2005 Highlights From: First Annual Lung Cancer Symposium, New York, NY, November 2005

meeting highlight s

2005 Highlights From: First Annual Lung Cancer Symposium New York, NY, November 2005 Preliminary Analysis of a Randomized Phase II Trial Comparing Paclitaxel/ Carboplatin with or Without Panitumumab, a Fully Human Epidermal Growth Factor Receptor Monoclonal Antibody To date, epidermal growth factor receptor (EGFR)–targeted therapies have achieved only a limited role in the treatment of patients with non–small-cell lung cancer (NSCLC). Most notably, erlotinib, a small-molecule tyrosine kinase inhibitor (TKI), showed a statistically significant improvement in overall survival when compared with placebo in patients with relapsed/refractory NSCLC for whom previous platinum agent–based chemotherapy had failed.1 Despite this important achievement, clinical trial failures with EGFR-targeted agents have far outnumbered successes. As a prime example, although some preclinical models predicted a synergistic effect with the combination of EGFR-targeted agents and cytotoxic chemotherapy, 4 randomized trials combining either of the small-molecule EGFR TKIs (gefitinib or erlotinib) with platinum agent–based first-line chemotherapy failed to demonPrepared by: Amy D’Orazio, PhD; G. Kesava Reddy, PhD Reviewed by: Eric Nadler, MD; David R. Gandara, MD; Vinay K. Jain, MD

strate a benefit in response, time to progression, or overall survival (Table 1).2-6 The reasons why these combination therapies failed to improve outcomes are unclear. Potential explanations include lack of patient selection for the molecular target (EGFR) and/or antagonism between EGFR TKIs and chemotherapy based on TKI-induced G1 cell cycle arrest, blocking effects of chemotherapy in subsequent phases of the cell cycle.7 This latter effect, if proven, might be similar to the results seen with chemotherapy plus tamoxifen in the adjuvant treatment of breast cancer.8 Despite the negative results of EGFR TKIs in combination with chemotherapy in the 4 large trials cited, EGFR inhibitors with alternative mechanisms of action might hold promise. For example, in other malignancies, monoclonal antibodies such as cetuximab and rituximab have been shown to be effective when given concurrently with chemotherapy. Panitumumab is a novel EGFR monoclonal antibody that differs from cetixumab primarily in that it is fully humanized. As recently reported, phase III data in relapsed colorectal cancer demonstrate that this agent significantly increases progression-free survival when used as a single agent, with a 46% decrease in the likelihood of relapse (P < 0.000000001).7 To determine its safety and efficacy in NSCLC, Crawford et al conducted a 2part, randomized, phase II trial studying the combination of panitumumab and

paclitaxel/carboplatin in the first-line setting.6 The first part of the study reported that the combination was safe with acceptable toxicity. The second part of the phase II trial was to preliminarily determine the activity of the novel combination. Patients enrolled in this study had previously untreated stage IIIB or IV NSCLC with measurable lesions. Tumor EGFR expression in > 10% of cells by immunohistochemistry (IHC; IHC 1+ to IHC 3+) was required. Patients were randomized in a 2:1 ratio to receive paclitaxel/carboplatin plus panitumumab (arm 1) or paclitaxel/carboplatin alone (arm 2), each at a paclitaxel dose of 200 mg/m2 and carboplatin at an area under the curve of 6, every 3 weeks, with those in the combination arm receiving panitumumab 2.5 mg/kg per week. One hundred twelve patients were treated with paclitaxel/carboplatin plus panitumumab, with 54 receiving chemotherapy alone.6 There were no notable imbalances in the patient demographics: approximately 75% had stage IV disease, 10% never smoked, 2% were Asian, the majority (60%-67%) had adenocarcinoma, and 43% were women. At a median follow-up time of approximately 7 months, median time to disease progression (the primary endpoint) was 4.2 months with paclitaxel/carboplatin plus panitumumab and 5.3 months with paclitaxel/ carboplatin alone (P = 0.55). Median survival times were also similar at 8.5 months with paclitaxel/carboplatin plus

