Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study

Lung Cancer 70 (2010) 180–187

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Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study Martin Reck a,∗ , Norbert Frickhofen b , Susana Cedres c , Ulrich Gatzemeier a , David Heigener a , Heinz-Georg Fuhr b , Aron Thall d , Silvana Lanzalone e , Patricia Stephenson f , Ana Ruiz-Garcia d , Richard Chao d , Enriqueta Felip c a

Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf 22927, Germany Department of Oncology, HSK, Dr Horst Schmidt Klinik, Wiesbaden, Germany c Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain d Pfizer Oncology, La Jolla, CA, USA e Pfizer Italia Srl, Milan, Italy f Rho, Inc., Chapel Hill, NC, USA b

a r t i c l e

i n f o

Article history: Received 29 September 2009 Received in revised form 21 January 2010 Accepted 24 January 2010 Keywords: Non-small cell lung cancer Sunitinib Gemcitabine Cisplatin

a b s t r a c t Purpose: To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated. Methods: Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50 mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25 mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m2 days 1, 8) and cisplatin (80 mg/m2 day 1). Results: A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses. Conclusions: The MTD was identified as sunitinib 37.5 mg (Schedule 2/1), gemcitabine 1250 mg/m2 , and cisplatin 80 mg/m2 , with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Platinum-based chemotherapy is a mainstay of treatment for many patients with advanced non-small cell lung cancer (NSCLC). A variety of chemotherapy regimens are available with comparable efficacy and median overall survival (OS) times generally reported as 8–10 months [1–4]. More recently, antiangiogenic agents given in combination with chemotherapy have been shown to improve outcome in patients with NSCLC [5–7]. In an Eastern Cooperative Oncology Group (ECOG) trial, the addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin versus paclitaxel and carboplatin alone improved median OS (12.3 months versus 10.3 months, hazard ratio [HR]

∗ Corresponding author. Tel.: +49 4102 601188; fax: +49 4102 691317. E-mail address: [email protected] (M. Reck). 0169-5002/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.01.016

0.79; p = 0.003) in patients with non-squamous advanced NSCLC with good ECOG performance status without brain metastases or history of hemoptysis [5]. Similarly in the Avastin in Lung (AVAiL) trial, when compared with gemcitabine and cisplatin alone, the addition of bevacizumab (7.5 or 15 mg/kg) to gemcitabine and cisplatin significantly prolonged median progression-free survival (PFS) (6.1 months versus 6.7 months in the low-dose group [HR 0.75, p = 0.003] and 6.1 months versus 6.5 months in the high-dose group [HR 0.82, p = 0.030]) [6]. The median OS was similar but unexpectedly high for all groups, suggesting a benefit from post-study therapies (median OS: 13.1 months with cisplatin and gemcitabine alone; 13.6 months in the low-dose bevacizumab group; 13.4 months in the high-dose bevacizumab group) [6]. Together, these studies support the paradigm of chemotherapy combined with antiangiogenic agents in patients with advanced NSCLC. Sunitinib malate (SUTENT® ) is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antiproliferative activity. It inhibits VEGF and platelet-derived growth factor receptor

M. Reck et al. / Lung Cancer 70 (2010) 180–187

(PDGFR) family members, colony-stimulating factor 1 receptor (CSF-1R), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 receptor (FLT3), and glial cell line-derived neurotrophic factor (REarranged during Transfection [RET]) [8–11]. Because sunitinib inhibits VEGF receptor (VEGFR) family members, it has been postulated to be potentially active in NSCLC and may provide greater inhibition of VEGFR pathways than singletarget VEGF inhibitors. In addition, sunitinib-mediated inhibition of PDGFR members may further increase angiogenic inhibition, as both VEGF and PDGF signaling play a key role in tumor-related angiogenesis. Elevated levels of VEGF and PDGF have been linked to tumor progression and decreased survival of NSCLC patients [12,13]. Strategies that interrupt receptor tyrosine kinase signaling of both VEGF and PDGF pathways have additive effects versus inhibition of single targets, especially when combined with chemotherapeutic agents [14]. Single-agent sunitinib demonstrated antitumor activity in a phase II trial in patients with advanced, platinum-refractory NSCLC, with confirmed partial responses (PRs) observed in 11.1% of patients and stable disease (SD) for ≥8 weeks in 28.6% of patients receiving sunitinib 50 mg daily on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) [15]. Single-agent sunitinib administered on a continuous daily dosing (CDD) schedule also appeared active, with a median PFS of 11.9 weeks (95% confidence interval [CI]: 8.6–14.1) and median OS of 37.1 weeks (95% CI: 31.1–69.7) [16]. Sunitinib was well tolerated in this patient population, and adverse events (AEs) were generally grade 1 or 2. Preclinical data have suggested that combination treatment with sunitinib and chemotherapy may provide greater antitumor activity than standard chemotherapy alone. Concurrent administration of sunitinib with gemcitabine or sunitinib with cisplatin in NCI-H460 NSCLC human tumor xenograft models demonstrated a significantly greater degree of tumor growth inhibition (40–100% increase; p < 0.05) compared with any agent alone [17]. Together, these data suggest that a triple combination of sunitinib with gemcitabine/cisplatin may be an active regimen for the treatment of metastatic NSCLC. We present data from this open-label, multicenter, dose-escalation phase I study of sunitinib in combination with gemcitabine/cisplatin as first-line treatment in patients with advanced NSCLC.

