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Clinical Cancer Research 13, 2684, May 1, 2007. doi: 10.1158/1078-0432.CCR-06-2889
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Alex A. Adjei1, Julian R. Molina2, Sumithra J. Mandrekar2, Randolph Marks2, Joel R. Reid2, Gary Croghan2, Lorelei J. Hanson2, James R. Jett2, Chenghua Xia3, Chetan Lathia3 and Ronit Simantov3

Authors' Affiliations: 1 Roswell Park Cancer Institute, Buffalo, New York; 2 Mayo Clinic, Rochester, Minnesota; and 3 Bayer Pharmaceuticals Corp., West Haven, Connecticut

Requests for reprints: Alex A. Adjei, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-4101; Fax: 716-845-3243; E-mail: alex.adjei{at}roswellpark.org.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non–small cell lung cancer.

Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.

Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib Cmax (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease ≥4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.

Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non–small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

Lung cancer is currently the leading cause of cancer mortality in the United States and throughout the world (1). It was estimated that 172,570 individuals would be diagnosed with lung cancer in the United States in 2006. Non–small cell lung cancer (NSCLC) comprises over 75% of lung cancers and has proven particularly difficult to treat. Curative resection is possible in only 30% of patients at diagnosis, with metastatic disease developing in 50% of patients within 5 years (2).

Increased understanding of lung cancer at the molecular level has led to the development of novel targeted therapies for this disease (3), and the use of these agents in NSCLC continues to grow. A wide variety of prognostic factors that predict response to targeted agents are being investigated for NSCLC and include tumor suppressor genes (p53 and Rb), growth factor receptors [epidermal growth factor receptor (EGFR)], and dominant oncogenes (Ras; ref. 4). Overexpression of EGFR has been found in 45% of NSCLC tumors, whereas its ligands transforming growth factor-{alpha} and amphiregulin have shown increased and decreased expression, respectively, in ~60% of NSCLCs, independent of stage (5). Ras is an important signaling molecule, which exerts its effects through downstream signal cascades (commonly Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase), to mediate cell proliferation and prolong survival. Furthermore, activating mutations of the K-ras oncogene have been found in 35% of adenocarcinomas (6) and have been shown to be predictive of poor survival (7).

Sorafenib (Nexavar; Bayer Pharmaceutical Corp. and Onyx Pharmaceuticals) is an oral multi-kinase inhibitor with antiangiogenic and antiproliferative activity that has been approved for the treatment of advanced renal cell carcinoma based on results of a global, randomized, placebo-controlled phase III trial (8, 9). Sorafenib has been shown to inhibit the vascular endothelial growth factor receptors 1 to 3, platelet-derived growth factor receptor {alpha} and ß, c-Kit, Flt-3, RET, and the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway (10–12). Hence, sorafenib inhibits all known isoforms of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, multiple cell surface tyrosine kinase receptors with roles in oncogenesis, and serine/threonine kinases involved in the downstream signaling from a number of cell surface receptors, including EGFR, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. Preclinical studies of sorafenib in human NSCLC xenograft models showed antitumor activity, particularly sustained disease stabilization (11). Sorafenib has shown encouraging antitumor activity in combination with other chemotherapy agents (13–17) as well as a good safety profile with manageable toxicities in phase I/II monotherapy trials (8, 9, 18–20).

The EGFR tyrosine kinase inhibitor gefitinib has been approved for third-line treatment of NSCLC in Japan and the United States based on an objective response rate of 10.6%. Iressa full prescribing information is available online.4 However, there was no increase in response rate or overall survival in NSCLC for the combination of gefitinib with conventional chemotherapy compared with chemotherapy alone (21, 22). Furthermore, the randomized, placebo-controlled phase III Iressa Survival Evaluation in Lung Cancer trial of gefitinib in advanced NSCLC patients who had received at least one previous chemotherapy regimen did not show a significant overall survival benefit for gefitinib in either the whole study population, or an adenocarcinoma subgroup (23).

