Portal de Periódicos da CAPES

Targeting Vascular Endothelial Growth Factor in Lung Cancer

2010; Elsevier BV; Volume: 5; Issue: 12 Linguagem: Inglês

10.1097/01.jto.0000391377.17179.6b

1556-1380

Arman Hasani, Natasha B. Leighl,

Hepatocellular Carcinoma Treatment and Prognosis

Vascular endothelial growth factor (VEGF), as a key mediator of angiogenesis and important prognostic factor in lung cancer, remains a major target in drug development for this disease. Recent developments and future directions were discussed at the 10th Annual Targeted Therapies of the Treatment of Lung Cancer in Santa Monica. Dr. Zhang (University of Southern California) presented an exploratory subset analysis of E4599, examining germline polymorphisms of angiogenic factors as potential predictive biomarkers for benefit from bevacizumab. Of 879 patients enrolled on E4599, samples from 133 were available, of whom 66 received bevacizumab. A profile of three single nucleotide polymorphisms in IL-8, VEGF, and ICAM-1 was generated from patients responding to bevacizumab-based therapy. This profile was associated with better progression-free survival (PFS; hazard ratio [HR]: 0.40; median: 9.2 versus 5.4 months; p = 0.002) and overall survival (OS; HR: 0.39; median: 16.8 versus 10.2 months; p = 0.0001). Interestingly, this profile was not prognostic in the cohort of chemotherapy-treated controls and will hopefully be validated in further studies. Professor Scagliotti (University of Torino) reviewed the development of aflibercept (VEGF Trap), a recombinant fusion protein that binds VEGF-A, VEGF-B, and placental growth factor. As a single agent, aflibercept achieved a high rate of stable disease (68.4%) but only 2% response rate (RR) in patients with platinum and erlotinib-resistant nonsquamous non-small cell lung cancer (NSCLC).1Massarelli E Miller VA Leighl NB et al.Phase II study of the efficacy and safety of intravenous (IV) AVE0005 (VEGF Trap) given every 2 weeks in patients (Pts) with platinum- and erlotinib- resistant adenocarcinoma of the lung (NSCLA).J Clin Oncol (Meeting Abstracts). 2007; 25: 7627Google Scholar A large phase III study of second-line docetaxel plus aflibercept/placebo has completed accrual, and a phase II study of first-line pemetrexed/cisplatin/aflibercept is ongoing. Dr. Doebele (University of Colorado) outlined the development of ramucirumab (IMC-1121B), a fully human anti-vascular endothelial growth factor receptor (VEGFR)-2 IgG1 monoclonal antibody. Phase II studies are underway or planned, combining ramucirumab with first-line chemotherapy. One trial focuses on patients with squamous histology, using gemcitabine/carboplatin ± ramucirumab; another will enrol patients with nonsquamous histology, to receive pemetrexed/carboplatin ± ramucirumab. The development of pazopanib (targets VEGFR, platelet derived growth factor receptor, and c-kit) in NSCLC was summarized by Prof. Scagliotti. A single-arm phase II study of preoperative pazopanib (median 16 days treatment) in 35 patients with early-stage NSCLC demonstrated tumor shrinkage in 86% and a RR of 8.6%. Baseline plasma levels of IL-12 and hepatocyte growth factor were associated with response (accuracy 81%), whereas changes in plasma IL-12, hepatocyte growth factor, and VEGFR2 were associated with reduction in tumor volume. Pazopanib plus pemetrexed demonstrated a 15% RR in 15 patients with NSCLC. Pazopanib plus erlotinib in 33 patients (13 with NSCLC) reported three responses, all in patients with NSCLC. Pazopanib plus carboplatin/paclitaxel in phase I demonstrated significantly increased exposure to paclitaxel and carboplatin, resulting in hematologic toxicity. Dr. Heymach (MD Anderson) reviewed NSCLC treatment with sorafenib (targets RAF, VEGFR-2, and platelet derived growth factor receptor). Sorafenib has demonstrated single-agent efficacy in NSCLC. Nevertheless, the phase III ESCAPE trial indicated that adding sorafenib to first-line carboplatin/paclitaxel for advanced NSCLC did not improve OS, and survival was inferior for patients with squamous cell carcinoma who received sorafenib.2Scagliotti G Novello S von Pawel J et al.Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer.J Clin Oncol. 2010; 28: 1835-1842Crossref PubMed Scopus (388) Google Scholar This study was terminated early, and the NExUS trial (cisplatin/gemcitabine with sorafenib/placebo) was amended to exclude patients with squamous histology. Dr. Schiller (University of Texas Southwestern) discussed axitinib in NSCLC (targets VEGFR-1, -2, and -3). A randomized phase II study in nonsquamous chemonaive patients of axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin, followed by maintenance axitinib or bevacizumab is ongoing. A phase III study of pemetrexed/cisplatin ± axitinib in patients with nonsquamous NSCLC has completed recruitment, and results are pending. A single-arm study of gemcitabine/cisplatin and axitinib in patients with squamous NSCLC has also completed accrual. The development of hypertension has been identified as a potential predictor of better OS from six trials of axitinib in multiple tumor types including NSCLC.3Rini BI Schiller JH Fruehauf JP et al.Association of diastolic blood pressure (dBP) >= 90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736).J Clin Oncol(Meeting Abstracts). 2008; 26: 3543Crossref PubMed Scopus (2730) Google Scholar Ongoing studies of sunitinib in NSCLC were also outlined by Dr. Schiller. These include a randomized phase II study of erlotinib ± sunitinib second line and a trial of maintenance therapy, sunitinib versus placebo, in patients who have not progressed on first-line platinum-based chemotherapy. Sunitinib is being combined with etoposide/cisplatin in extensive stage SCLC in the CALGB 30504 study (phase IB). Dr. Wakelee (Stanford) reviewed XL647 studies in NSCLC (targets EGFR, HER2, and VEGFR-2). A phase II trial of XL647 in 38 selected chemotherapy-naive patients with advanced NSCLC reported a 26% RR; three responders had wild-type EGFR in their tumors.4Rizvi NA Kris MG Miller VA et al.Activity of XL647 in clinically selected NSCLC patients (pts) enriched for the presence of EGFR mutations: results from phase 2.J Clin Oncol (Meeting Abstracts). 2008; 26: 8053Google Scholar Another study in 39 EGFR tyrosine kinase inhibitor (TKI)-resistant patients, one response and stable disease in 49% were seen. Nevertheless, plans for future studies are unclear. BIBF-1120 targets VEGFR, platelet derived growth factor receptor, FGFR and some SRC kinases. Dr. Wakelee summarized a phase II study of second- or third-line BIBF-1120 treatment of 73 patients with advanced NSCLC that demonstrated one response and a stable disease rate of 48%.5Reck M Kaiser R Eschbach C et al.A phase II double-blind study to investigate efficacy and safety of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small cell lung cancer.J Thor Oncol. 2009; 4: S707Google Scholar Phase I studies did not show pharmacokinetic interactions with pemetrexed or combination carboplatin/paclitaxel.6Camidge DR Conkling P Stephenson JJ et al.Pharmacokinetic (PK) analysis of a phase I study of continuous oral treatment with the angiokinase inhibitor BIBF 1120, in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC).J Clin Oncol (Meeting Abstracts). 2008; 26: 3567Crossref PubMed Scopus (78) Google Scholar, 7Hanna NH Zhao Y Kaiser R et al.Pharmacokinetic (PK) analysis of a phase I trial investigating continuous treatment with the angiokinase inhibitor BIBF 1120 combined with pemetrexed in previously treated patients with non-small cell lung cancer (NSCLC).J Clin Oncol (Meeting Abstracts). 2008; 26: 14511Google Scholar Phase II and III trials of these combinations in all NSCLC histologies are planned or ongoing. Dr. Herbst (MD Anderson) discussed the accumulating evidence for dual inhibition of the EGFR and VEGF pathways. The BETA-Lung and ATLAS studies have shown that combination bevacizumab and erlotinib result in a modest improvement in PFS compared with either alone but without improving OS.8Miller VA O'Connor P Soh C et al.A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC).J Clin Oncol (Meeting Abstracts). 