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Table 1: Randomized Trials of Chemotherapy Alone Versus Chemotherapy plus EGFR-Targeted Therapies in the First-Line Treatment of NSCLC2-6 Trial

Treatment

Median Survival (Months)

Median Time to Progression (Months)

Objective Response Rate (%)

Paclitaxel/Carboplatin

10.6

4.9

19

TRIBUTE5

Paclitaxel/Carboplatin plus Erlotinib

10.5

5.1

22

TALENT2

INTACT-13

INTACT-24

P Value

0.95

0.36

0.36

Gemcitabine/Cisplatin

10.1

5.6

57.7

Gemcitabine/Cisplatin plus Erlotinib

9.9

5.4

56.1

P Value

NS

0.74

– 45

Gemcitabine/Cisplatin

10.9

6

Gemcitabine/Cisplatin plus Gefitinib

9.9

5.5-5.8

50

P Value

0.46

0.76

NS

Paclitaxel/Carboplatin

9.9

5

29

Paclitaxel/Carboplatin plus Gefitinib

8.7-9.8

4.6-5.3

30

P Value

0.64

0.0562

NS

Abbreviation: NS = not significant

panitumumab and 8 months with paclitaxel/carboplatin alone (P = 0.81). Partial responses were seen in 15% and 11% of patients, respectively, with no complete responses in either arm. The comparison of randomized trials of chemotherapy alone versus chemotherapy plus TKIs is shown in Table 1. Serious adverse events are shown in Table 26 and occurred in similar proportions in both arms. Adverse events observed more frequently in the panitumumab-containing arm include rash/ acneiform dermatitis (all grades, 80%; grade 3/4, 16%) and diarrhea (6%).6 Only 7 patients had infusion-related adverse events possibly related to panitumumab, and all patients continued treatment without further episodes. In 80 evaluable patients with baseline and posttreatment samples available, there was no evidence of the formation of antihuman antibodies.

Clinical Relevance This randomized phase II trial was not statistically designed to gauge the relative efficacy of the 2 arms; however, the data do not suggest that the combination provides improved outcomes. Thus, these results are similar to those achieved in previous studies of small-molecule EGFR TKIs in combination with platinum-agent doublet chemotherapy. Further investigation should be made into the question of whether a subset of patients could achieve benefit. At the 2005 Annual Meeting of the American Association for Cancer Research, a subset of 60 patients was evaluated for the presence of potential activating EGFR mutations known to influence response to EGFR TKIs. Five somatic mutations were identified and present in 8 patients (13%), including a novel exon 20 alteration that has been reported to be associated with resistance to gefitinib.

Table 2: Selected Grade 3/4 Adverse Events Associated with Treatment6 Paclitaxel/Carboplatin plus Panitumumab (%)

Paclitaxel/Carboplatin (%)

16*

0

Diarrhea

6

2

Vomiting

8

9

Dyspnea

11

7

Dehydration

6

9

DVT/PE

10

11

Pneumonia

3

9

Adverse Event Rash/Acneiform Dermatitis

*80% of patients experienced rash (all grades). Abbreviations: DVT = deep vein thrombosis; PE = pulmonary embolism

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Preliminary Phase I/II Data on a Novel Epothilone: Patupilone in Patients with NSCLC Epothilones, naturally derived from the myxobacteria Myxococcus xanthus and Sorangium cellulosum, are a novel class of chemotherapeutic agents that stabilize microtubules and promote tubulin polymerization (Figure 1).9-11 However, their mechanism of action is distinct from that of taxanes, and they are not a substrate for P-glycoprotein. Epothilones, which exist in 1 of ≥ 4 forms (A-D), are G2/M phase–specific agents that lead to mitotic cell cycle arrest and eventually cell death through the apoptotic process.10 Furthermore, epothilones have demonstrated cytotoxicity in taxane-resistant tumors in preclinical studies. Epothilone B, a highly active form, and its derivatives are currently being investigated in patients with NSCLC.11-13 Patupilone, an epothilone-B analogue, has shown potent cytotoxic responses in xenograft mouse models of human breast, thyroid, and ovarian carcinomas as well as in leukemias and paclitaxel-resistant tumors.11 In addition, patupilone was found to accumulate to concentrations inside the cell that were several hundredfold higher than in the extracellular medium.14 Initial phase I dose-escalation studies of patupilone established the maximum tolerated dose (MTD) for the every-3-week regimen at 6 mg/m2 and at 2.5 mg/m2 for the weekly regimen.15-18 Diarrhea and asthenia were the most commonly observed dose-limiting toxicities (DLTs) of patupilone. Other adverse events included nausea, vomiting, and fatigue. In a phase I/II trial, Sachez and colleagues evaluated the MTD and efficacy of patupilone administered every 3 weeks Figure 1: Structure of Epothilone9-11