Although specific EGFR gene mutations have been shown to predict response to gefitinib, suggesting that selection of patients most likely to respond may be feasible, it is unclear whether the expression patterns of EGFR and its ligands are predictive of survival (24). The disappointing results observed in single-agent and combination clinical trials with gefitinib could be due to signaling pathway redundancy, which may be combated by the use of combination therapy with targeted agents. In particular, accumulating data suggest that NSCLC cells harboring K-ras mutations may be resistant to the EGFR tyrosine kinase inhibitors. Thus, by inhibiting the Ras/Raf pathway (11), sorafenib may confer sensitivity to a broad spectrum of NSCLCs when combined with gefitinib. This theoretical rationale is supported by preclinical studies showing that the combination of sorafenib and gefitinib is additive (25).

Based on this theoretical rationale and the supporting preclinical data, this phase I trial was undertaken to assess the safety/tolerability, pharmacokinetics, and antitumor efficacy of the combination of sorafenib and gefitinib in patients with unresectable or recurrent NSCLC.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient selection. Patients with advanced, histologically confirmed, unresectable or recurrent NSCLC, who were appropriate for gefitinib therapy, were eligible for this trial. Other inclusion criteria were age ≥18 years; expected survival of ≥3 months; Eastern Cooperative Oncology Group performance status ≤2; adequate bone marrow (platelets ≥100 x 109 cells/L, absolute neutrophil count ≥1.5 x 109 cells/L, hemoglobin >9.0 g/dL), hepatic [total bilirubin ≤1.5 mg/dL, alanine aminotransferase (ALT) ≤2.5 times the upper limit of normal] and renal (stable serum creatinine ≤1.5 x upper limit of normal) functions; no radiotherapy or biological therapy within 3 weeks before start of trial; and no chemotherapy, hormonal, or investigational drug therapy within 28 days before trial entry. Six or more weeks must have elapsed since prior nitrosourea or mitomycin C chemotherapy. Patients who had bone marrow transplant or stem cell rescue within 4 months of trial entry, active brain metastasis, or active infections (grade >2, National Cancer Institute-Common Terminology Criteria for Adverse Events, v3.0) were excluded.

All patients gave written informed consent in accordance with institutional and federal guidelines before trial participation, and the study was conducted in accordance with the Declaration of Helsinki.

Study design. This was a single-center, open-label, single-arm, phase I dose-escalation trial (Fig. 1 ) to assess the safety and tolerability of sorafenib in combination with gefitinib and to determine the appropriate dose of sorafenib to combine with a fixed, standard therapeutic dose of gefitinib (part A). Patients received escalating doses of sorafenib, up to the recommended single-agent phase II dose of 400 mg twice daily. After determination of the recommended phase II dose in part A, additional patients were studied to characterize further the toxicity and pharmacokinetic profiles of this combination. The steady-state pharmacokinetics of single-agent sorafenib and gefitinib were determined during a 42-day run-in period in part B. Patients were randomized to receive either sorafenib 400 mg twice daily or gefitinib 250 mg once daily for 21 days followed by a 7-day wash-out period and then crossed over to the other drug for an additional 21 days. After the run-in period, all patients received concurrent, continuous sorafenib plus gefitinib with a cycle length of 28 days. Patients who participated in either part A or B received treatment until the occurrence of unacceptable toxicity or disease progression.


Figure 1
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  		Fig. 1. Patient disposition.

 
Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events, v3.0. Dose-limiting toxicities were based on cycle 1 toxicities and defined as grade 4 neutropenia (absolute granulocyte count <0.5 x 109/L, ≥7 days), febrile neutropenia grade ≥3 (absolute granulocyte count <1.0 x 109/L and fever ≥38.5°C), platelet count <25,000/L or thrombocytopenic bleeding, ALT/aspartate aminotransferase grade ≥3 for 7 days, grade 3 nonhematologic toxicity (excluding unpremedicated nausea, vomiting, and diarrhea), and inability to administer the day 1 cycle 2 dose of both drugs within 14 days of the planned end of the previous cycle, as a result of an adverse event with relationship to trial medication.