2009; 27: LBA8002Google Scholar Vandetanib targets VEGFR-2, -3, and EGFR and has been studied in multiple NSCLC trials. ZODIAC randomized patients to second-line docetaxel plus vandetanib or placebo.9Herbst RS Sun Y Korfee S et al.Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZODIAC).J Clin Oncol (Meeting Abstracts). 2009; 27: CRA8003Google Scholar PFS (4 versus 3.2 months, HR, 0.722, p = 0.0012) and time to symptom deterioration were superior in the vandetanib arm, but there was no difference in OS. ZEAL tested pemetrexed ± vandetanib and showed a similar trend but was not significant for PFS benefit.10De Boer R Arrieta O Gottfried M et al.Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZEAL).J Clin Oncol (Meeting Abstracts). 2009; 27: 8010Google Scholar Vandetanib and erlotinib were compared in the ZEST trial and had similar PFS and OS.11Natale RB Thongprasert S Greco FA et al.Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: a randomized, double-blind phase III trial (ZEST).J Clin Oncol (Meeting Abstracts). 2009; 27: 8009Google Scholar ZEPHYR, a placebo-controlled randomized study of vandetanib after chemotherapy and EGFR TKI failure, has reported no improvement in survival, with data to be presented later this year. Dr. Goss (University of Ottawa) reviewed tivozanib, a potent VEGFR inhibitor, which seems well tolerated and achieved a high rate of disease control (84%) in patients with renal cancer12Bhargava P Esteves B Nosov DA et al.Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC).J Clin Oncol (Meeting Abstracts). 2009; 27: 5032Google Scholar and is in early phase studies in NSCLC. Studies of cediranib in NSCLC, another potent VEGFR inhibitor, were presented by Dr. Goss. Results of a phase I trial of cediranib plus cisplatin/etoposide in SCLC and neuroendocrine tumors are expected later this year, as are results from a randomized phase II study of first-line gemcitabine/carboplatin ± cediranib in advanced disease. Cediranib is also being combined with pemetrexed second line, and in 33 patients accrued, has shown a disease control rate of 71% and RR of 16%.13Gadgeel SM Wozniak A Edelman MJ et al.Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC).J Clin Oncol (Meeting Abstracts). 2009; 27: e19007Google Scholar The National Cancer Institute of Canada Clinical Trials Group BR.24 randomized phase II trial of paclitaxel/carboplatin plus cediranib/placebo demonstrated higher RRs (38% versus 16%) and a trend to better PFS (HR: 0.77, 95% CI: 0.56–1.08). For toxicity reasons, the subsequent National Cancer Institute of Canada CTG BR.29 phase II/III trial of paclitaxel/carboplatin ± cediranib will use a lower dose of cediranib, 20 mg daily reduced from 30/45 mg studied previously. In mesothelioma, SWOG 0507 demonstrated a disease control rate of 42% and median PFS of approximately 3 months with cediranib.14Garland LL Chansky K Wozniak A et al.SWOG S0509: a phase II study of novel oral antiangiogenic agent AZD2171 (NSC-732208) in malignant pleural mesothelioma.J Clin Oncol (Meeting Abstracts). 2009; 27: 7511Google Scholar A phase I/II study is planned by SWOG of combination cediranib with pemetrexed/cisplatin in mesothelioma. Although bevacizumab has been incorporated into standard therapy,15Sandler A Gray R Perry M et al.Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006; 355: 2542-2550Crossref PubMed Scopus (4953) Google Scholar particularly in the United States for eligible patients, several other VEGF inhibitors also demonstrate activity and are under development. Given the evolution of patient selection based on histology and genotype for different treatment options, future research will need to focus on the role of biomarkers to identify those patients who derive preferential benefit from VEGF inhibition.