A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer

Lung Cancer 78 (2012) 63–69

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A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer夽 Bjørn H. Grønberg a,b,∗ , Tudor Ciuleanu c , Øystein Fløtten d , Aija Knuuttila e , Edvard Abel f , Seppo W. Langer g , Kurt Krejcy h , Astra M. Liepa i , Maria Munoz h , Marjo Hahka-Kemppinen j , Stein Sundstrøm a a

The Cancer Clinic, St. Olavs Hospital – Trondheim University Hospital, Norway Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway c Institute of Oncology “Prof. Dr. Ion Chiricuta” Cluj-Napoca, Cluj, Romania d Haukeland University Hospital, Department of Thoracic Medicine, Bergen, Norway e Helsinki University Hospital, Department of Pulmonary Medicine, Helsinki, Finland f Sahlgrenska University Hospital, Department of Oncology, Gothenburg, Sweden g Rigshospitalet, Department of Oncology, Copenhagen, Denmark h Eli Lilly and Company and/or one of its subsidiaries, Vienna, Austria i Eli Lilly and Company, Indianapolis, IN, USA j Eli Lilly and Company and/or one of its subsidiaries, Helsinki, Finland b

a r t i c l e

i n f o

Article history: Received 19 March 2012 Received in revised form 19 July 2012 Accepted 21 July 2012 Keywords: Enzastaurin Brain metastases NSCLC SCLC Whole brain radiotherapy Phase II Randomized Placebo-controlled

a b s t r a c t Introduction: Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). Methods: Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. Results: Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4–11.9); placebo: 4.9 (95% CI: 3.6–not assessable); p = 0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6–5.6); placebo: 5.1 (95% CI: 3.7–5.7); p = 0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1–2.3); placebo: 2.0 (95% CI: 1.3–2.3); p = 0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p = 0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p = 0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. Conclusions: Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Approximately 40–50% of patients with lung cancer (LC) develop brain metastases (BMs); the majority have multiple lesions [1,2]. Responses to chemotherapy reflect chemosensitivity of the primary 夽 Clinical Trials Registry Identifier: NCT00415363. ∗ Corresponding author at: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, PO Box 8905, 7491 Trondheim, Norway. Tel.: +47 47 29 78 78; fax: +47 72 82 61 26. E-mail address: [email protected] (B.H. Grønberg). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.07.007

tumor, with best responses seen in small cell lung cancer (SCLC) and intermediate responses seen in non-small cell lung cancer (NSCLC); these responses may be less durable than with whole brain radiotherapy (WBRT) [3]. Thus, corticosteroids and WBRT remain the standard of care for patients with multiple BMs [1,2]. Approximately 60% of patients clinically respond to such therapy, but it is unclear if responses are due to WBRT and/or corticosteroids [2] With median overall survival (OS) under 4 months [4], improvements are needed. Enzastaurin (LY317615) is an orally active protein kinase C and PI3K/AKT inhibitor with apoptotic, anti-proliferative, and

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anti-angiogenic activities [5,6]. It has anti-cancer and antiproliferative activity in cells and xenografts derived from solid tumors, including NSCLC and SCLC [6–9]. In phase I trials, enzastaurin was active and well tolerated in solid tumors including LC [10]. In a phase II trial involving second- or third-line NSCLC patients treated with enzastaurin monotherapy, 13% of patients experienced progression-free survival (PFS) ≥6 months [11]. A phase I–II trial showed anti-tumor activity in recurrent malignant gliomas, suggesting that enzastaurin crosses the blood–brain barrier [12]. Enzastaurin’s tolerability made it attractive to use after radiotherapy. When the study was designed, no data were available regarding tolerability of concurrent enzastaurin and WBRT. Thus, we conducted a randomized phase II trial comparing maintenance therapy with enzastaurin to placebo following WBRT in patients with BMs from LC. 2. Materials and methods

