation

Nucleus Invasion

Abbreviations: MAPK = mitogen-activated protein kinase; MEKK = mitogen-activated protein kinase kinase; PKC = protein kinase C; PLC = phospholipase C; SOS = son of sevenless; TK = tyrosine kinase

with NSCLC has also been studied in a phase III trial. This trial accrued 616 eligible patients, stratified by disease stage and history of central nervous system metastases and randomized to 1 of 2 treatment arms. The first treatment arm consisted of carboplatin/paclitaxel in 3-week cycles, whereas the second arm consisted of 2 weeks of a continuous infusion of ISIS 3521 with carboplatin/paclitaxel beginning on day 3. Treatment continued for up to 6 cycles (or more if the patient benefited), with restaging for response every 2 cycles. The trial endpoints, as assessed in the follow-up after treatment, were survival and tumor progression. There was no significant difference in overall survival between the 2 groups (9.7 months vs. 10 months for arms 1 and 2, respectively).20 An analysis of survival in the 256 patients who completed the indicated course of chemotherapy showed that those patients who received ISIS 3521 had a significantly higher median survival (17.3 months) than those patients who received chemotherapy alone (14.3 months; P = 0.054).20 The combination therapy was well tolerated and there were no increases in serious toxicities in patients receiving ISIS 3521 plus chemotherapy. Patients who received ISIS 3521 plus chemotherapy had higher rates of thrombocytopenia, nausea, vomiting, and catheter-related infections.

Angiogenesis

Metastasis

Abbreviations: EGFR = epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; MEKK = mitogen-activated protein kinase kinase; SOS = son of sevenless; TGF-α = transforming growth factor–α; TK = tyrosine kinase Adapted with permission from Huang SM et al. Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs 1999; 17:259-269.

examined.22-24 Other ligands for EGFR include EGF and the heregulins. Ligand binding leads to receptor dimerization, which then activates the intracellular TK domain, resulting in EGFR-TK crossphosphorylation. In normal cells, EGFR-TK activity is tightly regulated, and its main function appears to occur during development. In human tumors, however, a variety of mechanisms may lead to increased EGFR-TK activity, which is linked with transformation, growth, and tumor progression. Such mechanisms may include abnormal expression of EGFR or its ligands, receptor crosstalk, decreased inactivation mechanisms, or mutations in EGFR that result in decreased receptor downregulation or constitutive activation of the TK domain.25-27 There are several new molecular agents in development that target the EGFR or the EGFR-TK enzyme, including the MoAb cetuximab (C225, Erbitux™) and the EGFR-TK inhibitors gefitinib (ZD1839, Iressa®) and erlotinib (OSI-774, Tarceva™). Gefitinib was recently approved for the treatment of NSCLC in the United States, Australia, and Japan.

Erlotinib (OSI-774, Tarceva™)

Epidermal Growth Factor Receptor Inhibitors The epidermal growth factor receptor (EGFR)–TK is another signal-transduction molecule known to play a central role in many of the processes underlying tumor development, including proliferation, differentiation, angiogenesis, resistance to apoptosis, invasion, and metastasis (Figure 3).21 Several studies have shown that EGFR and its ligand, transforming growth factor–α, are expressed in the majority (81%-99%) of lung cancers

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Erlotinib, a small-molecule EGFR-TK inhibitor, was tested in a phase II single-dose (150 mg/day) study in patients with NSCLC with disease progression or relapse following failure of platinum-based chemotherapy.28,29 Eligibility requirements for this study included having ≥ 10% of tumor cells expressing EGFR and no active brain metastasis. In 56 evaluable patients, the overall response rate was 12.3% (1 CR, 7 PRs) and 26.8% (n = 15) had SD. Median survival time was 8.4 months, with

