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Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

Yun Oh, Roy S. Herbst, Howard Burris, Ann Cleverly, Luna Musib, Michael Lahn, Gerold Bepler

From the M.D. Anderson Cancer Center, Houston, TX; The Sarah Cannon Cancer Center, Nashville, TN; Eli Lilly and Company, Indianapolis, IN; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and Eli Lilly and Company, Erlwood, United Kingdom

Corresponding author: Gerold Bepler, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612; e-mail: gerold.bepler{at}moffitt.org

	ABSTRACT

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Purpose Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non–small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.

Patients and Methods Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status 2, and two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.

Results Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).

Conclusion Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

	INTRODUCTION

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Patients with non–small-cell lung cancer (NSCLC) are usually diagnosed with advanced disease.¹ The efficacy of first- and second-line chemotherapy in patients with metastatic NSCLC has not changed appreciably during the last decade. Most first-line chemotherapy regimens provide brief responses and a median survival of 8 to 10 months,² and second-line therapeutic options are limited. Approved drugs for second- and third-line treatment include docetaxel, pemetrexed, and erlotinib, which provide a median progression-free survival (PFS) durations of 6.5, 2.9, and 2.2 months, respectively.^3-6 Regimens with proven efficacy for third-line therapy have not been reported.⁷ New interventions are needed that target the molecular mechanisms involved in cellular survival, proliferation, and angiogenesis.

Protein kinase C-beta (PKCβ) is a potential therapeutic target^8,9 because of its functional role in lung cancer development. Overexpression and increased activity of PKC have been implicated in transformation and tumorigenesis in NSCLC.^10-12 Recent evidence suggests a link between the PKC and protein kinase B/AK transforming (AKT) pathways.^13,14 Inhibition of AKT leads to radiosensitization,¹⁵ whereas activation of AKT (for example, through loss of phosphatase and tensin homolog [PTEN]) is associated with poor prognosis.¹⁶

Enzastaurin, an oral serine/threonine kinase inhibitor, targets the PKC and AKT pathways and also inhibits phosphorylation of glycogen synthase kinase-3β and S⁶kinase.¹⁷ Recently, Nakajima et al¹⁸ showed that enzastaurin inhibited the growth of a panel of NSCLC and small-cell lung cancer cell lines. The antitumor and antiangiogenic activity of enzastaurin was demonstrated in tumor xenograft models, including NSCLC, and was confirmed using a standardized clonogenic assay in patient-derived tumor explants.^19-22 In a phase I dose-escalation study of daily oral enzastaurin (20 to 750 mg), four patients with advanced lung cancer had stable disease for 3 to 12 months.²³

On the basis of these data, a phase II study was initiated to evaluate the efficacy of daily oral enzastaurin in patients with NSCLC who had experienced treatment failure with first- or second-line therapy. The patient population and objectives were chosen based on phase II trials of gefitinib.^24,25 The primary objective was to estimate the rate of PFS at 6 months. Secondary objectives included safety, pharmacokinetics, and overall survival (OS). We also explored the potential prognostic or predictive value of plasma biomarkers for the future clinical development of enzastaurin.²⁶

	PATIENTS AND METHODS

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Eligibility Criteria
Adult patients (age 18 years) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, adequate organ function, and a histologically or cytologically documented diagnosis of stage IIIB or IV NSCLC were eligible. Patients had to have experienced relapse or disease progression on prior platinum-based therapy. Patients with up to two prior chemotherapy regimens, radiotherapy, or other investigational therapy were eligible. Patients had to have completed the previous treatment at least 30 days before study entry. Patients with documented CNS or leptomeningeal metastasis (brain metastasis), a serious concomitant disorder, or a second primary malignancy were excluded from the study. Patients with adequately treated basal cell carcinoma of the skin and patients who had malignancy in the past but were disease-free for more than 2 years were eligible. Other exclusion criteria included ECG abnormalities, a myocardial infarction that occurred less than 6 months before inclusion, symptomatic angina pectoris, cardiac failure not controlled by medicine, or other clinically significant cardiac abnormalities; an uncorrected electrolyte disorder, including potassium less than 3.4 mEq/L; and an inability to swallow tablets.