Patient evaluations. Pretreatment evaluations were conducted within 7 days before drug administration. These included complete history and physical examination, baseline toxicity assessment, hematology (including prothrombin time, partial thromboplastin time, and international normalized ratio), biochemistries, urinalysis, pregnancy test for women of childbearing potential, and 12-lead electrocardiogram. Baseline radiologic assessments (i.e., scans or radiographs) for disease documentation and electrocardiogram were done within 28 days of the start of treatment. Baseline biological samples for blood, plasma, and urine were also collected up to 7 days before part B of the trial.

Dose modifications. During the first cycle, if a dose-limiting toxicity occurred during or after the administration of both therapies, treatment was withheld until the toxicity had resolved to grade ≤2, at which time both drugs could be administered at reduced doses. If the toxicity did not resolve, the patient was withdrawn from the trial and not replaced. In subsequent cycles, patients experiencing a dose-limiting toxicity were withdrawn from one or both of the agents at the investigator's discretion. The patient was then re-challenged with a reduced dose of both study drugs, if the toxicity resolved to grade ≤2. Patients were withdrawn from the trial if toxicity did not resolve, unless they were deriving clinical benefit from the treatment.

Plasma pharmacokinetics. The plasma pharmacokinetics of single-agent and combination treatments was evaluated in part B to investigate the potential for interaction between sorafenib and gefitinib and the potential relationship between pharmacokinetic variables and toxicity.

Blood samples for determination of sorafenib alone were collected before dosing, and 0.5, 1, 2, 4, 6 to 8, and 12 h after dosing on days 21 or 42 of the run-in period. Blood samples for determination of gefitinib alone were collected at these time points and at 24 h after dose. In patients receiving the combination of sorafenib and gefitinib, blood sample collection was repeated at the same times, including 24 h after dose on day 28 of cycle 1. The evaluation during the 42-day run-in period permitted the steady-state pharmacokinetics of each single agent to be determined, thereby allowing comparison with the combination.

A validated liquid chromatography tandem mass spectrometry (MS/MS) assay was used for the measurement of sorafenib in plasma (18). Sample preparation was done using protein precipitation of plasma, and analysis was done using reverse-phase chromatography followed by detection with MS/MS. An aliquot of plasma (0.2 mL) was diluted with labeled internal standard and precipitated with acetonitrile/methanol. After centrifugation, clear supernatant was injected onto high-performance liquid chromatography column and analyzed by MS/MS. The calibration range for the method was 0.01 to 12 mg/L for sorafenib. Mean inter-assay precision during the analysis of study samples ranged from 93.8% to 102.0%, and accuracy ranged from 1.13% to 6.69%.

Gefitinib was also analyzed using a validated liquid chromatography MS/MS method. This method also involved protein precipitation of plasma, reverse-phase chromatography, and MS/MS detection. An aliquot of plasma (0.15 mL) was precipitated with methanol-containing internal standard. After centrifugation, clear supernatant was injected onto high-performance liquid chromatography and analyzed by MS/MS. The calibration range for the method was 0.5 to 500 µg/L for gefitinib. Mean inter-assay precision during the analysis of study samples ranged from 96.0% to 112.3%, and accuracy ranged from 9.2% to 12.8%.

Pharmacokinetic variables were calculated by standard noncompartmental methods using WinNonlin (version 4.0). The following pharmacokinetic variables were determined from plasma concentration profiles of sorafenib and gefitinib given alone and in combination: maximum drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) from 0 to 12 h for sorafenib (AUC0-12) and from 0 to 24 h for gefitinib (AUC0-24).

Antitumor activity. All patients with measurable disease and who had received at least one dose of sorafenib or gefitinib were eligible for evaluation for response by the Response Evaluation Criteria in Solid Tumors. All responses were confirmed by repeated tumor assessment after 4 weeks.