2. Materials and methods 2.1. Study population Patients ≥18 years with an ECOG performance status of 0 or 1 and histologically proven stage IIIB or stage IV NSCLC not amenable to curative surgery or radiation therapy and who provided informed consents were recruited. Eligible patients had no prior immunotherapy or treatment with antiangiogenesis agents or chemotherapy (except adjuvant therapy completed >6 months prior to start of study treatment); life expectancy of ≥12 weeks; resolution of all acute toxic effects of prior radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade ≤1 (except alopecia); and adequate organ function. Patients receiving treatment with anticonvulsant agents or coumarin-derivative anticoagulants within 2 weeks of starting study treatment were ineligible for inclusion in the trial. Patients were also excluded if they had grade 3 hemorrhage or evidence of hemoptysis <4 weeks before starting treatment; uncontrolled hypertension; history of or known brain metastases, spinal cord compression or carcinomatous meningitis or new evidence of brain or leptomeningeal disease; prior irradiation to >25% of the bone marrow (pelvic irradiation to 25%); history of cardiac disease,

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Table 1 Dose levels for Schedule 2/1a and the CDD schedule.a . Sunitinib (mg)

Gemcitabine (mg/m2 )/cisplatin (mg/m2 )

Schedule 2/1b Dose level 1

37.5

Dose level 2c

37.5

Dose level 3

50

Dose level 4

50

Gemcitabine 1000/cisplatin 80 Gemcitabine 1250/cisplatin 80 Gemcitabine 1000/cisplatin 80 Gemcitabine 1250/cisplatin 80

CDDa Dose level 1

25

Dose level 2

37.5

Dose level 3

50

Gemcitabine 1250/cisplatin 80 Gemcitabine 1250/cisplatin 80 Gemcitabine 1250/cisplatin 80

CDD = continuous daily dosing; IV = intravenous. a CDD schedule: sunitinib 25 or 37.5 mg orally started on day 1 and dosed daily thereafter; cisplatin 80 mg/m2 by IV infusion on day 1 of each cycle; gemcitabine 1000 or 1250 mg/m2 /day by IV infusion on days 1 and 8 of a 21-day cycle. b Schedule 2/1: sunitinib 37.5 or 50 mg orally on days 1–14 of a 21-day cycle except for cycle 1; cisplatin 80 mg/m2 by IV infusion on day 1 of each cycle; gemcitabine 1000 or 1250 mg/m2 /day by IV infusion on days 1 and 8 of a 21-day cycle. c Following a protocol amendment.