meal on Day 1; beginning on Day 2, patients received enzastaurin 500 mg daily within 30 min of the largest meal. Placebo-treated patients received an equivalent number of placebo tablets appearing identical to enzastaurin. All patients received best supportive care (BSC) allowing for corticosteroids in addition to study treatment. Patients were treated until BM progression, initiation of a new systemic anti-cancer regimen, or unacceptable toxicity. Patients were followed until death or study closure. 2.4. Dose adjustments Study treatment was suspended until resolution of Common Terminology Criteria for Adverse Events (CTCAE) grade 3/4 toxicity. If the event resolved to ≤CTCAE grade 1 or baseline, therapy was reinitiated at 250 mg daily. If the event did not recur within 21 days of restarting therapy, the dose could be re-escalated to 500 mg daily at investigator’s discretion. If the event did not resolve to ≤CTCAE grade 1 or baseline within 3 weeks, or another event occurred at the reduced dose, the patient was discontinued from study therapy.

2.1. Patient eligibility 2.5. Patient evaluations Patients (≥18 years old) with histologically or cytologically proven SCLC or NSCLC; radiologically proven BMs prior to the initiation of WBRT; Eastern Cooperative Oncology Group performance status (PS) of 0–2; and not in immediate need for systemic cancer therapy were eligible. Patients with single brain lesions were eligible if they were ineligible for surgery or radiosurgery. Prior to randomization, patients received WBRT of 20 Gy (4 Gy × 5 or 5 Gy × 4) or 30 Gy (3 Gy × 10); the schedule was decided by the study sites. The inclusion of both SCLC and NSCLC patients was based on a Nordic study where there was no difference in drop-out rates between SCLC and NSCLC patients with BMs receiving WBRT [13]. The 20 Gy schedule was the standard of care at many participating centers; the 20 Gy and 30 Gy schedules have equivalent efficacy [14,15]. Key exclusion criteria were: inability to take oral medication; serious concomitant systemic disorders that could compromise patient safety; and systemic anti-cancer treatment within 2 weeks prior to enrollment. Also excluded were patients having other clinically active cancers or receiving concurrent enzyme-inducing anti-epileptic drugs (EIAEDs; phenytoin, carbamazepine, phenobarbital) because these drugs lower enzastaurin serum exposure [12]. Patients initiating EIAEDs after enrollment could remain on study. Each center’s institutional review board approved the protocol in compliance with local regulations. This study was conducted in accordance with good clinical practices, the Declaration of Helsinki, and applicable regulations. Patients provided written informed consent prior to undergoing study procedures or receiving study treatment. 2.2. Randomization Following WBRT, patients were randomized (enrolled) 1:1 to receive either oral enzastaurin or placebo within 14 days after the last RT fraction. Treatment groups were assigned using a central computerized interactive voice response system. Randomization was stratified by PS (0/1 vs. 2), tumor type (SCLC vs. NSCLC), and WBRT (20 Gy vs. 30 Gy). 2.3. Treatment plan Study treatment began within 14 days after the last RT fraction. Patients randomized to the experimental arm received an enzastaurin loading dose (375 mg 3 times daily) within 30 min of each

At baseline, medical history, pregnancy test, physical examination, and laboratory tests were performed; PS was assessed; health-related quality of life (HRQoL) information was collected; and magnetic resonance imaging (MRI) of intracranial lesions and computed tomography (CT) scan of extracranial lesions were performed. Within 3–4 weeks after enrollment, intracranial and extracranial lesions were assessed as before and were then repeated every 6 weeks (±7 days) during the first 6 months of treatment and every 2 months thereafter, until objective progression or start of new systemic anti-cancer therapy. Concomitant medication, PS, CTCAE grading, hematology, and HRQoL were assessed at the same intervals as imaging and 30 days post therapy. Blood chemistry was assessed every 3 weeks during the first 6 months and at the same intervals as blood counts thereafter. 2.6. Statistical considerations This was a randomized, double-blind, parallel, placebocontrolled phase II trial. The primary objective was the betweenarm comparison of TTP of BMs in enzastaurin-treated patients versus placebo-treated patients. Time to progression was determined for the full analysis population including all randomized patients. Secondary endpoints were time to objective progression (TTOP) of BMs, PFS, OS, response rates for extracranial tumor manifestation(s), HRQoL, and safety. The response rate of BMs was determined in a post hoc analysis. All secondary time-to-event efficacy endpoints were conducted on the full analysis population. Safety analyses were conducted on all patients receiving at least one dose of study drug. Time to progression of BMs was the time from the date of study enrollment to the date of first observation of BM progression. Progression of BMs was evaluated according to both Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) [16] using MRI and clinical progression. If the PS or neurological status of a patient worsened so that radiological confirmation of progression was not feasible, the investigator could discontinue the patient based on clinical progression of BMs. In these cases, the date of increased steroid dose was considered the date of progression for TTP analysis. Deaths without evidence of intracranial progression were treated as censored events. The planned enrollment of 108 patients was based on a 1:1 randomization and an observation of 85 events. This would allow detection of a 1.2-month improvement in TTP of BMs from 2 to 3.2 months corresponding to a TTP hazard ratio (HR) of approximately