Statistical analysis. All patients who received at least one dose of sorafenib or gefitinib were included in the safety analyses. For the pharmacokinetic analyses, the derived variables (Cmax and AUC) were calculated for sorafenib and gefitinib given alone and in combination. Cmax and AUC values were analyzed using ANOVA. A 90% two-sided confidence interval for the ratio of geometric means of the compared treatment conditions was calculated. Progression-free survival was estimated using the Kaplan-Meier method. Statistical analyses were done using SAS, version 8.0 (SAS Institute).


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. A total of 32 patients with advanced NSCLC were enrolled between February 2004 and December 2004; patient disposition is shown in Fig. 1. Twelve patients were recruited into part A, the dose-finding section of the trial. Cohort 1 (n = 6) received sorafenib 200 mg twice daily plus gefitinib 250 mg once daily, and cohort 2 (n = 6) received sorafenib 400 mg twice daily plus gefitinib 250 mg once daily. Of the 20 patients enrolled in part B, one patient did not receive either drug treatment and was excluded from the safety and efficacy analyses because the patient was diagnosed with bladder cancer following study enrollment and was withdrawn from the study. Of the remaining patients in the single-agent run-in phase of part B, all 19 patients received sorafenib (400 mg twice daily administered to 16 patients and 200 mg twice daily administered to 3 patients due to a dosing error), and 16 patients received gefitinib 250 mg once daily. Three of the 19 patients discontinued sorafenib treatment and did not receive gefitinib due to an adverse event (n = 2) and progressive disease (n = 1). Of the 16 patients eligible for the combination phase of treatment, 10 patients received the sorafenib-gefitinib combination, and 6 patients did not receive the combination because 5 had progressive disease, and 1 had an adverse event following the run-in phase.

Patients' baseline characteristics are presented in Table 1 . Twenty-eight patients (90%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. In 16 patients (52%), the NSCLC histology was identified as adenocarcinoma. Thirteen patients (42%) had received two or more prior chemotherapy regimens for NSCLC, and 8 patients (26%) had received previous radiation therapy. Ten patients (32%) had received no prior systemic therapy. The median treatment duration for all patients with sorafenib was 104 days (range, 12-368 days) and 108 days (range, 19-367 days) with gefitinib.


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  		Table 1. Patient demographics, n (%)

 
Safety. At the time of analysis, 24 patients (75%) had discontinued treatment: 17 due to disease progression, 5 due to adverse events, 1 due to consent withdrawal, and 1 did not receive either drug treatment as discussed previously and was therefore excluded from the safety analyses.

No dose-limiting toxicities were observed in patients receiving sorafenib 200 mg twice daily, and only one dose-limiting toxicity (elevated ALT) was observed at 400 mg twice daily. The dose selected for part B was sorafenib 400 mg twice daily combined with gefitinib 250 mg once daily. The most common drug-related adverse events of any grade (n = 31 patients) were diarrhea (64.5%), elevated ALT (41.9%), dermatologic effects (dermatology: other, 41.9%; rash, 29.0%), and fatigue (38.7%; Table 2 ). The majority of adverse events were grade 1/2, with relatively few drug-related grade 3/4 adverse events reported (Table 2). The most frequent grade 3/4 adverse events included diarrhea and elevated ALT (both 9.7%). Hematologic, cardiovascular, or renal toxicities were infrequent.


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  		Table 2. Incidence of drug-related adverse events (all grades) in ≥10% of all patients, n (%)

 
Drug-related serious adverse events occurred in four patients (12.9%). These included diarrhea (n = 1), elevated ALT at sorafenib 200 mg twice daily (n = 1), and dyspnea at 400 mg twice daily (n = 1) in part A and fever (n = 1) in part B.

Five patients withdrew from the trial because of adverse events: fatigue (grade 1); dermatology, other (grade 1); pneumonia (grade 2); musculoskeletal weakness, other and induration (both grade 3); fatigue (grade 4); and whole-body/generalized muscle weakness (grade 3).