cerebrovascular disease or pulmonary embolism in the 12 months prior to start of study treatment; or ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade, prolongation of the QTc interval or history of torsade de pointes. 2.2. Study design and dosing regimen Treatment was administered in 3-week cycles. Patients received sunitinib intermittently on Schedule 2/1 (2 weeks on treatment, 1 week off treatment) or on a CDD schedule in combination with gemcitabine/cisplatin. Patients continued treatment for a maximum of six cycles. Patients who experienced clinical benefit at the end of this period were allowed to continue treatment on an extended-use protocol. Treatment schedules are presented in Table 1. On Schedule 2/1, doses were escalated sequentially in serial cohorts of 3 patients. If a dose-limiting toxicity (DLT) was reported during the first treatment cycle, the cohort was expanded to include 6 patients. Doses on the CDD schedule were initiated based on data from patients enrolled on Schedule 2/1. This study was approved by the institutional review board of each participating center and was carried out in accordance with the International Conference on Harmonization Good Clinical Practice guidelines protocol, as well as applicable local laws and regulatory requirements. 2.3. Study assessments The primary objective of this study was the determination of the maximum tolerated dose (MTD) of the sunitinib plus gemcitabine/cisplatin combination based on DLT. AEs were assessed (graded by NCI CTCAE, version 3.0). Other safety assessments included laboratory tests (hematology, blood chemistry, coagulation, urinalysis), physical examination, electrocardiogram, and vital signs. Dose-limiting toxicities were assessed in the first cycle of sunitinib plus gemcitabine/cisplatin (21 days) for both schedules. The MTD was the dose at which no more than 1 of 6 patients experienced a DLT, with the next higher dose having at least 2 of 3 or 2

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Table 2 Definition of a dose-limiting toxicity (DLT)a . Toxicity category

DLT-defining criteria

Hematologic

• Grade 4 neutropenia lasting ≥7 days • Febrile neutropenia, defined as concurrent grade 4 neutropenia and fever >38.5 ◦ C lasting over 24 h • Either grade ≥3 thrombocytopenia with bleeding or grade 4 thrombocytopenia lasting ≥7 days (lymphopenia is not considered a DLT unless accompanied by an opportunistic infection)

Non-hematologic

• Grade 3 or 4 toxicities including fatigue lasting ≥7 days (except for skin or hair discoloration, alopecia, hyperamylasemia or hyperlipasemia without other clinical evidence of pancreatitis, and asymptomatic hyperuricemia) • Nausea, vomiting, or diarrhea persisting at grade 3/4 despite maximal medical therapy

a

DLTs were assessed during cycle 1 for Schedule 2/1 and CDD in all cohorts.

of 6 patients experiencing a DLT. If a DLT was observed in 1 of 3 patients, an additional 3 patients were enrolled. If at least 2 of 3 patients in any cohort (or at least 2 of 6 in the expanded cohort) experienced a DLT, then 3 patients were added at the preceding dose level if there were only 3 patients treated at that prior dose. If the MTD was not reached at 50 mg/daily for sunitinib, 1250 mg/m2 for gemcitabine, and 80 mg/m2 for cisplatin, no additional escalating cohorts were added and the last cohort was declared the recommended phase II dose. Once the MTD was determined, up to 10 additional patients were enrolled to further characterize the safety profile of the treatment combination. Hematologic and nonhematologic DLTs are defined in Table 2. Secondary endpoints included pharmacokinetic (PK) parameters and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) [18].

For the PK analysis on Schedule 2/1, the first dose of sunitinib in cycle 1 was administered 7 days prior to the start of gemcitabine/cisplatin treatment and the 14-day sunitinib treatment schedule was started on day 3 of cycle 1. Full PK profiles were measured for gemcitabine, cisplatin (day 1 of cycles 1 and 2), sunitinib and its metabolite (SU12662), and total drug (sunitinib plus SU12662) on day 7 before cycle 1 and on day 1 of cycle 2 at 1, 2, 4, 6, 8, and 10 h after gemcitabine infusion. For the CDD cohort, a similar collection pattern was followed with the exception of sunitinib, SU12662, and total drug, where samples were collected on day 15 of cycle 1 and on day 1 of cycle 2. For both schedules, trough samples were collected predose on days 1 and 15 of cycles 1–4. Analytes were measured and assessed using standard, validated PK assays [19–21]. Antitumor activity was evaluated through radiologic tumor assessments conducted at screening, on day 21 of even-numbered cycles, whenever disease progression was suspected, to confirm a PR or complete response (CR) at least 4 weeks after initial documentation of response, and at the time of withdrawal from the study. 2.4. Statistical methods All patients who received at least one dose of study treatment were included in the safety analyses. Patients evaluable for DLT had to complete the first cycle of treatment; patients evaluated for tumor response were required to have measurable disease at baseline with at least one response assessment made by the investigator; and sufficient sampling was required for patients to be evaluable for PK analysis. Descriptive statistics were used to summarize all patient characteristics, treatment administration and compliance, efficacy endpoints, and safety parameters. PK parameters (paired observations) were estimated for each patient using noncompartmental analysis of concentration–time data using WinNonlin, Version 4.1.