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0.625. The assumed median PFS of 2 months in the control arm was based on a previous Nordic trial comparing WBRT to temozolomide in patients with BMs from LC, where 27–49% of patients were discontinued before week 8, mainly due to BM progression [13]. The null hypothesis was TTP HR ≥ 1.00. If the true HR = 0.625 and 85 events were included in the analysis, there would be 80% statistical power for rejecting the null hypothesis at a one-sided 10% significance level. These assumptions were based on a 12-month accrual period with a maximum follow-up of 24 months. Time to BM progression was analyzed by Kaplan–Meier estimation [17]. The one-sided log-rank test at a significance level of ˛ = 0.10 was used. Hazard ratio estimation using the Cox regression model with treatment and potential prognostic factors was used for further data exploration. Time to objective progression (TTOP) of BMs was the time from the date of randomization to the date of first observation of objective progression of BMs assessed by MRI. For patients dying without objective progression of BMs, TTOP of BMs was censored at date of last objective progression-free disease assessment. For patients not known to have died as of the data cut-off date and not having objective progression of BMs, TTOP of BMs was censored at the date of the last objective progression-free disease assessment. Progression-free survival was the time from the date of study enrollment to the first date of progressive disease (PD) or death from any cause. Overall survival was the time from the date of study enrollment to the date of death from any cause. Response was evaluated according to RECIST [16]; rates were compared using Fisher’s exact test. Magnetic resonance imaging was considered as accurate as spiral CT. Efficacy analyses were performed by histology subgroups (SCLC and NSCLC). Health-related quality of life was assessed using the European Organization of Research and Treatment of Cancer questionnaire, QLQ-C30 (version 3), and the brain cancer-specific module, QLQ-BN 20 (version 1) [18,19]. Only patients for whom there were validated translations in which the patient was fluent completed the instruments. Physical functioning, fatigue, diarrhea, nausea/vomiting, and headache were considered the primary HRQoL endpoints. Changes in mean scores at each assessment time point were compared. For individual patients, changes in scores from baseline were calculated and graded as follows: mild change (5–10 points), moderate change (10–20 points), and marked change (>20 points). 3. Results From December 2006 to April 2010, 109 patients were enrolled at 11 hospitals (Denmark, Finland, Norway, Poland, Romania, and Sweden). Fifty-five patients were randomized to enzastaurin; 54 were randomized to placebo. Fig. 1 shows the CONSORT diagram. The minimum follow-up time for all patients was 9 months.

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Fig. 1. CONSORT flow diagram. The disposition of all study participants is shown. Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; HRQoL, healthrelated quality of life; N, population size; n, number of patients in group.

regression analysis, SCLC patients had a shorter TTP of BMs than NSCLC patients (HR: 3.56 [95% CI: 1.80–7.05]; p = 0.0003). There were no statistical differences in TTP of BMs HRs for patients receiving 30 Gy vs. 20 Gy WBRT (HR: 0.76 [95% CI: 0.40–1.41]; p = 0.38) or PS 0/1 vs. 2 (HR: 0.99 [95% CI: 0.51–1.96]; p = 0.99). The median TTOP of BMs was 5.0 months (95% CI: 3.1–8.4) and 3.7 months (95% CI: 3.4–8.2) for enzastaurin and placebo, respectively (HR: 0.91 [95% CI: 0.47–1.75]; p = 0.77). Due to the high number of censored patients (35, enzastaurin; 32, placebo) dying before documented PD in the brain, the analysis of the primary objective as planned in the protocol was not feasible. All patients were followed until either they had documentation of objective progression in the brain or documentation of progression was not feasible due to death or loss to follow-up. Thus, in addition to the planned analysis, a sensitivity analysis was performed