The protocol was approved by the institutional review board of each participating institution. Written informed consent was obtained from each patient before study enrollment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable laws and regulations.

Study Design and Treatment Plan
In this single-arm, multicenter, phase II study, patients received 500 mg of oral enzastaurin (supplied as 100- and 200-mg tablets) once daily after breakfast during each 28-day cycle of therapy for a planned duration of up to six treatment cycles (24 weeks). Patients who experienced treatment response had the option of continuing on study with the agreement of the investigator. Enzastaurin was discontinued if patients developed progressive disease or unacceptable toxicity.

Baseline and Treatment Assessments
At baseline and before each cycle, medical and physical examinations, tumor measurements of palpable or visible lesions, ECOG PS evaluation, and serum chemistry and hematology laboratory tests were completed. A 12-lead ECG was obtained at baseline, on day 1 of cycle 1 (pretreatment), on day 1 of cycle 2 (2 to 4 hours after dosing), and 30 days after discontinuation. Mandatory chest and abdominal/pelvic computed tomography scans were done at baseline. At every other cycle and 30 days after discontinuation, each patient was assessed with radiologic imaging studies using the same method used at baseline. Long-term follow-up continued every 2 months until death and included documentation of ECOG PS and post-treatment therapy.

Response was assessed using the Response Evaluation Criteria in Solid Tumors and was confirmed at least 4 weeks from the time of initial response. PFS time was measured from the date of the first dose to the first date of documented progressive disease or death, whichever occurred first. OS time was measured from the date of the first dose to the date of death from any cause. For patients with confirmed stable disease (SD), the duration of SD was measured from the date of the first dose until the first date of documented progressive disease or death, whichever occurred first. All enrolled patients were assessed every 4 weeks (before each cycle) for treatment-related toxicity using Common Toxicity Criteria (CTC), version 2.0.

Statistical Methods
Up to 50 patients were to be enrolled onto this study. This number ensured that there was 81% power at the 12% (one-sided) significance level to differentiate between 10% and 20% progression-free rates at 6 months; assuming that 10% and 20% progression-free rates were respectively unworthy and worthy of future study. Kaplan-Meier estimates of time-to-event distributions and quartiles were produced using data on enrolled patients. CIs were computed at the 95% level.

Pharmacokinetic Assessment
Plasma samples for pharmacokinetic evaluation were collected during cycles 1, 2, and 3 for each patient. Samples were assayed for enzastaurin and its metabolites using high-performance liquid chromatography with tandem mass spectrometry.²⁵ A population pharmacokinetic approach was used for the pooled plasma concentration time data of all patients, which was analyzed using nonlinear mixed effect modeling. The plasma concentration time data from this study was combined with data from reference studies for estimation of clearance and area under the concentration time curve at steady-state. The average plasma concentration at steady-state (C_av,ss) for each individual patient was computed by dividing the area under the concentration time curve at steady-state by the dosing interval of 24 hours.

Plasma Vascular Endothelial Growth Factor Assessment
Levels for plasma biomarkers, such as cytokines and chemokines, were analyzed as part of a multianalyte profile panel at Rules Based Medicine (Austin, TX) using multiplexed microspheres and Luminex technology as described elsewhere.²⁷ From this panel, plasma vascular endothelial growth factor (VEGF) was analyzed to determine whether there was evidence of changes in VEGF concentrations across cycles or between two subgroups of patients categorized by PFS time (> or 2 months). Plasma samples were collected at baseline, before cycle 1 (day 0), on day 28, and on day 56. Data were transformed to log scale and analyzed using a mixed-effects method with patient subgroup and cycles as fixed effects and patient as a random effect.