Table 3 Patient characteristics at baseline for Schedule 2/1 and CDD. Schedule 2/1

CDD

Sunitinib 37.5 mg

Sunitinib 50 mg Gemcitabine 1000 mg/m2 Cisplatin 80 mg/m2 Cohort 3 (n = 7)

Sunitinib 25 mg Gemcitabine 1000 mg/m2 Cisplatin 80 mg/m2 (n = 7)

Gemcitabine 1000 mg/m2 Cisplatin 80 mg/m2 Cohort 1 (n = 6)

Gemcitabine 1250 mg/m2 Cisplatin 80 mg/m2 Cohort 2 (n = 8)

Age in years Median Range

58.5 48–68

61.0 55–70

61.0 55–68

60.0 34–68

Male/female, n

3/3

7/1

5/2

6/1

ECOG PS, n 0/1

3/3

4/4

1/6

0/7

NSCLC histology, n (%) Adenocarcinoma Large cell Squamous cell Other

3 (50.0) 1 (16.7) 2 (33.3) 0

3 (37.5) 0 4 (50.0) 1 (12.5)

5 (71.4) 1 (14.3) 1 (14.3) 0

7 (100.0) 0 0 0

Disease stage, n (%) IIIB IV

1 (16.7) 5 (83.3)

2 (25.0) 6 (75.0)

0 7 (100.0)

2 (28.6) 5 (71.4)

Sites of metastases, n (%) Lung Regional lymph nodes Pleural effusion Liver Bone Peritoneum Distal lymph nodes Other

6 (100.0) 3 (50.0) 3 (50.0) 1 (16.7) 1 (16.7) 1 (16.7) 0 3 (50.0)

7 (87.5) 2 (25.0) 1 (12.5) 2 (25.0) 2 (25.0) 0 0 5 (62.5)

7 (100.0) 5 (71.4) 2 (28.6) 1 (14.3) 0 0 1 (14.3) 2 (28.6)

7 (100.0) 7 (100.0) 2 (28.6) 2 (28.6) 3 (42.9) 0 2 (28.6) 2 (28.6)

CDD = continuous daily dosing; ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = non-small cell lung cancer.

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Table 4 Patient disposition for Schedule 2/1 and CDD. Schedule 2/1

CDD

Sunitinib 37.5 mg 2

Sunitinib treatment cycles Median started (range)

Sunitinib 50 mg Gemcitabine 1000 mg/m2 Cisplatin 80 mg/m2 Cohort 3a (n = 7)

Sunitinib 25 mg Gemcitabine 1000 mg/m2 Cisplatin 80 mg/m2 (n = 7)

Gemcitabine 1000 mg/m Cisplatin 80 mg/m2 Cohort 1 (n = 6)

Gemcitabine 1250 mg/m Cisplatin 80 mg/m2 Cohort 2 (n = 8)

4 (2–5)

3 (1–5)

4 (0–6)

4 (0–5)

5

3

6

1 2 0

0 3 2

0 2 2

6 0 0 1 1

4 0 0 0 0

3 2 1 0 1

4 Number of patients with at least one dose delay for sunitinibb (n) Number of patients with at least one dose reduction (n) Sunitinib 3 Gemcitabine 0 Cisplatin 0 Reason for discontinuation (n) AE Disease progression Death Noncompliance Other

2

2 2 1 0 1

AE = adverse event; CDD = continuous daily dosing. a After study completion, 2 patients received further sunitinib treatment in a continuation study (n = 1 continued sunitinib treatment for approximately 20 days; n = 1 remained in the study for nearly 7 months). b The number of patients with at least one dose delay for gemcitabine and cisplatin was the same as for sunitinib.

Table 5 Safety findings: (A) incidence (%) of most frequent (≥15%), all-causality, non-hematologic adverse events (AEs) for Schedule 2/1 and CDD; (B) hematologic laboratory abnormalities. Schedule 2/1a N = 21 Grade 1/2, n (%) (A) Non-hematologic, all-causality AEs Nausea Fatigue Vomiting Mucosal inflammation Constipation Pyrexia Anorexia Asthenia Cough Epistaxis Hiccups Diarrhea Dysgeusia Dyspepsia Dyspnea Vertigo Weight decreased Chest pain Pneumonia Polyneuropathy Pain in extremity Pulmonary embolism