3.1. Patient characteristics and treatment Table 1 shows patient baseline characteristics and prior therapies. Fifty-four patients received enzastaurin; 53 received placebo. Median percent compliance was 100% with enzastaurin and 99.8% with placebo. Mean ± standard deviation number of days on therapy was 81 ± 65 and 100 ± 85 days with enzastaurin and placebo, respectively. One placebo-treated patient received oxcarbazepine; otherwise, EIAEDs were not used. 3.2. Efficacy The median TTP of BMs was enzastaurin: 6.9 months (95% confidence interval [CI]: 3.4–11.9); placebo: 4.9 months (95% CI: 3.6–not assessable) (HR: 0.93 [95% CI: 0.51–1.71]; p = 0.82) (Fig. 2). In a Cox

Fig. 2. Time to progression of brain metastases. Kaplan–Meier plots of TTP of brain metastases are shown for the enzastaurin and placebo groups using the full analysis population (enzastaurin, solid lines; placebo, dashed lines). Abbreviations: CI, confidence interval; HR, hazard ratio; N/A, not assessable; TTP, time to progression.

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Table 1 Baseline characteristics (enrolled population).

Median age (range), years Sex, n (%) Female Male ECOG performance status, n (%) 0 1 2 RPA class, n (%)a 1 2 3 Pathological diagnosis, n (%) Small cell Non-small cell Adenocarcinoma Squamous cell carcinoma Large cell neuroendocrine carcinoma Neuroendocrine carcinoma Non-small cell carcinoma Large cell carcinoma Poorly differentiated Prior therapies, n (%) Whole brain radiotherapy Brain surgery Radiotherapy outside the brain Radiosurgery to brain Chemotherapy Adjuvant Neoadjuvant Locally advanced Metastatic 1 regimen 2 regimens ≥3 regimens Whole brain irradiation, n (%) 30 Gy 20 Gy

Enzastaurin (N = 55)

Placebo (N = 54)

61.5 (47.5, 78.4)

65.2 (35.5, 80.7)

24 (43.6) 31 (56.4)

20 (37.0) 34 (63.0)

4 (7.3) 35 (63.6) 16 (29.1)

4 (7.4) 34 (63.0) 16 (29.6)

13 (23.6) 26 (47.3) 16 (29.1)

9 (16.7) 29 (53.7) 16 (29.6)

16 (29.1) 39 (70.9) 25 (45.5) 9 (16.4) 0

13 (24.1) 41 (75.9) 32 (59.3) 4 (7.4) 1 (1.9)

0 0 2 (3.6) 3 (5.5)

1 (1.9) 1 (1.9) 2 (3.7) 0

55 (100) 10 (18.2) 21 (38.2)

54 (100) 8 (14.8) 17 (31.5)

1 (1.8) 43 (78.2) 3 (5.5) 2 (3.6) 10 (18.2) 30 (54.5) 37 (67.3) 5 (9.1) 1 (1.8)

0 41 (75.9) 6 (11.1) 0 8 (14.8) 29 (53.7) 34 (63.0) 3 (5.6) 4 (7.4)

29 (52.7) 26 (47.3)

31 (57.4) 23 (42.6)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; N, total population size; n, number in group; RPA, recursive partitioning analysis. a Calculated based on Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745–51 and Buccheri G, Ferrigno D, Tamburini M. Karnofsky and ECOG performance status scoring in lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J Cancer 1996;32A:1135–41. We defined EGOG 0–1 as a criterion for RPA 1.