O S

R

12

OH

15

N

7

O 1 R = H: Epothilone A R = Ch3: Epothilone B

O

OH

O

Table 3: Dose-Escalation Scheme of Patupilone (N = 50)19 Patients (n)

Patupilone Dose (mg/m2)

Dose-Limiting Toxicity

1

3

6.5

None

2

3

7

None

3

6

7.5

Grade 3 asthenia (n = 1)

4

6

8

Grade 3 diarrhea (n = 1)

5

6

8.5

Grade 3 diarrhea (n = 1)

6

3

9

None

7

3

9.5

None

8

3

10

None

9

3

10.5

None

10

3

11

None

11

3

11.5

None

12

3

12

None

13

5

13

Grade 3 diarrhea (n = 1)

Cohort

in patients with NSCLC, with intensive management of chemotherapy-induced diarrhea. The results, presented at ECCO-13, the European Cancer Conference, held in Paris, France, October 30 through November 3, 2005, are summarized herein.19 Fifty patients with relapsed stage IIIB NSCLC with presence of pleural effusion or stage IV NSCLC were included in the study. Eligible patients were required to have a World Health Organization performance status of 0/1, adequate hematopoeitic function, and to have received previous platinum agent–based therapy. Patients in the initial cohort received patupilone at a starting dose of 6.5 mg/m2 via 20-minute intravenous infusion once every 3 weeks. Subsequent cohorts received doses escalated by 0.5mg/m2 increments (which were increased to 1-mg/m2 increments after the 12-mg/m2 cohort) in a standard 3 × 3 study design until the MTD was reached. Importantly, aggressive, proactive antidiarrheal management was implemented at the first sign of abdominal cramping, loose stools, or excessive diarrhea. During the ongoing phase II portion of this trial, patients will receive patupilone at the MTD until disease progression or unacceptable toxicity. At the time of analysis, a total of 50 patients with stage IIIB or IV NSCLC with a median age of 59 years (range, 33-77 years) were enrolled. All 50 patients had received previous platinum agent–based therapy, and 15 of the patients (30%) had received previous

taxane therapy. Patupilone at the initial 2 doses (6.5 mg/m2 or 7 mg/m2) had no DLT. However, between doses of 7.5 mg/m2 and 8.5 mg/m2, 1 of 6 patients in each cohort experienced a DLT, including grade 3 asthenia and grade 3 diarrhea. Interestingly, no DLTs were observed in the higher-dose cohorts of patupilone until 1 patient in the 13-mg/m2 dose cohort developed grade 3 diarrhea (Table 3).19 No grade 4 adverse events were seen among any of the 50 patients who received patupilone treatment. The most commonly observed grade 3 toxicities included febrile neutropenia (n = 1), thrombocytopenia (n = 1) diarrhea (n = 7), vomiting (n = 3), neuropathy (n = 3), and fatigue (n = 1; Table 4).19

Table 4: Grade 3 Adverse Events and Preliminary Efficacy of Patupilone (N = 50)19 Adverse Event

Patients (%)

Febrile neutropenia

1 (2)

Thrombocytopenia

1 (2)

Fatigue

1 (2)

Vomiting

3 (6)

Neuropathy

3 (6)

Diarrhea

7 (14)

Efficacy Complete response

0

Partial response

5 (10)

Stable disease

16 (32)

Progressive disease

25 (50)

Unknown

4 (8)

Forty-six patients were evaluable for tumor response. Preliminary antitumor activity was observed, with 5 patients (10%) having partial responses and 16 patients (32%) exhibiting disease stabilization. Progressive disease occurred in 25 patients (50%). No clear correlation between dose and clinical activity was reported in the phase I segment of the trial.