11 (52.4) 9 (42.9) 8 (38.1) 7 (33.3) 6 (28.6) 6 (28.6) 5 (23.8) 5 (23.8) 5 (23.8) 5 (23.8) 4 (19.0) 4 (19.0) 4 (19.0) 4 (19.0) 4 (19.0) 2 (9.5) 2 (9.5) 1 (4.8) 1 (4.8) 1 (4.8) 0 0

(B) Hematologic abnormalities Anemia Leukopenia Lymphopenia Neutropenia Thrombocytopenia

16 (76.2) 8 (38.1) 8 (38.1) 2 (9.5) 8 (38.1)

CDD = continuous daily dosing; AE = adverse event. a Includes all cohorts. b Sunitinib 25 mg + gemcitabine 1,000 mg/m2 + cisplatin 80 mg/m2 . c Includes one grade 5 AE.

CDDb N=7 Grade 3/4, n (%)

Grade 1/2, n (%)

Grade 3/4, n (%)

3 (14.3) 1 (4.8) 1 (4.8) 1 (4.8) 0 0 0 1 (4.8) 0 0 0 1 (4.8) 0 0 4 (19.0) 0 0 0 4c (19.0) 1 (4.8) 0 4c (19.0)

4 (57.1) 2 (28.6) 3 (42.9) 2 (28.6) 1 (14.3) 2 (28.6) 1 (14.3) 0 1 (14.3) 2 (28.6) 1 (14.3) 1 (14.3) 1 (14.3) 0 2 (28.6) 3 (42.9) 3 (42.9) 2 (28.6) 0 2 (28.6) 3 (42.9) 0

1 (14.3) 3 (42.9) 0 0 0 0 0 0 0 0 0 1 (14.3) 0 0 1 (14.3) 0 0 0 2 (28.6) 0 0 1 (14.3)

2 (9.5) 12 (57.1) 6 (28.6) 16 (76.2) 12 (57.1)

4 (57.1) 1 (14.3) 5 (71.4) 1 (14.3) 3 (42.9)

2 (28.6) 5 (71.4) 2 (28.6) 5 (71.4) 3 (42.9)

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3. Results 3.1. Patient baseline characteristics and disposition A total of 28 patients were enrolled; 21 patients in the Schedule 2/1 cohort and 7 patients in the CDD cohort (Table 3). Based on tolerability observed in patients on Schedule 2/1, dosing for the CDD cohort was initiated at sunitinib 25 mg + gemcitabine 1000 mg/m2 + cisplatin 80 mg/m2 (n = 7). Baseline characteristics are given in Table 3. Median age was 60 years and similar across all cohorts. All patients in the CDD cohort had adenocarcinoma. Most patients across the Schedule 2/1 cohorts had adenocarcinoma (52.4%) or squamous cell carcinoma (33.3%). Frequently reported sites of disease included lung, lymph nodes, and pleural effusion. Table 4 summarizes patient disposition for Schedule 2/1 and CDD cohorts. For Schedule 2/1, 2 patients (33.3%) discontinued treatment due to AEs (both due to neutropenia) in cohort 1. In cohort 2, 6 patients (75.0%) discontinued due to AEs (cystitis, intestinal obstruction and neutropenia, hearing impairment, recurrent myelotoxicity [n = 1 each], and pulmonary embolism [n = 2]). One patient in cohort 2 was also discontinued after receiving an incorrect cisplatin dose of 100 mg/m2 not specified in the protocol. Four patients (57.1%) in cohort 3 discontinued treatment due to AEs (pulmonary edema, mucosal inflammation, pulmonary embolism, pneumonia, n = 1 each). One patient assigned to cohort 3 developed an allergic reaction to gemcitabine on day 1 of cycle 1 and was included in the safety analysis. The study was completed per protocol by 3 patients in cohort 3. For the CDD cohort, 3 patients (42.9%) discontinued due to AEs (anemia, neutropenia, pericardial and pleural effusion, n = 1 each). Two patients discontinued due to disease progression, 1 patient died, and 1 discontinued for an unknown reason. 3.2. Determination of MTD Nineteen of the 21 patients enrolled on the sunitinib Schedule 2/1 were evaluable for DLTs. None of the patients treated in cohorts 1 and 2 experienced a DLT. Six of 7 patients in cohort 3 were evaluable for DLTs. Two patients developed DLTs: grade 3 sinusitis frontalis (n = 1) and grade 4 poststenotic pneumonia (n = 1), each of 16 days’ duration. Thus, the MTD on Schedule 2/1 was determined to be sunitinib 37.5 mg/day + gemcitabine 1250 mg/m2 + cisplatin 80 mg/m2 (dose level 2). On the CDD schedule, 0 of 6 evaluable patients developed DLTs; however, due to the myelosuppression and dose delays observed, higher dose levels were not investigated. 3.3. Safety and tolerability There were 4, 5, and 3 patients with dose delays in Schedule 2/1 cohorts 1, 2, and 3, respectively. Sunitinib dose reductions were reported for 3 patients in cohort 1 and 1 patient in cohort 2. No sunitinib dose reductions were reported for cohort 3 or the CDD cohort. Six patients experienced at least one dose delay in the CDD cohort (Table 4). Most reported AEs were grade 1 or 2 in severity, including those in the Schedule 2/1 MTD cohort (Table 5). The most frequently reported non-hematologic, all-causality AEs were nausea (66.7%), fatigue (47.6%), and vomiting (42.9%) for the Schedule 2/1 cohorts, and fatigue (71.4%) and nausea (71.4%) for the CDD cohort. Grade 3/4 non-hematologic AEs included dyspnea (19%), nausea (14.3%), pneumonia (14.3%), and pulmonary embolism (14.3%) on Schedule 2/1, and fatigue (42.9%) and pneumonia (28.6%) on the CDD schedule. The most frequently reported grade 3/4 hematologic abnormalities on Schedule 2/1 were neutropenia (76.2%), leukopenia (57.1%), and thrombocytopenia (57.1%). At the doses