Immunohistochemistry
Tumor samples, if available at the time of the initial diagnosis, were requested and analyzed to determine phosphorylation of PKCβ. Immunohistochemistry was performed at Ventana Medical Systems, Inc (Tucson, AZ), using a mouse monoclonal antibody specific to the PKCβ2 isoform (Sigma Chemical Co, St Louis, MO; catalog no. P2584, clone PK-B26) as described previously.²⁸

	RESULTS

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Patient Characteristics
Fifty-five patients, with a median age of 63 years (range, 44 to 82 years), were enrolled onto the study (Table 1) from March 2005 to January 2007. The majority of the 55 patients had an ECOG PS of 1 (77%) and stage IV disease (78%). Twenty-two percent of patients had stage IIIB disease at the time of the original diagnosis and had experienced disease progression before study entry. Adenocarcinoma was the most common diagnosis (65%). Enzastaurin was administered as second-line therapy in 32 patients, as third-line therapy in 21 patients, and as fourth-line therapy in two patients (after receiving an exception from the enrollment requirements). Sixteen patients had relapsed after prior epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) therapy.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Kaplan-Meier graph for progression-free survival (PFS). (B) Waterfall plot demonstrating reduction in total tumor size in all patients, following enzastaurin treatment. Lesion measurement data were available for 44 of 55 patients. (C) Kaplan-Meier graph for overall survival (OS). Abbreviation: SD, stable disease.

Toxicities
All 55 patients were evaluated for safety (Table 3). Fatigue was the most common toxicity (n = 17). Ataxia, pulmonary embolism, and anemia (in one patient each) were the only grade 3 enzastaurin-related toxicities. Grade 1 QTc interval prolongation of greater than 50 milliseconds (with no clinical symptoms) was observed in three patients who had a history of cardiovascular disease.

Pharmacokinetics
Plasma concentration data were available from 50 patients during cycle 1, 39 patients during cycle 2, and 12 patients during cycle 3. Exposures of enzastaurin and its active metabolite, LY326020, were similar to the exposures seen at the 525-mg dose in the phase I dose-escalation study.²⁵ Exposures seen in cycle 2 and 3 were comparable, suggesting that the pharmacokinetics of enzastaurin are not altered over time. The geometric mean (% coefficient of variation) of enzastaurin apparent clearance was 43.74 L/h (73.68%); the geometric mean for enzastaurin C_av,ss was 923.82 nmol/L (73.68%), and the geometric mean for the metabolite LY326020 C_av,ss was 835.66 nmol/L (47.52%). The C_av,ss for both enzastaurin and LY326020 were not different for patients who had SD versus those who experienced disease progression in less than two cycles.

Plasma VEGF and Immunohistochemistry
VEGF data for individual patients are shown in Fig 2A. The percentage estimate of intrapatient coefficient of variation (% CV) for VEGF was approximately 30%. As shown in the box-whisker plot of Fig 2B, there was no evidence to suggest a change across cycles for either subgroup of patients (PFS time > or 2 months), but mean VEGF levels were consistently lower (P < .05), including at day 0, in the subgroup of patients with PFS time greater than 2 months. Averaged across cycles, geometric mean values were approximately 25% lower in this subgroup (95% CI, –1% to –40%). The geometric mean of the 28 patients with PFS less than 2 months was 267 pg/mL (95% CI, 228 to 312 pg/mL) compared with 178 pg/mL (95% CI, 130 to 244 pg/mL) for the five patients with PFS more than 6 months (data not shown). Although changes were observed for some of the other plasma markers over time, the pattern of change was the same in both groups of patients (data not shown).

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Plasma vascular endothelial growth factor (VEGF) levels are elevated in patients with progression-free survival (PFS) time (LE) 2 months compared with patients with PFS time more than (GT) 2 months. VEGF data are presented as individual patient line plots (A) and box-whisker plots (B). The box-whisker plots show the median, interquartile range, 10th, 90th, and fifth and 95th percentiles. Data were log transformed before analysis.