Six patients (21%) required a dose delay of gefitinib: 5 because of toxicity and 1 due to patient error. No dose reductions were necessary. Nine patients (29%) required a sorafenib dose delay because of adverse events. Two sorafenib dose reductions occurred in cohort 1 of part A, both due to grade 3 diarrhea, whereas in cohort 2, three dose reductions were necessary: two due to elevated ALT and aspartate aminotransferase (both grade 3) and one due to hand pain (grade 3) and hand swelling (grade 4). Five dose reductions in part B resulted from a variety of toxicities: diarrhea (grade 3) and acne (grade 2), pruritus and erythema multiforme (both grade 2), hand-foot skin reaction (grade 3), diarrhea (grade 2), and elevated ALT (grade 4) and aspartate aminotransferase (grade 3).

Six deaths occurred during the trial, attributable to pneumonia (n = 1), respiratory failure (n = 1), and disease progression (n = 4). None was considered related to either sorafenib or gefitinib.

Pharmacokinetics. Of the 19 patients in part B, pharmacokinetic variables could be calculated for single-agent sorafenib in 8 patients and for single-agent gefitinib in 12 patients. Paired pharmacokinetic data, for either drug administered alone (run-in) and in combination (cycle 1), were available for sorafenib in four patients and for gefitinib in eight patients.

Comparison of Cmax and AUC values of sorafenib alone (run-in period) and sorafenib combined with gefitinib (cycle 1) showed that gefitinib had no significant effect on steady-state sorafenib pharmacokinetics (Table 3 ). However, mean Cmax and AUC values of gefitinib were reduced by 26% (P = 0.0131) and 38% (P = 0.0035), respectively, when gefitinib was coadministered with sorafenib (cycle 1) versus gefitinib alone (Table 3). A representative plasma concentration-time profile of gefitinib given as a single agent and in combination with sorafenib is shown in Fig. 2 .


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  		Table 3. Plasma pharmacokinetics of sorafenib (400 mg twice daily) and gefitinib (250 mg) when given as single agents or after coadministration (geometric mean)

 

Figure 2
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  		Fig. 2. Plasma concentration versus time curve for single-agent gefitinib 250 mg once daily for 21 d and in combination with sorafenib 400 mg twice daily for 28 d in an individual patient.

 
Tumor response. A total of 31 patients were evaluable for tumor response (Table 4 ). One partial response was observed in cohort 1. A 75-year-old female patient diagnosed with adenocarcinoma, who had received three prior chemotherapy regimens, had a 45% decrease in size of a lung mass and resolution of pleural effusion and was on this study for 40 weeks. Twenty patients (65%) achieved stable disease (8 patients from part A and 12 patients from part B), and 8 patients (26%) progressed. Of the 20 patients who had stable disease, 13 patients showed stable disease for ≥4 months, and 10 patients showed stable disease for 6 months. Median progression-free survival for the 20 patients with stable disease was 23.2 weeks (range, 5.7-56.7 weeks). Median progression-free survival for all patients was 19 weeks (i.e., 133 days; Table 4). Seven patients remained on study at the time of the analysis.


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  		Table 4. Tumor response (n = 31)

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
NSCLC is the leading cause of cancer death throughout the world (1, 26). Although there have been improvements in first-line treatment of NSCLC, cytotoxic therapies still have limitations in refractory disease (26). Response rates of ~10% have been reported with second-line monotherapy with docetaxel and pemetrexed (27, 28). Gefitinib and erlotinib have shown a 10% to 20% response rate as monotherapies in previously treated, chemotherapy-refractory, advanced NSCLC patients (29). Clinical activity of single targeted agents may be limited due to a lack of target expression by the tumor, or redundancies and multiplicity of signaling pathways. Therefore, anticancer activity may be enhanced by combining small-molecule inhibitors that have different mechanisms of action to target multiple signaling pathways. This phase I study evaluated the safety, tolerability, and efficacy of sorafenib given in combination with gefitinib and investigated the pharmacokinetics of both agents given alone and in combination. Sorafenib 400 mg twice daily plus gefitinib 250 mg once daily was the recommended dose for further evaluation in phase II trials. These are the single-agent recommended doses of both drugs. Although drug-related adverse events were generally mild to moderate in severity (grades 1 and 2) and medically manageable, five patients required dose delays in later cycles because of toxicity, indicating that these doses were optimal for chronic administration.