Fig. 1. Log-linear mean (+SD) plasma concentration of total drug, gemcitabine, and total platinum content versus time profiles at MTD on Schedule 2/1 (subjects with paired observations only). (a) Total drug (sunitinib + SU12662)* (b) Gemcitabine† (c) Total platinum in plasma† MTD was sunitinib 37.5 mg/day + gemcitabine 1250 mg/m2 + cisplatin 80 mg/m2 (cohort 2). * PK samples for sunitinib, SU12662, and total drug (sunitinib plus SU12662) were collected on day −7 before cycle 1 and on day 1 of cycle 2 at 1, 2, 4, 6, 8, and 10 h after gemcitabine infusion. † PK samples were collected on day 1 of cycles 1 and 2 for gemcitabine and cisplatin.

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Table 6 Pharmacokinetic parameters (subjects with paired observations only) at MTDa on Schedule 2/1. Sunitinib alone

Sunitinib + gemcitabine/cisplatin

Mean (%CV)

Mean (%CV)

Geometric mean ratio: (sunitinib + gemcitabine/cisplatin)/sunitinib alone Mean

Sunitinibb (n = 16) Tmax (h) Cmax (ng/mL) AUC0–24 (ng h/mL)

6.0 (4.0–10.0) 19.0 (31) 293 (28)

5.0 (1.0–24.0) 21.0 (24) 330 (34)

N/A 1.12 1.09

SU12662 Tmax (h) Cmax (ng/mL) AUC0–24 (ng h/mL)

6.0 (4.0–10.0) 3.27 (53) 53.7 (48)

6.0 (4.0–24.0) 3.34 (52) 51.1 (45)

N/A 1.02 0.93

Total drugc Tmax (h) Cmax (ng/mL) AUC0–24 (ng h/mL)

6.0 (4.0–10.0) 22.3 (31) 347 (27)

5.0 (2.0–24.0) 24.2 (25) 381 (34)

N/A 1.09 1.03

Gemcitabineb (n = 17) Tmax (h) Cmax (␮g/mL) AUC0–24 (␮g h/mL)

0.5 (0.5–0.8) 16.4 (33) 8.13 (33)

0.5 (0.5–0.5) 18.1 (38) 8.64 (31)

N/A 1.08 1.08

Total platinumb (N = 17) Tmax (h) Cmax (␮g/mL) AUC0–24 (␮g h/mL)

2.5 (1.0–3.0) 2.73 (17) 39.3 (12)

2.5 (2.5–4.0) 3.43 (48) 46.4 (22)

N/A 1.20 1.17

CV = coefficient of variation; MTD = maximum tolerated dose; N/A = not applicable. a MTD was defined as sunitinib 37.5 mg/day + gemcitabine 1250 mg/m2 + cisplatin 80 mg/m2 . b For combination treatment, 37.5 mg sunitinib + gemcitabine 1250 mg/m2 + cisplatin 80 mg/m2 was used for dose correction. c Total drug = sunitinib + SU12662.