View larger version (102K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Immunohistochemical analysis of protein kinase C-beta (PKCβ), epidermal growth factor receptor, and glycogen synthase kinase-3β expression in non–small-cell lung cancer. Slides were quantitated by an automated image analyzer and independently reviewed by pathologists. Staining intensity was measured on a semi-quantitative scale of 0 (or negative) to 3. (A) Control; (B) PKCβ.

	DISCUSSION

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Given the predominantly cytostatic activity of enzastaurin, we chose PFS rate as a primary end point to evaluate efficacy.²⁶ PFS rate has also been used in other phase II trials of antiangiogenic agents for the treatment of advanced NSCLC.^5-7 In our study, the observed 6-month PFS rate was 13% (95% CI, 3.9% to 21.5%), the median PFS was 1.8 months, and no objective responses were seen. Our goal of achieving a 6-month PFS rate of 20% was based on the published 6-month PFS rate of gefitinib.^6,7 Although this objective was not formally met in this study, a small subset of patients experienced prolonged disease stabilization. Additionally, two patients (3.6%), who had experienced disease progression before enzastaurin therapy, had minimal response initially, subsequently followed by SD for more than 1 year.

Response rate (RR) has traditionally been used to evaluate the activity of cytotoxic agents.²⁹ In second-line therapy for NSCLC, the observed RR is generally 10% to 13%, which translates into a median OS of approximately 8 months and a median PFS of less than 3 months.² In clinical trials of new, single-agent, antiangiogenic agents in NSCLC, the objective RR ranges between 2% and 12% and the median PFS remains dismal (< 4 months).^30,31 Although we did not observe responses as defined by Response Evaluation Criteria in Solid Tumors in this study, some reduction in disease burden occurred, as shown by the overall tumor size reduction (Fig 1B). Overall, the results of this trial are consistent with the activity of enzastaurin as a tumor-growth inhibitory agent that lacks direct tumor cytotoxicity capable of causing tumor regression.

Enzastaurin was well tolerated, with minimal toxicity. There were no grade 4 toxicities related to enzastaurin. This is especially important because many patients with advanced NSCLC are unable to receive chemotherapy because of comorbidities or debilitation from the disease. In addition, the low toxicity profile of enzastaurin may equate with better quality of life, which has been shown to be correlated with improved survival in patients with NSCLC.^32,33 Thus compared with other drugs used as second- or third-line treatment, enzastaurin may be a less toxic alternative for patients with advanced NSCLC.

To tailor enzastaurin treatment, molecular targets and markers predictive of enzastaurin treatment outcome need to be identified. Immunohistochemical analysis of archived tumor samples from this study suggested that PKCβ was expressed at a similar frequency (six of 12, or 50%) as described earlier.¹³ Although low frequency of PKCβ expression may, in part, explain the lack of correlation between PKCβ expression and clinical benefit, the small number of tumor samples and the lack of immediate pre-enzastaurin treatment biopsies are also important contributing factors. Lastly, enzastaurin may not only affect PKCβ expression, but also AKT activity and glycogen synthase kinase-3β and S⁶kinase phosphorylation. The novel staining protocol for PKCβ established in this study, however, combined with additional new staining procedures, will enable subsequent clinical studies to better evaluate the correlation of enzymes in the AKT pathway^18,19 and PKC expression with clinical outcome.