Coadministration of gefitinib did not alter the pharmacokinetics of sorafenib. The Cmax and AUC values of sorafenib 400 mg twice daily administered alone or in combination with gefitinib in these NSCLC patients were similar to those reported in a phase I trial in patients with mixed solid tumors, who received continuous single-agent sorafenib (20). However, sorafenib reduced gefitinib AUC by 38%. Gefitinib is extensively metabolized by human liver microsomes in vitro. Oxidation of gefitinib is largely dependent on CYP3A4, with some dependency on CYP2D6 (30, 31). Clinical coadministration of the CYP3A4 inhibitor itraconazole with gefitinib resulted in a 78% increase in gefitinib AUC, whereas the CYP3A4 inducer rifampicin decreased gefitinib AUC by 83% (32). However, the decrease in gefitinib exposure with concurrent sorafenib does not seem to be due to CYP3A4 induction (33). In a probe substrate clinical trial, sorafenib in combination with the CYP3A4 substrate midazolam showed no significant changes in midazolam exposure, indicating that sorafenib was neither an inhibitor nor an inducer of CYP3A4 (33). In vitro microsomal data indicate that sorafenib undergoes glucuronidation and phase I oxidative metabolism mediated by CYP3A4. Sorafenib N-oxide was formed in vitro, as shown with the application of human liver microsomes or recombinant CYP3A4, and is also the main circulating metabolite in human plasma (34, 35). Determination of the concentration-dependent formation rate of sorafenib N-oxide in human liver microsomes revealed autoactivation to be important for this CYP3A4-mediated pathway, as indicated by non–Michaelis-Menten in vitro kinetics. Activation occurs when the rate of a biotransformation reaction is increased in the presence of another compound. Unlike induction, activation does not change the amount of specific metabolizing enzyme but increases the velocity of the reaction. In vitro activation of CYP3A4-mediated pathways has been described for several compounds. However, few animal studies have shown activation of CYP-mediated biotransformation reactions in vivo (36, 37). To our knowledge, CYP3A4 activation in vitro has not been reported to correlate with clinical findings for any marketed CYP3A4 substrate. The underlying mechanism(s) responsible for CYP3A4 activation leading to increased metabolism is not fully known. Several models have been proposed to explain these unusual kinetic characteristics with CYP3A4 involving two substrates (38–40). Currently, there are no data on the predictive value or relationship between in vitro activation of CYP3A4 and increased metabolism in humans. Sorafenib may stimulate the biotransformation of gefitinib resulting in decreased gefitinib exposure via activation, and studies are ongoing to evaluate this mechanism.

Several phase I/II trials of sorafenib in combination with standard cytotoxic chemotherapies have been conducted. In general, sorafenib was generally safe and well tolerated when combined with various chemotherapy agents, including oxaliplatin, carboplatin/paclitaxel, docetaxel, and gemcitabine (13, 16, 41, 42). No clinically relevant drug-drug interactions or significantly increased toxicities were observed in standard therapy combination trials with sorafenib, despite slight increases in doxorubicin, docetaxel, or irinotecan exposure with the combinations (14, 42, 43).

Phase I trials of sorafenib have shown antitumor activity in several solid tumors, including NSCLC (18, 20). A phase II trial of sorafenib monotherapy in relapsed or refractory advanced NSCLC patients has been reported (44). In that trial, although there were no objective responses, 59% of patients achieved stable disease and had a median progression-free survival of ~5.5 months (44). In the current trial, antitumor activity was shown with one partial response, 65% of patients with stable disease for at least 4 months, and a median progression-free survival of 19 weeks. Currently, five patients remain on study for >24 months. These preliminary antitumor data are encouraging and consistent with those reported in the phase II single-agent trial (44), and other single-agent studies of novel agents, such as vandetanib (45) and sunitinib (46), in NSCLC.