Clinical Relevance The every-3-week patupilone regimen appeared to be safe and well tolerated in pretreated patients with NSCLC. Preliminary evidence of single-agent activity was seen in refractory NSCLC, even though 30% of patients had received previous taxane therapy. Diarrhea and asthenia were the most common toxicities associated with patupilone. Although the MTD has not been reached with the standard 3 × 3 testing design, the recommended dose of patupilone for the ongoing phase II trial is 10 mg/m2.

Combining Novel Mammalian Target of Rapamycin Inhibitors with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Advanced-Stage NSCLC: Results of a Phase I Trial Everolimus (RAD001) is a novel, orally administered inhibitor of the mammalian target of rapamycin (mTOR) pathway (Figure 2) located downstream of the PI3K/AKT pathway and integral to cell survival and proliferation (Figure 3). In early-phase trials, everolimus has demonstrated preliminary evidence of activity and/or clinical benefit in patients with lung, colorectal, and other cancers. Although the mechanism of clinical resistance to EGFR-TKIs remains unknown, inhibition of the PI3K/AKT pathway has restored sensitivity to gefitinib in preclinical studies,20 thus providing the rationale for evaluating the combination of gefitinib and everolimus.21 Based on such preclinical underpinnings, an ongoing phase I/II trial is evaluating this combination in advanced-stage NSCLC. Preliminary data from this study

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237

Table 5: Results of a Phase IA Trial of Everolimus in Various Solid Tumors22

Figure 2: Rapamycin Analogues in the Clinic

Tumor

Weekly Dose of Everolimus (mg)

Best Response

Time on Everolimus (Weeks)

1

Hepatocellular

10

SD

28

2

Fibrosarcoma

10

SD

28

3

Colorectal

10

SD

29

4

Colorectal

20

SD

19

5

NSCLC

30

SD

22

6

NSCLC

30

PR

28

Patient

were presented by Miller at the Second Annual Symposium on the Future of Lung Cancer, held November 11-12, 2005, in Washington, DC.22 The objectives of the phase I portion of this trial were to determine the toxicity profile and optimal dosing of everolimus when administered in combination with gefitinib at a dose of 250 mg per day in patients with advanced-stage NSCLC (Table 5).22 The objective of the phase II portion of the study was to assess the efficacy of the combination in patients with treatment-naive and platinum agent–pretreated NSCLC. Patients enrolled in the phase I study had stage III/IV NSCLC, a Karnofsky performance status of ≥ 70%, and had received previous treatment with ≥ 1 chemotherapy regimen that included a platinum agent and docetaxel. Previous treatment with an EGFR-targeted TKI was not permitted. The oral treatment regimen consisted of a single dose of

O P

238

HO

Grade 3 (%)

Grade 4 (%)

Grade 5 (%)

Lymphopenia

1 (17)

1 (17)

–

–

Rash

2 (33)

–

–

–

Fatigue

2 (33)

–

–

–

Stomatitis

1 (17)

–

–

–

Pneumonia

1 (17)

–

–

–

Hypertriglyceridemia

1 (33)

–

–

–

Diarrhea

2 (67)

–

–

–

Stomatitis

–

1 (33)*

–

–

Increased creatinine

–

1 (33)*

–

–

Hypokalemia

–

1 (33)

–

–

Acidosis

–

–

1 (33)

–

Hypotension

–

–

–

1 (33)†

–

Clinical Lung Cancer January 2006

Temsirolimus O

Grade 2 (%)

*Dose-limiting toxicity. †Relationship to treatment undetermined.