in which all deaths from study disease were also considered PD. In the sensitivity analysis for TTP of BMs (enzastaurin, 46 events; placebo, 45 events), the median TTP of BMs was enzastaurin: 3.1 months (95% CI: 2.3–4.8); placebo 3.6 months (95% CI: 2.4–3.9) (HR: 1.07 [95% CI: 0.70–1.62]; p = 0.75). The median OS was 3.8 months (95% CI: 2.6–5.6) and 5.1 months (95% CI: 3.7–5.7) with enzastaurin and placebo, respectively (HR: 1.16 [95% CI: 0.78–1.71]; p = 0.47) (Fig. 3). The median PFS was enzastaurin: 2.2 months (95% CI: 1.1–2.3); placebo, 2.0 months (95% CI: 1.3–2.3) (HR: 0.94 [95% CI: 0.63–1.39]; p = 0.75). The best overall response rate (ORR) of extracranial disease was 0% with enzastaurin and 4.5% with placebo (2 partial responses [PRs]) (p = 0.49). Five enzastaurin-treated patients experienced stable disease compared to 11 placebo-treated patients. The ORR of BMs was enzastaurin: 9.3% (4 PR); placebo: 6.8% (1 complete response; 2 PRs) (p = 0.71). Fifteen enzastaurin-treated patients and 22 placebo-treated patients experienced BMs stabilization. Progressive disease was documented in 83/109 (76%) patients. In 15 cases, the brain was the first site of PD (9 enzastaurin; 6 placebo); in 60 cases, extracranial disease occurred first (28

Fig. 3. Overall survival. Kaplan–Meier plots of OS are shown for the enzastaurin and placebo groups using the full analysis population. Abbreviations:. CI, confidence interval; HR, hazard ratio; N, total population size; n, number in group; N/A, not assessable; OS, overall survival; PFS, progression-free survival.

enzastaurin; 32 placebo); and 8 cases had PD in both brain and extracranially (5 enzastaurin; 3 placebo). Table 2 shows the efficacy results of the NSCLC and SCLC subgroups. There were no statistical differences between enzastaurinand placebo-treated patients in patients within histology types in any of the studied efficacy parameters. 3.3. Safety Six enzastaurin-treated patients experienced at least one serious treatment-emergent AE (TEAE) possibly related to study treatment: (1) grade 3 deep vein thrombosis/grade 3 nausea/grade 1 diarrhea; (2) grade 2 pancreatitis; (3) grade 4 headache/grade 4 neck pain/death of unknown cause; (4) grade 3 diarrhea; (5) grade 3 decreased appetite; (6) grade 3 fatigue/grade 3 decreased appetite. One placebo-treated patient experienced a serious TEAE possibly drug-related (death from pulmonary embolism). Nineteen patients died from study disease during study treatment (12 enzastaurin; 7 placebo). Two deaths were considered possibly study drug-related (1 enzastaurin [unknown cause], 1 placebo [pulmonary embolism]); the death in the placebo arm occurred during the 30-day follow-up period. Table 3 shows grade 3/4 non-laboratory TEAEs and laboratory toxicities (regardless of causality) occurring in ≥5% of patients in either arm. Grade 4 thrombocytopenia and neutropenia were experienced by 5.6% of enzastaurin-treated patients, and grade 4 thrombocytopenia was experienced by 1.9% of placebo-treated patients. Numerically, the incidences of grade 3 and grade 4 fatigue, nausea, motor neuropathy, and vomiting were higher in the enzastaurin arm, while the incidences of grade 3 and grade 4 thrombosis/embolism and lung infection were higher in the placebo arm. 3.4. Health-related Quality of Life The percentage compliance for on-study visits for the QLQ-C30 was 74.4% for the enzastaurin arm and 82.8% for the placebo arm. The percentage compliance for the QLQ-BN20 was 55.3% for enzastaurin and 66.0% for placebo. Fewer translations were available for the QLQ-BN20 than the QLQ-C30. There were no statistical differences between arms in change from baseline in any of the HRQoL scores. At the first on-study assessment (Week 4), mean scores for physical functioning, fatigue, and diarrhea score had worsened, were relatively unchanged for nausea/vomiting, and had improved for headache. These changes in mean scores are consistent with the pattern of individual

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Table 2 Efficacy in the NSCLC and SCLC subgroups. NSCLC