The effect of the reduced gefitinib AUC (38%) on the efficacy of this combination is unknown. However, given the relative lack of efficacy of a 250 mg dose of gefitinib in an unselected NSCLC population in the Iressa Survival Evaluation in Lung Cancer trial,5 it is reasonable to speculate that, in the context of the pharmacokinetic interactions identified here, the dose of gefitinib may have been subtherapeutic. Our data suggest that careful pharmacokinetic assessments are needed during initial studies of anticancer combinations. Taken together, our data argue for further evaluation of sorafenib in combination with other EGFR tyrosine kinase inhibitors, and studies in patients evaluating the combination of erlotinib and sorafenib are of interest.


   Acknowledgments
 
We thank Dr. Martin Radtke for performing the in vitro drug metabolism studies.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

4 http://www.astrazeneca-us.com/pi/iressa.pdf Back

5 Data from AstraZeneca website press release 2004 (http://www.astrazeneca.com/pressrelease/4245.aspx), unpublished data. Back

Received 12/ 7/06; revised 1/ 9/07; accepted 2/ 9/07.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

  1. Ries LAG, Eisner MP, Kosary CL, Hankey BA. SEER cancer statistics review 1975-2002. Bethesda (MD): National Cancer Institute; 2005.
  2. Fossella FV, Lee JS, Hong WK. Management strategies for recurrent non-small cell lung cancer. Semin Oncol 1997;24:455–62.[Medline]
  3. Martin P, Kelly CM, Carney D. Epidermal growth factor receptor-targeted agents for lung cancer. Cancer Control 2006;13:129–40.[Medline]
  4. Scagliotti GV, Masiero P, Pozzi E. Biological prognostic factors in non-small cell lung cancer. Lung Cancer 1995;12 Suppl 1:S13–25.[CrossRef][Medline]
  5. Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:2379–85.[Abstract/Free Full Text]
  6. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11–22.[CrossRef][Medline]
  7. Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 1990;323:561–5.[Abstract]
  8. Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005;23:LBA4510.
  9. Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Eur J Cancer Suppl 2005;3:226.
  10. Levy AP, Pauloski N, Braun D, et al. Analysis of transcription and protein expression changes in the 786-O human renal cell carcinoma tumor xenograft model in response to treatment with the multi-kinase inhibitor sorafenib (BAY 43-9006) [abstract and oral presentation]. Proc Am Assoc Cancer Res 2006;47:213–4.
  11. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109.[Abstract/Free Full Text]
  12. Lierman E, Folens C, Stover EH, et al. Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. Blood 2006;108:1374–6.[Abstract/Free Full Text]
  13. Kupsch P, Henning BF, Passarge K, et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 2005;5:188–96.[Medline]
  14. Richly H, Henning BF, Kupsch P, et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 2006;17:866–73.[Abstract/Free Full Text]
  15. Flaherty KT, Brose M, Schuchter LM, et al. Sorafenib combined with carboplatin and paclitaxel for metastatic melanoma: PFS and response versus B-Raf status. Ann Oncol 2006;17:iii33.
  16. Siu LL, Awada A, Takimoto CH, et al. Phase I/II trial of sorafenib and gemcitabine in advanced solid tumors and in advanced pancreatic cancer. Clin Cancer Res 2006;12:144–51.[Abstract/Free Full Text]
  17. Eisen T, Ahmad T, Gore ME, et al. Phase I trial of BAY 43-9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients [abstract]. J Clin Oncol 2005;23:7508.
  18. Awada A, Hendlisz A, Gil T, et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 2005;92:1855–61.[CrossRef][Medline]
  19. Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a Phase II, placebo controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005;23:388s.
  20. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965–72.[Abstract/Free Full Text]
  21. 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;22:777–84.[Abstract/Free Full Text]