AP23573

HO

5-mg Dose Level (n = 6)

43

O

HO

everolimus at 5 mg or 10 mg administered on day 1, followed by daily gefitinib at 250 mg per day beginning on day 8, and, finally, daily everolimus at 5 mg or 10 mg per day beginning on day 22. The first response assessment occurred on day 50, and pharmacokinetics were evaluated on days 1, 15, and 22. Ten patients with a median age of 64 years were treated as part of the phase I study. All had stage IV disease, and 1 (10%) had never smoked. Seven patients (70%) had received 2 previous lines of treatment. No DLTs were seen at the lower dose level (5 mg) of everolimus, with only 1 grade 3 adverse event (lymphopenia; Table 6).22 Among the 3 patients treated with everolimus at 10 mg per day, 2 experienced grade 3-5 toxicities. At the 10-mg dose, significant toxicities included grade 3 diarrhea, grade 3 metabolic derangements, and even grade 5 hypotension, although it is unclear whether the drug

10-mg Dose Level (n = 3)

R-O

Rapamycin

H

Table 6: Adverse Events: Phase I Trial of Everolimus plus Gefitinib in Pretreated NSCLC22 Adverse Event

R=

N O O O HO O O

O

OH

O O

O

Everolimus

Figure 3: mTOR Signaling Pathway Growth Factors

PTEN PI3K P Nutrients

Akt

High Oxygen Status High Energy State (high ATP) Raptor

P P

TSC1/2

mTOR

GβL

P P 4E-BP1 P P

P

elF4E

P

P S6K1

P

P P S6

P

Cap-dependent translation Tumor cell VEGF production

P

5'TOP messenger RNA translation

Synthesis of G1 ➞ S cell growth cell cycle and division progression machinery

Increase in cell size

Nutrient-sensing pathway dominates growth factor pathway

Abbreviation: ATP = adenosine triphosphate

contributed to the episode of hypotension. With regard to efficacy in this early phase I trial, 2 responses were reported among the 8 evaluable patients. The 2 responders were men and had a history of smoking; 1 had adenocarcinoma, and the other had squamous cell histology.

Clinical Relevance Preliminary data from this study suggest that combining an mTOR inhibitor (everolimus) with an EGFR TKI is safe and well tolerated at daily doses of 5 mg of everolimus and 250 mg of gefitinib. Two confirmed responses were seen among 8 heavily pretreated patients. The phase II portion of the trial, which will include 2 cohorts of patients (1 chemotherapy-naive and 1 pretreated), will be presented at the 2006 Annual Meeting of the American Society of Clinical Oncology.

Early Clinical Trial Data with HGS-ETR1/ETR2, Agonists of TRAIL, in Patients with NSCLC and Other Solid Tumors HGS-ETR1 (mapatumumab) and HGS-ETR2 are novel agonistic monoclonal antibody therapies targeting the TRAIL-R1 and TRAIL-R2 receptor, respectively (Figure 4). These transmembrane receptors belonging to the tumor necrosis factor (TNF) superfamily are expressed on a wide variety of tumor cells lines. Engagement of the TRAIL-R1 receptor with HGS-ETR1 leads to induction of apoptotic cell death via activation of caspases 3, 9, and 8 and related death pathways.23 Coadministration of HGSETR1 also potentiates the effects of cytotoxic agents such as 5-fluorouracil, irinotecan, and topotecan in colorectal cancer cell lines. Similar data have also been shown in lymphoma cell lines with enhancement of cytotoxicity from doxorubicin and bortezomib.24 A phase I trial of HGS-ETR1 in patients with various solid tumors was undertaken with the purpose of evaluating the safety of this agent administered every 14 or 28 days at escalating doses of 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg.25 Patient eligibility consisted of relapsed/ refractory advanced-stage solid tumors or non-Hodgkin’s lymphoma with an adequate performance status. Forty-nine patients were enrolled, 33% of whom had colorectal cancer, with 12% each having lung cancer or sarcoma and 8% each having renal cell cancer or prostate cancer. Figure 4: Potential Methods for Therapeutic TRAIL-R1 Activation Small molecule