Alan B. Sandler

Gefitinib Gefitinib, a selective EGFR-TK inhibitor, produced multiple responses in all phase I NSCLC studies. The primary endpoint of these trials is median survival. Approximately one third of the 100 patients with NSCLC who were treated with gefitinib experienced SD for ≥ 3 months, including some for > 1 year despite previous failed chemotherapy regimens.30 The efficacy of gefitinib for previously treated patients with advanced NSCLC has been investigated in the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) trials, in which > 400 patients with advanced NSCLC were enrolled. In IDEAL 1, eligible patients had stage IIIB/IV NSCLC with recurrent disease after 1 or 2 prior chemotherapy regimens, ≥ 1 of which was platinumbased. In IDEAL 2, patients had ≥ 2 prior chemotherapy regimens, including a platinum agent and docetaxel given concurrently or separately. Overexpression of EGFR in tumors was not an eligibility requirement in either of these trials. Gefitinib was administered at 250-mg/day and 500-mg/day doses, well below the maximum tolerated dose of 700-1000 mg/day. In IDEAL 1, the response rates were 18% in the 250-mg/day group and 19% in the 500-mg/day group. Overall survival times were 7.6 months and 8.0 months, respectively.31 In IDEAL 2, the response rates were 12% and 9%, respectively (Figure 4).32 Median survival times were 6.1 months and 6.0 months, respectively. In both IDEAL trials, treatment with gefitinib also resulted in improvements in lung cancer–related symptoms and quality of life.31,32 In IDEAL 2, symptom improvement was a primary endpoint; therefore, all patients were required to be symptomatic at baseline. Symptom response was assessed with the Lung Cancer Scale (LCS), a 28-point scale with a score of 28 indicating symptom-free status. A score of ≤ 24 at baseline was considered to indicate symptomatic status in the IDEAL trials. Symptom response was defined as an improvement of ≥ 2 points on the LCS.33 Patients receiving gefitinib at 250-mg/day and 500-mg/day doses showed symptom-improvement rates of 43% and 35%, respectively (Figure 4). Improvements in symptoms and quality of life correlated with tumor response and survival. Nearly all patients who achieved a tumor response also showed symptom improvement on the LCS, and 71% of those with SD also had symptom improvement.32 In contrast, only 17% of pa-

Figure 4 Response and Symptom Improvement Rates in Phase II Trial of Gefitinib32 Gefitinib 250 mg/day Gefitinib 500 mg/day

60 50

43% Patients (%)

48% survival at 1 year. Of the 8 responders, 6 had adenocarcinomas and 2 had large-cell carcinomas. All of these tumors were immunohistochemically positive for EGFR expression. Eighteen patients (32%) had diarrhea (1 patient ≥ grade 3) and 28 patients (50%) had acneiform dermatitis (1 patient ≥ grade 3). Almost all patients had some form of adverse skin events associated with treatment with erlotinib. Erlotinib is currently being investigated in combination with various chemotherapy regimens. In phase I pilot studies, some dose-limiting toxicities were seen with erlotinib plus cisplatin/gemcitabine combination therapy. Based on results from these pilot studies, 2 large phase III trials are under way to assess the effects of erlotinib in combination with carboplatin/paclitaxel (TRIBUTE) or cisplatin/gemcitabine (TALENT) in NSCLC.

40

35%

30 20 12% 10 0

9%

Response Rate

Symptom Improvement Rate

Response is radiographic tumor response. In this Iressa Dose Evaluation in Advanced Lung Cancer 2 trial, all responses were partial. Symptom response rate was defined as an improvement of ≥ 2 points on the Lung Cancer Scale lasting for ≥ 28 days.

tients with progressive disease had symptom improvement. In IDEAL 2, quality of life, as assessed by Functional Assessment of Cancer Therapy–Lung criteria, improved for 34% of patients in the 250-mg/day group and 23% of those in the 500-mg/day group, and also correlated with tumor response.32 Based on the results of the IDEAL trials, the US Food and Drug Administration recently approved gefitinib in third-line NSCLC. Two large phase III trials of gefitinib plus a combination of gemcitabine and cisplatin (Iressa NSCLC Trial Assessing Combination Therapy [INTACT]–1) or paclitaxel and carboplatin (INTACT-2) have recently been completed. While some of the data are still under analysis, combination therapy with gefitinib plus chemotherapy demonstrated no significant survival benefit compared with chemotherapy alone.

Cetuximab Cetuximab, an anti-EGFR MoAb, blocks ligand binding to the extracellular domain of EGFR, and has been shown in preclinical models to enhance the activity of cytotoxic drugs in several tumor types. Clinical trials of cetuximab include a study of colorectal cancer treated with irinotecan,34 a study of head and neck cancer treated with cisplatin,35 and a study of pancreatic cancer treated with gemcitabine.36 The synergism of cetuximab with chemotherapy has been demonstrated preclinically in NSCLC.37 Pilot studies of first-line therapy with carboplatin/ gemcitabine or carboplatin/paclitaxel, and second-line therapy with docetaxel/cetuximab are planned.