Median TTP of BMs, monthsb 95% CI Median OS, months 95% CI

d

ORR extracranial, % 95% CI ORR intracranial, %e 95% CI

SCLC

Enz N = 39

Placebo N = 41

HR (95% CI) P-valuea

Enz N = 16

Placebo N = 13

HR (95% CI) P-valuea

8.2 5.0–N/A 4.3 2.3–6.2

9.3 3.7–N/A 5.1 3.4–5.5

1.14 (0.52–2.51) 0.74 1.09 (0.69–1.73) 0.72

3.4 2.3–N/A 3.7 2.5–6.0

2.4 2.0–3.9 5.5 2.9–7.8

0.62 (0.23–1.67) 0.34 1.45 (0.67–3.13) 0.35

Enz

Placebo

P-valuec

Enz

Placebo

P-valuec

0 0–12.3 9.7 2.0–25.8

2.9 0.1–14.9 2.9 0.1–14.9

1.00

0 0–24.7 8.3 0.2–38.5

11.1 0.3–48.2 22.2 2.8–60.0

0.41

0.33

0.55

Abbreviations: BMs, brain metastases; CI, confidence interval; Enz, enzastaurin; HR, hazard ratio; MRI, magnetic resonance imaging; N, total population size; N/A, not assessable; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SCLC, small cell lung cancer; TTP, time to progression. a Wald’s P-value. b Defined as the time from the date of study enrollment (randomization) to the date of first observation of progression of BMs. This includes both objective criteria (RECIST) and clinical progression. c One-sided Fisher’s exact test. d In the NSCLC group, N = 28 for enzasaurin and N = 35 for placebo. In the SCLC group, N = 13 for enzastaurin and N = 9 for placebo. e In the NSCLC group, N = 31 for enzastaurin and N = 35 for placebo. In the SCLC group, N = 12 for enzastaurin and N = 13 for placebo. Table 3 Grade 3/4 laboratory toxicities and non-laboratory treatment-emergent adverse events occurring in ≥5% of patients in treatment arm. Enzastaurin (N = 54)

Laboratorya,b Platelets (thrombocytopenia) Neutrophils (neutropenia) Non-laboratorya,b Fatigue Thrombosis/thrombus/embolism Lung infection Nausea Motor neuropathy Dyspnea Vomiting

Placebo (N = 53)

Grade 3 n (%)

Grade 4 n (%)

Grade 3 n (%)

Grade 4 n (%)

0 0

3 (5.6) 3 (5.6)

0 0

1 (1.9) 0 (0.0)

7 (13.0) 2 (3.7) 4 (7.4) 7 (13.0) 3 (5.6) 3 (5.6) 3 (5.6)

2 (3.7) 5 (9.3) 1 (1.9) 0 1 (1.9) 0 0

4 (7.5) 3 (5.7) 6 (11.3) 3 (5.7) 1 (1.9) 4 (7.5) 2 (3.8)

1 (1.9) 6 (11.3) 0 0 0 0 0

Abbreviations: N, total population size; N, number in group. a Regardless of causality. b Adverse events codes using Common Terminology Criteria for Adverse Events Version 3.0.

patient changes, with most patients reporting marked or no change (Electronic Supplementary File 1). 3.5. Post-study therapy Seventeen (31.5%) enzastaurin-treated patients and 16 (30.2%) placebo-treated patients received post-study systemic therapy. Some patients may have received more than one regimen. Postdiscontinuation radiotherapy to extracranial lesions was received by 3 (5.6%) enzastaurin-treated patients and 6 (11.3%) placebotreated patients. 4. Discussion Although maintenance enzastaurin following WBRT was well tolerated, it did not improve efficacy. There was no difference in TTP of BMs, which was the primary outcome of this trial. Likewise, there were no differences between enzastaurin- and placebo-treated patients in PFS, OS, best ORR of extracranial manifestations, or HRQoL. Although enzastaurin-treated patients appeared to experience a higher frequency of TEAEs, enzastaurin was generally well tolerated. The frequency of grade 3/4 thrombocytopenia and neutropenia was 5.6% each in enzastaurin-treated patients. The most