Peptide

Antibody TRAIL

TRAIL-R1

Apoptosis

Table 7: ETR1-ST01–Related Adverse Events*25 Worst Toxicity Grade by NCI-CTC, Version 2 (N = 49) Event

1

2

3

4

Pyrexia

5

1

0

0

Myalgia

3

1

0

0

Hypotension

4

0

0

0

Hyperbilirubinemia

0

0

1

0

Nausea

1

1

0

0

Thrombocytopenia

1

1

0

0

Fatigue

2

2

0

0

Diarrhea

2

0

0

0

Rash

2

0

0

0

ARDS

0

0

0

1

Transaminitis

0

0

1

0

Peripheral Sensory Neuropathy

0

0

1

0

*Events considered at least possibly related to HGS-ERT1 occuring in ≥ 2 patients (any grade) or ≥ 1 patient (grade ≥ 3) up to the 10-mg/kg dose level. Abbreviations: ARDS = acute respiratory distress symdrome; NCI-CTC = National Cancer Institute Common Toxicity Criteria

Treatment was tolerated well, with rare or no DLTs seen until treatment was administered at 10 mg/kg every 14 days; at this dose level, 2 of 11 patients experienced a DLT. Overall, the only grade 3 toxicities seen included transaminitis, hyperbilirubinemia, and peripheral neuropathy in 1 patient each, and only 1 patient experienced a grade 4 adverse event (acute respiratory distress syndrome; Table 7).25 Stable disease was the best response seen in this patient cohort. Additional phase I and phase IB clinical trials are ongoing with HGS-ETR1 in

various solid tumors as well as nonHodgkin’s lymphoma, including evaluation of this agent in combination with chemotherapy regimens such as paclitaxel/carboplatin and gemcitabine/cisplatin. In an ongoing phase II trial in patients with NSCLC, single-agent HGS-ETR1 was administered at a dose of 10 mg/kg every 21 days, producing disease stabilization in 29% of a heavily pretreated patient population. HGS-ETR2 is also undergoing evaluation in phase I clinical trials. In a phase I trial in advanced solid tumors, HGS-ETR2

Table 8: ETR1-ST01–Related Adverse Events* (N = 37)25 Grade 1

Grade 2

Grade 3

Grade 4

Increased ALT

0

0

–

2

Increased AST

0

0

–

2

Increased Blood Amylase

1

0

2

–

Increased Bilirubin

0

0

1

–

Increased GGT

0

1

–

–

Nausea

4

0

–

–

Constipation

0

1

–

–

Acute Renal Failure

0

0

–

1

Fatigue

4

1

1

–

Pyrexia

1

1

–

–

Migraine

0

1

–

–

Epistaxis

0

1

0

0

Hypotension

0

1

0

0

Ovarian Failure

0

1

0

0

Event

*Events considered at least possibly related to HGS-ETR1 occuring in ≥ 2 patients or any grade ≥ 2 event up to the 20-mg/kg dose level. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = γ glutamyl transpeptidase

Clinical Lung Cancer January 2006

239

was administered to 37 patients at escalating doses (0.1-20 mg/kg) every 3 weeks.25 Grade 3/4 adverse events include increased liver enzyme levels in 4 patients (11%), increased blood amylase in 2 patients (5%), and increased bilirubin, acute renal failure, and fatigue in 1 patient (3%) each (Table 8).25 Three patients who experienced grade 3/4 adverse events were among the 7 treated at the highest dose

Targeting TRAIL receptors is a rational therapeutic strategy based on their ability to initiate a cascade of events leading to programmed cell death. Two monoclonal antibodies that target these receptors

are currently in clinical development (HGS-ETR1 and HGS-ETR2). Both of these agents appear to be able to cause tumor stabilization in heavily pretreated patients with various solid tumors, with DLTs including increased liver enzyme levels and lipases and renal toxicity. Additional phase I/II clinical trials are ongoing.