studied, the CDD schedule appeared to be poorly tolerated due to cumulative myelosuppression. Seventy-one percent of patients each reported grade 3/4 leukopenia and neutropenia, and 42.9% of patients reported thrombocytopenia (Table 5b). AEs considered by the investigator to be serious were reported in 15 patients on Schedule 2/1 (cohort 1, n = 2; cohort 2, n = 7; cohort 3, n = 6) and in 5 patients in the CDD cohort. Five patients on the Schedule 2/1 MTD had serious AEs considered related to the study medication; 1 patient had neutropenia and thrombocytopenia (both grade 4); 1 patient had neutropenia, diarrhea, intestinal obstruction (all grade 3; this patient also had grade 3 pneumonia and grade 5 sepsis not due to study medication); 1 patient reported pneumonia (grade 4); 1 patient had atrial thrombosis, pulmonary embolism, thrombosis of the left leg (all grade 4), nausea, dehydration (both grade 3), and periodontal abscess (grade 2); and 1 patient had pneumonia, clinical symptoms suggestive of amyotrophic lateral sclerosis, and pulmonary embolism (all grade 5; pneumonia was not considered to be related to study medication). Most grade ≤4 events resolved, although 3 patients were permanently withdrawn from the study.

3.5. Efficacy Tumor response was evaluated in 18 patients on Schedule 2/1 and 6 patients in the CDD cohort. Most patients showed decreases in their target lesion measurements while on the study. Fig. 2 presents the best percentage change from baseline in target tumor lesion size in each patient for all cohorts (n = 23). One patient missing the postbaseline measurement was excluded from this figure. The ORR was 20.8%; confirmed PRs were achieved in 5 of 24 evaluable patients. The highest response rate was observed in cohort 3 (4 of 6 evaluable patients [66.7%] achieved confirmed PRs). 4. Discussion Based on the positive results from previous trials of VEGF inhibitors combined with chemotherapy in NSCLC [5,6], we evaluated sunitinib in combination with gemcitabine and cisplatin.

3.4. Pharmacokinetics Mean total drug (sunitinib plus SU12662), gemcitabine, and total platinum in plasma concentration–time profiles when administered alone and in combination are shown in Fig. 1a–c, respectively, for patients treated at the MTD on Schedule 2/1. Plasma PK parameter values and geometric mean ratios for subjects with paired observations at the MTD are presented in Table 6. For sunitinib, SU12262, and total drug following a single dose of sunitinib alone or with gemcitabine/cisplatin, the geometric mean ratios of Cmax and AUC0–24 were 1.12 and 1.09 for sunitinib, 1.02 and 0.93 for SU12662, and 1.09 and 1.03 for total drug. For gemcitabine, the geometric mean ratios of Cmax and AUC0–24 were both 1.08. The geometric mean ratios of Cmax and AUC0–24 for total platinum content were 1.20 and 1.17, respectively.

Fig. 2. Best percentage change from baseline in target tumor lesion size per patient (all cohorts). n = 23; one patient missing the post-baseline measurement was excluded.