Angiogenesis Inhibition Increased vascularization is essential to the continued growth of a tumor and is another process targeted for antitumor strategies. Several approaches have been taken to block angiogenesis, including inhibiting VEGF and/or its TK receptor, cyclooxygenase (COX)-2, or MMPs.

Vascular Endothelial Growth Factor Many human tumors require VEGF for angiogenesis and

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Molecular Agents in Non–Small-Cell Lung Cancer Table 2

Phase II Trial of Carboplatin/Paclitaxel with or Without Anti-VEGF in Non–Small-Cell Lung Cancer40 All Patients

Parameter

Carboplatin/ Paclitaxel (n=32)

Patients with Non–Squamous-Cell Carcinoma

Carboplatin/ Carboplatin/ Paclitaxel plus Paclitaxel plus Carboplatin/ 7.5 mg/kg 15 mg/kg Paclitaxel rHuMoAb VEGF rHuMoAb VEGF (n=25) (n=32) (n=35)

Carboplatin/ Paclitaxel plus 7.5 mg/kg rHuMoAb VEGF (n=22)

Carboplatin/ Paclitaxel plus 15 mg/kg rHuMoAb VEGF (n=32)

Response Rate

18.8%

28.1%

31.4%

12%

31%

31%

25%

21.9%

34.3%

20%

27%

41%

Investigators

18.4

18.7

32.1*

16.9

19.1

32.1

IRF

25.8

17.7

29.6

16.9

22.2

31.3

56.8

49.9

61.5

53.4

61.2

77.7

Investigators IRF Time to Progression (Weeks)

Median Survival (Weeks)

*P < 0.044. Abbreviations: IRF = independent review facility; rHuMoAb = recombinant humanized monoclonal antibody; VEGF = vascular endothelial growth factor

growth, and the expression of VEGF is substantially increased in the majority of tumors.38 A murine anti-VEGF neutralizing antibody (muMoAb VEGF A461) has been shown to inhibit the growth of a variety of human tumor xenografts, leading to the generation of a recombinant, humanized version of this antibody. Phase I trials of recombinant humanized MoAb (rHuMoAb) VEGF determined therapeutic doses and established its tolerability as a single agent and in combination with chemotherapy.39 In a phase II trial, 99 previously untreated patients with stage IIIB/IV NSCLC were randomized to receive carboplatin/paclitaxel with or without rHuMoAb VEGF (7.5 mg/kg or 15 mg/kg) every 3 weeks. At the time of disease progression, patients in the control arm were eligible to receive rHuMoAb VEGF 15 mg/kg as a single agent. Enrolled patients had a mean age of 62 years and 61% were men. Most patients (93%) had a performance status of 0/1, 66% had stage IV NSCLC, and 18% had recurrent disease after surgery.40 In this trial, tumor responses were evaluated by an independent review facility as well as by study investigators. Results from both evaluations are shown in Table 2.40 There was a trend toward improvement in the high-dose rHuMoAb VEGF arm for overall response rate, time to progression, and median survival time; however, the only statistically significant difference was seen in the investigator evaluation of time to progression (32.1 weeks carboplatin/paclitaxel + high-dose anti-VEGF vs. 18.4 weeks carboplatin/paclitaxel alone; P < 0.044). Six patients (9%) treated with rHuMoAb had a life-threatening hemorrhage, 4 of which were fatal. All 6 patients who experienced these hemorrhages had large (> 3 cm) central lesions. Three hemorrhages occurred early, within the first chemotherapy cycle, whereas the other 3 occurred late in treatment, after the first 200 days. Five of these events occurred at

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Clinical Lung Cancer Vol 5 • Suppl 1 September 2003

the lower rHuMoAb dose. In the subcategory of non–squamous-cell carcinoma, the incidence of hemorrhage was only 4% (2 of 53), whereas the incidence in patients with squamous cell cancer was 31% (4 of 13). Squamous cell histology was also found to be associated with an increased incidence of hemoptysis. A subanalysis of the patients with non–squamouscell carcinoma showed a clearer trend toward improved time to progression and survival at the higher dose of anti-VEGF antibody (Table 2). Based on these results, the ECOG has an ongoing phase III trial of carboplatin/paclitaxel with or without anti-VEGF 15 mg/kg (ECOG 4599). No treatment crossover is allowed and survival is the primary endpoint. Because of the concern for life-threatening hemorrhage, patients with squamous-cell carcinoma are not eligible.