common non-hematologic grade 3/4 TEAEs in enzastaurin-treated patients were fatigue, thrombosis, lung infection, and nausea. In this trial, extracranial disease was assessed before and during study treatment. Enrolled patients were considered to not be in immediate need of conventional systemic therapy because their extracranial disease had not progressed. Some had already received chemotherapy and would not be considered for more systemic therapy until progression. For patients who might be candidates for systemic therapy, the standard of care at participating centers was a gap of 3–4 weeks between WBRT and systemic chemotherapy, so systemic therapy was not delayed for patients in this study. By closely monitoring patients with CT and MRI while administering a drug that may have a systemic effect on the underlying LC, it was hoped that the introduction of other, potentially more toxic chemotherapy could be delayed. Thus, this trial was considered ethical in the absence of lesion progression. The tolerability and oral delivery of enzastaurin makes it an attractive agent to use as maintenance after RT. This is supported by a pre-clinical study using a mouse model where LNT-229 glioma cells were stereotactically implanted into the striatum of nude mice [20]. Mice were irradiated on Day 7 and received enzastaurin on Days 14–28. These animals experienced longer symptom-free survival than animals treated with either agent alone. In mice treated with RT on Day 7 and daily enzastaurin treatment beginning on Day

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7 until progression, neurological symptoms were prevented for >90 days. These studies, in part, provided the rationale for our clinical trial. The results here are consistent with negative results obtained in other randomized trials testing enzastaurin combination therapy or monotherapy in patients with NSCLC and recurrent intracranial glioblastoma, respectively [21–24]. The OS reported here (3.8–5.1 months) is consistent with that of WBRT in patients with multiple central nervous system (CNS) metastases (3.4–4.6 months) [4,25] and in a randomized phase III trial comparing WBRT/topotecan to WBRT in patients with CNS metastases due to SCLC or NSCLC (2.9–3.2 months) [26]. Likewise, the PFS reported here (2.0–2.2 months) is comparable to the PFS of 2.2–2.4 months reported in the phase III trial [26]. Because pharmacodynamic measurements were not performed in this study, we cannot exclude the possibility of enzastaurin not crossing the blood–brain barrier in sufficient quantities to cause target inhibition in these patients. However, this explanation seems unlikely given the objective radiological responses experienced by some enzastaurin-treated patients with recurrent glioma [12,27]. A pre-defined subset analysis demonstrated that SCLC patients had a shorter TTP of BMs than NSCLC patients. However, there were no efficacy differences between enzastaurin-treated patients and placebo-treated patients within the NSCLC and SCLC subgroups. 5. Conclusion Maintenance therapy with enzastaurin following WBRT did not improve efficacy or HRQoL relative to placebo, but was well tolerated in patients with BMs from LC. Conflict of interest Dr Grønberg received honoraria and travel expenses from Eli Lilly and Company to speak to professional groups about lung cancer; these lectures were unrelated to this manuscript. Dr. Knuuttila received honoraria for participating in advisory board meetings for Eli Lilly and Company, Roche, AstraZeneca, Pfizer, and participated in a meeting as a speaker for AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, and Roche. Dr. Fløtten received an honorarium and travel expenses from Eli Lilly and Company to speak at a meeting in 2010. Dr Langer received an honorarium from Eli Lilly and Company for participating in advisory board meeting. Drs HahkaKemppinen, Munoz, Liepa, and Krejcy are employees of, and own stock in, Eli Lilly and Company. Drs Ciuleanu, Abel, and Sundstrøm have no relevant financial interests to report. Role of funding source This study was sponsored by Eli Lilly and Company and/or one of its subsidiaries. The study was designed in collaboration between the Nordic investigators and the sponsor. The sponsor was responsible for the design and the collection, analysis, and interpretation of data. The sponsor contracted with PharmaNet/i3 for medical writing support. Cancer Research Resource Group (CRRG) performed the monitoring in Sweden, Norway, and Denmark, and ICON performed the monitoring in Poland, Romania, and Finland. Acknowledgements The authors wish to acknowledge the patients, their families, and the study personnel who participated in this clinical trial. Medical writing support was provided by Lori Kornberg, who is a full-time employee of PharmaNet/i3, part of the inVentiv Health Company.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.lungcan.2012.07.007.

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