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This combination was also investigated based on the rationale that sunitinib-mediated inhibition of both PDGF and VEGF signaling pathways may be a more effective treatment strategy for NSCLC than agents inhibiting the VEGF pathway alone [12,22]. Using the criteria defined in this study, the MTD on Schedule 2/1 was identified as sunitinib 37.5 mg/day plus gemcitabine 1250 mg/m2 and cisplatin 80 mg/m2 in this population of previously untreated, advanced-stage NSCLC patients. Although no DLTs were observed at this dose level, almost all patients developed myelosuppression and underwent dose reduction and/or experienced dose delays in subsequent cycles. Similarly on the CDD schedule, sunitinib in combination with gemcitabine/cisplatin appeared to be poorly tolerated due to cumulative myelosuppression. Dose delays due to myelosuppression occurred frequently and resulted in discontinuation of treatment by cycle 4. Myelosuppression was observed with the initial CDD dose level; this schedule was poorly tolerated as all patients experienced lymphopenia and nearly 90% of patients reported having neutropenia and anemia. As such, further dose-escalation of the study drug on the CDD schedule was not pursued. Although myelosuppression can be a significant toxicity that occurs among patients undergoing treatment with gemcitabine/ cisplatin [23–26], it is generally manageable [25,26] and phase II and III trials have consistently demonstrated the activity and feasibility of this regimen with response rates of 30–41% [23,24,27]. In this study, it is difficult to specifically characterize the safety profile of each individual drug when they have been administered as a combination therapy. Myelosuppression did not appear to result from clinically relevant drug–drug interactions when sunitinib was combined with gemcitabine/cisplatin. Based on the PK data, clinically significant changes in the geometric mean ratios Cmax and AUC0–24 were not observed when sunitinib, gemcitabine, and cisplatin were administered together, compared with administration of sunitinib alone or compared with gemcitabine/cisplatin. When administered as a single agent, sunitinib has been associated with myelosuppression in only a small proportion of patients. One possible explanation for this myelosuppression is that it results from inhibition of c-KIT, FLT3, and colony-stimulating factor receptor (c-fms); therefore, inhibition of these pathways may also play a role in recovery of blood cells following myelosuppressive chemotherapy. Since neutropenia was the primary factor causing dose delays and limited the dose intensity of all drugs in the combination, granulocyte colony-stimulating factor (G-CSF) may improve the tolerability of this regimen, although use of growth factor support must be considered with caution [28,29]. While the potential for G-CSF to limit dose delays was not evaluated in this study, it is noteworthy that unpublished data from a CALGB trial of cisplatin and etoposide plus sunitinib on Schedule 2/1 in patients with extensive stage small cell lung cancer revealed severe neutropenia and sepsis occurred when G-CSF was added after chemotherapy and concurrent with sunitinib. Despite the myelosuppression observed in this study, this treatment regimen appears to have activity as evidenced by the 5 patients with confirmed PRs. In addition to studies combining the triple combination with G-CSF, trials incorporating sequential administration of sunitinib before or after chemotherapy may also be warranted.

4.1. Summary This phase I trial identified the MTD on Schedule 2/1 as sunitinib 37.5 mg/day, when combined with gemcitabine 1250 mg/m2 and cisplatin 80 mg/m2 . The myelosuppression observed limits the fea-

sibility of this combination at the dose levels studied in the NSCLC broad patient population. Conflict of interest M. Reck receives honoraria as a speaker and is compensated for serving on advisory boards for Hoffman–La Roche, Lilly, Merck, and Pfizer. U. Gatzemeier receives honoraria from Roche, Merck, Lilly, Novartis, Pierre Fabre, and Astra Zeneca. He also serves on the advisory boards for Roche, Mundipharma, GSK, Lilly, Astra Zeneca, Bayer, and Merck. D. Heigener receives honoraria from Roche. S. Lanzalone is an employee of Pfizer Italia Srl and holds stock in Pfizer Inc., the makers of SUTENT® . A. Thall and R. Chao are employees of Pfizer Inc. and hold stock in Pfizer Inc. A. Ruiz-Garcia is an employee of Pfizer Inc. N. Frickhofen, S. Cedres, H.G. Fuhr, P. Stephenson, and E. Felip have no conflict of interest to disclose. Acknowledgements Patricia Stephenson is an employee of Rho, Inc., who were contracted statistical consultants to Pfizer in connection with the development of the manuscript. Medical writing support was provided by Sîan Marshall at ACUMED (Tytherington, UK) and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc. References [1] Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346(2):92–8. [2] Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21(16):3016–24. [3] D’Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinumbased versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005;23(13):2926–36. [4] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: NSCLC v.2.2008. http://www.nccn.org/professionals/physician gls/PDF/nscl.pdf. [5] Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355(24):2542–50. [6] Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsch V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27(8):1227–34. [7] Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-smallcell lung cancer (FLEX): an open-label randomised phase III trail. Lancet 2009;373(9674):1525–31. [8] Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2(5):471–8. [9] Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9(1):327–37. [10] Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003;20(8):757–66. [11] O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003;101(9):3597–605. [12] Shikada Y, Yonemitsu Y, Koga T, Onimaru M, Nakano T, Okano S, et al. Plateletderived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas. Cancer Res 2005;65(16):7241–8. [13] Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 2001;19(2):432–41. [14] Hasumi Y, Klosowska-Wardega A, Furuhashi M, Ostman A, Heldin CH, Hellberg C. Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int J Cancer 2007;121(12):2606–14.

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