Cyclooxygenase-2 Another molecule implicated in angiogenesis and other cellular processes associated with cancer progression is COX-2. The closely related COX-1 is constitutively expressed and is involved in homeostatic functions such as maintenance of the gastrointestinal and renal tracts, platelet function, and macrophage differentiation. COX-2, conversely, is inducible and plays a role in inflammation and cancer cell growth. COX-2 is expressed in premalignancies, neovasculature, and in tumors. 41 It appears to play a particularly important role in colorectal cancer.42 Specific inhibitors of COX-2 are available and are currently being investigated for their anticancer potential. In an ongoing study conducted through Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center Affiliate Network, patients with NSCLC who have a performance status of ≤ 1 and have received prior chemotherapy are being treated with a combination of docetaxel and the specific COX-2 inhibitor celecoxib.

Alan B. Sandler Matrix Metalloproteinases Matrix metalloproteinases are believed to play a role in several tumor-related processes, including invasion, angiogenesis, and metastasis. In preclinical studies, MMP inhibitors have been shown to interfere with these processes. Several studies have described MMP expression in lung cancer, even though the level of expression and association with tumor stage are difficult to establish because of the small sample sizes and different approaches used.43 The role of MMPs in advanced NSCLC was investigated in a phase III trial of prinomastat (AG3340), a selective nonpeptidomimetic MMP inhibitor.44 Patients enrolled in this trial (N = 676) had stage IIIB/IV or recurrent disease, with a performance status of ≤ 2. These patients were previously untreated, and received prinomastat together with carboplatin/paclitaxel. There was no significant difference between the treatment arms for survival or overall response rate (Table 3).44 There was a trend toward improved survival at the higher dose of prinomastat compared with placebo (40% vs. 29%); however, due to the inclusion of 2 lower-dose arms, the trial was not sufficiently powered to determine statistical significance. This result illustrates the potential pitfalls of progressing too rapidly to larger clinical trials for these new, less-toxic therapies before carefully determining the biologically effective doses. Like many MMP inhibitors, prinomastat is associated with assorted joint symptoms, including pain and stiffness.43

Table 3

Placebo

Drugs that stimulate apoptosis, or programmed cell death, in cancer cells are currently in development. For example, exisulind (Aptosyn®) selectively inhibits cyclic guanosine monophosphate–phosphodiesterase (cGMP-PDE) and induces apoptosis in some cancer cells. Inhibition of cGMP-PDE increases cGMP levels, which, in turn, activates several signaling pathways that activate apoptosis. In preclinical studies, it was shown that exisulind induced apoptosis in a variety of cell lines. Exisulind has also been found to inhibit tumor growth in animal models. Exisulind is currently being evaluated alone and in combination with various types of chemotherapy in clinical trials in lung, colon, breast, and prostate cancers.

Conclusion A variety of new target therapies are being tested in combination with chemotherapy agents. In May 2003, gefitinib became the first EGFR-TK inhibitor to be approved by the US Food and Drug Administration. Proof of concept for gefitinib as a single agent has been established in the IDEAL monotherapy trials in patients with NSCLC who have received prior chemotherapy. Trials of the MMP inhibitor prinomastat in combination with carboplatin/paclitaxel or cisplatin/gemcitabine closed early because there were no demonstrable benefits. A trial of another MMP inhibitor, BMS275291, combined with carboplatin/paclitaxel is ongoing, and has completed accrual. Also, an ECOG trial (E4599) of rHuMoAb VEGF combined with carboplatin/paclitaxel in patients with lung cancer is ongoing, and the results are eagerly awaited. The apoptosis-inducing agent exisulind is also currently under investigation in

Prinomastat 5 mg

10 mg

15 mg

Response Rate

21%

27%

19%

18%

1-Year Survival

29%

30%

35%

40%

Progression-Free Survival (Months)

3.5

3.6

3.3

4.3

Median Survival (Months)

10.2

9.3

8.6

9.1

lung cancer. It is anticipated that future trials will test combinations of targeted agents (such as an EGFR-TK inhibitor plus antisense oligonucleotides or antiangiogenesis MoAbs) either alone or with chemotherapy. Several studies are underway to evaluate the potential clinical benefits of combining targeted therapies such as EGFR-TKIs with other targeted therapies. One example is the combination of the EGFR-TKI erlotinib with the anti-VEGF antibody bevacizumab (AvastinTM) for previously treated advanced NSCLC.45

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9. 10.

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12. 13. 14. 15. 16.

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