Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer

doi:10.1016/j.lungcan.2012.03.009

Lung Cancer

Volume 77, Issue 2, August 2012, Pages 359-364

https://doi.org/10.1016/j.lungcan.2012.03.009 Get rights and content

Abstract

Background

Inhibition of angiogenesis may be effective in the treatment of small-cell lung cancer (SCLC). Sunitinib, an oral agent that inhibits the VEGF signaling pathway, may delay progression in sequence with chemotherapy. This phase II trial was designed to evaluate the role of sunitinib monotherapy following 6 cycles of irinotecan and carboplatin in patients with newly diagnosed extensive-stage (ES) SCLC.

Method

Patients aged ≥18 years with previously untreated ES-SCLC were eligible. Additional criteria included: ECOG PS 0–1, no active brain metastases, and adequate organ function. Patients received 28-day cycles of irinotecan (60 mg/m², days 1, 8, 15) and carboplatin (AUC = 4, day 1), and were assessed for response every 8 weeks. After 6 cycles of chemotherapy, patients with stable disease or responding disease proceeded to sunitinib monotherapy (25 mg orally daily) until disease progression or unacceptable toxicity. The primary endpoint was 1-year overall survival (OS).

Results

Between 2/09 and 10/09, 34 patients (median age 65 years [range, 41–80]) were enrolled. 53% of patients were male, 47% had ECOG PS 0.21 patients (62%) completed 6 cycles of chemotherapy, and 17 (50%) initiated sunitinib monotherapy (median duration: 9 weeks; range, 2–28+ weeks). After a median follow-up of 50 weeks (range: 37–68 weeks), 22 (62%) of the patients remain alive. The objective response rate with chemotherapy was 59%, and an additional 20% had stable disease. 1-year OS was 54% and median time to progression was 7.6 months. Grade 3/4 toxicity was rare during sunitinib monotherapy.

Conclusions

This phase II trial provides support for further study of sunitinib maintenance therapy following platinum-doublet chemotherapy in patients with ES-SCLC. The 1 year OS of 54% is encouraging, and a randomized trial would be appropriate to assess sunitinib's impact following chemotherapy.

Introduction

Doublet chemotherapy is standard first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Platinum-based doublets are associated with high response rates and early improvement in disease-related symptoms [1], [2], [3], [4], [5], [6], [7], [8]. However, the majority of patients will experience relapse of their disease within the first year, and fewer than 10% of patients will survive beyond 2 years [9]. Newer strategies are needed to prevent disease relapse.

Angiogenesis plays an important role in cancer cell survival and metastasis in many solid tumors including SCLC [10], [11], [12]. Sunitinib is an oral multikinase inhibitor of angiogenesis and cellular proliferation [13]. Sunitinib inhibits several molecular targets including the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), Flt-3, and C-kit. Sunitinib is FDA-approved for the treatment of advanced renal cell cancer (RCC) and gastrointestinal stromal tumors (GIST), and has been studied in multiple advanced cancer settings including non-small-cell lung cancer (NSCLC) [14], [15], [16], [17]. Sunitinib has been combined safely with irinotecan-based combinations in patients with advanced colorectal cancer [18] and glioblastoma [19], [20], and with carboplatin and paclitaxel in advanced solid tumors [21].

Platinum/irinotecan doublets have been extensively studied in SCLC including carboplatin and irinotecan [1], [2], [3], [4], [5], [6], [8], [22], [23], [24]. These doublets are equivalent in efficacy to platinum/etoposide regimens, with less myelosuppression, but more severe diarrhea [25], [26], [27], [28], [29]. Herein we report on a multicenter phase II trial where sunitinib was administered as monotherapy following irinotecan and carboplatin in patients with newly diagnosed ES-SCLC.

Section snippets

Patients and methods

This trial was initiated in February 2009. Participating centers included the Sarah Cannon Research Institute and select sites from the Sarah Cannon Oncology Research Consortium, a national community-based research network (see Appendix A). The trial was registered with ClinicalTrials.gov, a service of the NIH (#NCT00695292).

Patient characteristics

Thirty-four patients were enrolled from February 2009 to October 2009, not including the 3 patients who were treated with concurrent sunitinib prior to the modified design. Baseline characteristics for all patients are described in Table 1. The median age was 65 years (range, 41–80 years). Eighteen (53%) patients were male and 16 patients were female. ECOG PS was 0 in 16 (47%) patients and 1 in 18 patients.

Treatment received

The median follow-up is 50 weeks (range, 37–68 weeks). Twenty-one (62%) patients completed 6

Discussion

Despite high response rates and early symptom control with chemotherapy, few patients diagnosed with ES-SCLC will live beyond 2 years. The most recent advance in the care of patients with ES-SCLC was with the use of prophylactic cranial irradiation in patients who had responded to first-line chemotherapy [34]. However, even in this selected group of patients, the 1-year overall survival was less than 30%. Newer approaches in treatment are needed.

Inhibiting angiogenesis has proven to be an

Conflict of interest statement

Eric Lubiner reported stock or ownership interests to disclose with Pfizer. All other authors had none to declare.

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^☆: Supported in part by a grant from Pfizer, Inc., New York, NY.

^☆☆: Preliminary data presented at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, 2010 and the Chicago Multidisciplinary Symposium in Thoracic Oncology, Chicago, IL, 2010.

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Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer☆,☆☆

Abstract

Background

Method

Results

Conclusions

Introduction

Section snippets

Patients and methods

Patient characteristics

Treatment received

Discussion

Conflict of interest statement

Ann Oncol

J Thorac Oncol: Off Publ Int Assoc Stud Lung Cancer

J Thorac Oncol: Off Publ Int Assoc Stud Lung Cancer

J Thorac Oncol: Off Publ Int Assoc Stud Lung Cancer

Lung Cancer

Ann Oncol

J Thorac Oncol

J Am Coll Surg

Ann Oncol

Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer

N Engl J Med

S0124: a randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC)

J Clin Oncol (Meeting Abstracts)

Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer

Brit J Cancer

Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial

J Clin Oncol

Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer

J Clin Oncol

Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer

J Clin Oncol

Phase II trial of irinotecan and carboplatin for extensive or relapsed small-cell lung cancer

J Clin Oncol

Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database

J Clin Oncol

Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin: neuron-specific enolase or lactate dehydrogenase

Respirology

Relationship between vessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in small cell lung cancer in vivo and in vitro

Clin Cancer Res

A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma

Brit J Cancer

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

Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer

Brit J Cancer