class of non-taxane microtubule-stabilizing agents. Curr Pharm Des 2002; 8:1707-1712. Goodin S, Kane MP, Rubin EH. Epothilones: mechanism of action and biologic activity. J Clin Oncol 2004; 22:2015-2025. Rothermel J, Wartmann M, Chen T, et al. EPO906 (epothilone B): a promising novel microtubule stabilizer. Sem Oncol 2003; 30(suppl 6):51-55. Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 1995; 55:2325-2333. Kowalski RJ, Giannakakou P, Hamel E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol) (R). J Biol Chem 1997; 272: 2534-2541. Wartmann M, Koppler J, Larigot M, et al. Epothilones A and B accumulate several-hundred fold inside cells. Proc Am Assoc Cancer Res 2000; 41:213 (Abstract #1362). Calvert PM, O’Neill V, Twelves C, et al. A phase I clinical and pharmacokinetic study of EPO906 (epothilone B), given every three weeks, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001; 20:108a (Abstract #429). Calvert PM, O’Neill V, Azzabi A, et al. A phase I clinical and pharmacokinetic study of EPO906 (epothilone B) in patients with advanced solid tumors. Clin Cancer Res 2000; 6:4581S (Abstract #575). Rubin EH, Siu LL, Beers S, et al. A phase I and pharmacologic trial of weekly epothilone B in patients with advanced malignancies. Proc Am Soc Clin Oncol 2001; 20:68a (Abstract #270). Oesterlind K, Sanchez J, Zatloukal P, et al. A phase I/II dose-escalation trial of patupilone (EPO906) administered every 3 weeks in patients with non-small cell lung cancer (NSCLC). Ann Oncol 2004; 15(suppl 3):167 (Abstract #631PD). Sanchez JM, Oesterlind, K, Perry M et al. Phase I/II dose-escalation trial of patupilone every 3 weeks in

patients with non-small cell lung cancer (NSCLC). Presented at: ECCO-13, the European Cancer Conference; October 30 through November 3, 2005; Paris, France. Abstract #1133. Han S-W, Hwang PG, Chung DH, et al. Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa®, ZD1839) in chemotherapy-resistant non-small cell lung cancer. Intl J Cancer 2005; 113:109-115. Stallings-Mann M, Wharen R, Thomas CY. Resistance of glioblastoma cells to an EGFR kinase inhibitor is associated with maintenance of signaling by phosphatidylinositol-3-kinase (PI3K) and constitutive phosphorylation of the Gab1/Gab2 adapter proteins. Proc Am Soc Clin Oncol 2002; 21:19a (Abstract #72). Goudar RK, Shi Q, Hjelmeland MD, et al. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 2005; 4:101-112. Pukac L, Kanakaraj P, Humphreys R, et al. HGSETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Brit J Cancer 2005; 92:1430-1441. Georgakis GV, Li Y, Humphreys R, et al. Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Brit J Haematol 2005; 130:501-510. Pacey S, Plummer RE, Attard G, et al. Phase I and pharmacokinetic study of HGS-ETR2, a human monoclonal antibody to TRAIL R2, in patients with advanced solid malignancies. J Clin Oncol 2005; 23(16 suppl):205s (Abstract #3055).

level; therefore, 10 mg/kg was established as the MTD. Additional trials are planned.

Clinical Relevance

References 1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123-132. 2. Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004; 23:617 (Abstract #7010). 3. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1. J Clin Oncol 2004; 22:777-784. 4. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 2. J Clin Oncol 2004; 22:785-794. 5. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892-5829. 6. Crawford J, Sandler A, Hammond L, et al. ABX-EGF in combination with paclitaxel and carboplatin for advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004; 23:634 (Abstract #7083). 7. Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out? J Clin Oncol 2005; 23:5856-5858. 8. Albain K, Barlow W, O’Malley F, et al. Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, nodepositive estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). Presented at the 27 Annual San Antonio Breast Cancer Symposium; December 2-14, 2004; San Antonio, TX. Abstract #37. 9. Altaha R, Fojo T, Reed E, et al. Epothilones: a novel

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10. 11. 12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.