In addition to evaluating tissue samples, we examined important plasma markers associated with PKCβ inhibition, such as VEGF.^22,34,35 We did not observe a consistent change in plasma VEGF levels in this study or the typical toxicities associated with VEGF/VEGF R1/VEGFR-2 pathway-directed antiangiogenic therapies, such as hypertension, thromboembolic disease, or hemoptysis,³⁶ which are thought to be mediated by vasodilation³⁷ and altered endothelial and platelet function.^38,39 In our study, high VEGF levels were prognostic of poor PFS. If enzastaurin reduces tumoral VEGF production, its therapeutic impact may be predominantly paracrine. Low levels of circulating VEGF may allow tumors to experience this paracrine effect, whereas high circulating levels might overwhelm the reduction of tumoral VEGF achieved by enzastaurin. Thus low baseline plasma VEGF levels, known to be associated with indolent growth and slower progression,⁴⁰ may provide conditions in which enzastaurin can exert a therapeutic effect. Future randomized studies are needed to determine whether VEGF levels can be used as a predictive marker of enzastaurin activity.

For its future application, enzastaurin should be evaluated similar to other antiangiogenic compounds that have been shown to enhance the efficacy of front-line chemotherapies despite modest effects as single agents. Unlike EGFR-TKIs,^41,42 antiangiogenic agents combined with cytotoxics or with EGFR-TKIs have demonstrated clinical benefit in lung cancer by improving PFS.^43-45 Multikinase inhibitors targeting various pathways, including those involved in neoangiogenesis, have also shown activity in NSCLC.⁴⁶ Therefore, clinical trials evaluating enzastaurin in combination with other cytotoxic agents are currently being pursued, especially because enzastaurin does not add to the toxicity of cytotoxic agents.^47-49

In conclusion, this phase II study of single-agent enzastaurin as second- or third-line therapy in patients with metastatic NSCLC has shown disease stabilization for 6 months in 13% of patients and prolonged stabilization ranging from 7 to 20 months in six of 55 patients. Future single-agent enzastaurin trials should focus on the identification of potential markers to tailor enzastaurin treatment. Furthermore, the tolerability of enzastaurin justifies evaluating it in combination with other drugs, especially cytotoxic agents. This approach should establish whether enzastaurin has an additive benefit for combination regimens similar to that seen in other currently investigated antiangiogenic compounds.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Ann Cleverly, Eli Lilly and Company (C); Luna Musib, Eli Lilly and Company (C); Michael Lahn, Eli Lilly and Company (U) Consultant or Advisory Role: Roy S. Herbst, Genentech (C), Astra Zeneca (C); Gerold Bepler, Eli Lilly and Company (C) Stock Ownership: Ann Cleverly, Eli Lilly and Company; Michael Lahn, Eli Lilly and Company Honoraria: Gerold Bepler, Eli Lilly and Company Research Funding: Gerold Bepler, Eli Lilly and Company, Sanofi Aventis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Roy S. Herbst, Howard Burris, Luna Musib, Michael Lahn, Gerold Bepler

Provision of study materials or patients: Yun Oh, Roy S. Herbst, Howard Burris, Gerold Bepler

Collection and assembly of data: Yun Oh, Roy S. Herbst, Howard Burris, Gerold Bepler

Data analysis and interpretation: Yun Oh, Roy S. Herbst, Howard Burris, Ann Cleverly, Luna Musib, Michael Lahn, Gerold Bepler

Manuscript writing: Yun Oh, Roy S. Herbst, Ann Cleverly, Luna Musib, Michael Lahn, Gerold Bepler

Final approval of manuscript: Yun Oh, Roy S. Herbst, Howard Burris, Luna Musib, Michael Lahn, Gerold Bepler

	ACKNOWLEDGMENTS

 
The study was conducted when Hurricane Katrina forced the medical staff at M.D. Anderson to respond to the emergency. We would like to thank everyone at M.D. Anderson for their hard work during this time and for keeping the study open. We also thank Philip McNealy and Nathan Enas for statistical analysis and Asavari Wagle and Noelle Gasco for writing and editorial support.

	NOTES

 
Sponsored by Eli Lilly and Company.

Presented in part at the 18th European Organization for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposia, Prague, Czech Republic, November 7-10, 2006, and at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted September 7, 2007; accepted November 14, 2007.

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