  22. 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;22:785–94.[Abstract/Free Full Text]
  23. Thatcher N, Chang A, Parikh P, Pemberton K, Archer V. Results of a Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proc Am Assoc Cancer Res 2005;46:LB–6.
  24. Hirsch FR, Witta S. Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Curr Opin Oncol 2005;17:118–22.[CrossRef][Medline]
  25. Carter CA, Chen C, Brink C, et al. Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Cancer Chemother Pharmacol 2006;59:183–95. Epub 2006 May 25.[CrossRef][Medline]
  26. Massarelli E, Herbst RS. Use of novel second-line targeted therapies in non-small cell lung cancer. Semin Oncol 2006;33:S9–16.[Medline]
  27. Fossella FV. Docetaxel for previously treated non-small-cell lung cancer. Oncology (Huntingt) 2002;16:45–51.
  28. Shepherd FA. Pemetrexed in the treatment of non-small cell lung cancer. Semin Oncol 2002;29:43–8.[Medline]
  29. Cascone T, Morelli MP, Ciardiello F. Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. Ann Oncol 2006;17:ii46–8.[Abstract/Free Full Text]
  30. McKillop D, McCormick AD, Miles GS, et al. In vitro metabolism of gefitinib in human liver microsomes. Xenobiotica 2004;34:983–1000.[CrossRef][Medline]
  31. McKillop D, McCormick AD, Millar A, et al. Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 2005;35:39–50.[CrossRef][Medline]
  32. Swaisland HC, Ranson M, Smith RP, et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 2005;44:1067–81.[CrossRef][Medline]
  33. Flaherty KT, Redlinger M, Schuchter LM, et al. Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43-9006 alone in patients with metastatic melanoma [abstract 3037]. Proc Am Soc Clin Oncol 2005;23:201s.
  34. Lathia C, Lettieri J, Cihon F, et al. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 2006;57:685–92.[CrossRef][Medline]
  35. Radtke M, Schmeer K, Hafner FT, Brendel E, Lathia C. Oxidative metabolism of sorafenib. Drug Metab Rev 2005;37:67.
  36. Tang W, Stearns RA, Kwei GY, et al. Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism. J Pharmacol Exp Ther 1999;291:1068–74.[Abstract/Free Full Text]
  37. Lasker JM, Huang M-T, Conney AH. In vivo activation of zoxazolamine metabolism by flavone. Science 1982;216:1419–21.[Abstract/Free Full Text]
  38. Wang RW, Newton DJ, Liu N, Atkins WM, Lu AY. Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos 2000;28:360–6.[Abstract/Free Full Text]
  39. Shou M, Grogan J, Mancewicz JA, et al. Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site. Biochemistry 1994;33:6450–5.[CrossRef][Medline]
  40. Korzekwa KR, Krishnamachary N, Shou M, et al. Evaluation of atypical cytochrome P450 kinetics with two-substrate models: evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 1998;37:4137–47.[CrossRef][Medline]
  41. Flaherty KT, Brose M, Schuchter L, et al. Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma [abstract]. J Clin Oncol 2004;22:7507.
  42. Awada A, Hendlisz A, Gil T, et al. A Phase I study of BAY 43-9006, a novel Raf kinase and VEGFR inhibitor, in combination with taxotere in patients with advanced solid tumors. Presented at EORTC meeting 2004.
  43. Steinbild S, Baas F, Gmehling D, et al. Phase I study of BAY 43-9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors [abstract]. J Clin Oncol 2005;23:3115.
  44. Gatzemeier U, Blumenschein G, Fosella F, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol (Meeting Abstracts) 2006;24:7002.
  45. Ranson M, Bodkin D, Govindan R, et al. Results of a randomized, double-blind phase II trial of ZD6474 versus gefitinib in patients with NSCLC. Eur J Cancer Suppl 2005;3:324–5.
  46. Socinski MA, Novello S, Sanchez JM, et al. Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial. J Clin Oncol 2006;24:7001.



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Angiogenesis in the Treatment of Non-Small Cell Lung Cancer
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