This year in the US, the American Cancer Society estimates that lung cancer will kill more people than breast, prostate, colon, liver, and kidney cancers combined, making it the leading cause of cancer death among Americans.
Inhibition of Angiogenesis with Bevacizumab Shows Promise in the Treatment of Recurrent or Advanced Non—Small-Cell Lung Cancer
his year in the US, the American Cancer Society estimates that lung cancer will kill more people than breast, prostate, colon, liver, and kidney cancers combined, making it the leading cause of cancer death among Americans.1 There will be more than 213,000 new cases of lung cancer diagnosed in 2007, and lung cancer will account for about 15% of all new cancers.1
Because most lung cancers are diagnosed late in the course of the disease, only about 15% of patients survive 5 years or more.2 Investigations comparing various platinum-based regimens failed to produce a significant impact in the outcomes for patients with non-small cell lung cancer (NSCLC),3,4 and this therapeutic modality may be reaching a plateau. Therapeutic advances will likely require the addition of agents with a different mechanism of action.
Overview of Bevacizumab
Bevacizumab (Avastin®, Genentech/Roche) is a recombinant humanized antibody to vascular endothelial growth factor (VEGF), a protein that plays a critical role in tumor angiogenesis. It was formerly known as anti-VGEF. Bevacizumab binds VEGF and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells.5 The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.6
Treatment with bevacizumab has been shown to benefit patients with a variety of cancers. It is the first US Food and Drug Administration (FDA)—approved therapy designed to inhibit angiogenesis, and is currently approved, in combination with intravenous 5-fluorouracil–based chemotherapy, for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum, and in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.
ECOG Study E4599
Recently, the results of a large-scale, multicenter, randomized, open-label, Eastern Cooperative Oncology Group (ECOG) trial (ECOG Study E4599) evaluating bevacizumab for the treatment of recurrent or advanced non-small-cell lung cancer were reported.7 In this trial, 878 patients with recurrent or advanced non-small-cell lung cancer (Stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (n=444) or paclitaxel and carboplatin plus bevacizumab (n=434). Chemotherapy was administered every 3 weeks for 6 cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival.
The median survival was 12.3 months in patients treated with chemotherapy plus bevacizumab, compared with 10.3 months in those treated with chemotherapy alone (P = 0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (P < 0.001), with corresponding response rates of 35% and 15% (P < 0.001).
The rates of the following severe (Grade 3-5 for nonhematologic and Grade 4-5 for hematologic) adverse events were significantly greater in patients receiving bevacizumab plus chemotherapy compared to those receiving chemotherapy alone: hypertension, proteinuria, bleeding, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache. Neutropenia occurred in 26% of patients treated with bevacizumab plus chemotherapy and 17% of those who received chemotherapy alone.
The rate of hemoptysis requiring medical intervention among patients treated with bevacizumab plus chemotherapy arm was 1.9%, compared to 0.2% among those treated with chemotherapy alone. There were 15 deaths related to the adverse treatment effects in patients treated with bevacizumab plus chemotherapy, of which 5 were due to pulmonary hemorrhage, 5 were due to complications of febrile neutropenia, and the remainder were due to other sites of hemorrhage and a probable pulmonary embolism. Among patients treated with chemotherapy alone, two deaths related to the adverse effects of treatment occurred, of which one was from gastrointestinal hemorrhage and one from febrile neutropenia.
In previous clinical-trial experience with bevacizumab in combination with paclitaxel and carboplatin in NSCLC,8 patients with squamous-cell NSCLC had a greater risk of experiencing life-threatening or fatal pulmonary bleeding. Squamous cells are particular kinds of cells that form in the lining of the air ducts in the lung. Because of the risk of bleeding attributed to this population, patients with NSCLC classified as predominantly squamous histologically were not included in this trial.
The investigators concluded that the addition of bevacizumab to paclitaxel plus carboplatin in the selected patients with NSCLC confers a significant survival benefit, with a risk of increased toxicity. Bevacizumab is the first and only treatment in more than a decade to show a survival benefit in this patient population.
According to Alan B. Sandler, MD, lead author of the study and Director of Medical Thoracic Oncology at Vanderbilt-Ingram Cancer Center in Nashville, TN, “This is the first large, randomized clinical study in which a targeted therapy, combined with chemotherapy, extended survival beyond one year in patients with advanced lung cancer. The results of this study have changed the treatment standard of care for this devastating disease—an important step forward for patients with advanced lung cancer.”
Ed Holdener, Head of Roche Pharmaceuticals Development, stated, “The filing of Avastin in the USA is a critical step forward. The benefits seen in the Avastin study are significant, and we look forward to the potential of bringing new hope to the patients who are diagnosed with this specific type of lung cancer. We are committed to working with regulatory authorities around the world in order to make it available to patients suffering from lung cancer as soon as possible.”
Correlative Assessment of Biomarkers in the ECOG Study E4599 Population
A correlative analysis of biomarkers in the E4599 study population was performed by Dowlati and colleagues.9 The rationale for markers used in the correlative study were based on VEGF, basic fibroblast growth factor (bFGF), and soluble intercellular adhesion molecule-1 (ICAM) in NSCLC and changes in response to endothelial apoptosis.
Prospective laboratory correlates included measurements of pretreatment plasma VEGF as well as pretreatment and Week-7, bFGF, ICAM, and E-Selectin. One hundred sixty-six patients had pretreatment and 112 had post-treatment measurements made by enzyme-linked immunosorbent assay (ELISA). Low and high levels were defined as < or > than the median.
There were significant associations between E-Selectin and ICAM (P=0.003) and between bFGF and VEGF (P = 0.01). E-Selectin (P = 0.01) and bFGF (P = 0.004) showed significant decreases from baseline at week 7 in both arms. Only baseline ICAM showed a significant association with response. Patients with low baseline ICAM in both arms had a greater response rate of 29% vs 13% in high ICAM group (P = 0.03). Patients with low baseline ICAM levels had significantly better overall survival (P = 0.00005) compared with patients who had high ICAM levels, as well as a better 1-year survival (65% vs 25%). No other factor predicted survival.
This subanalysis suggests a benefit from bevacizumab in the group with low baseline ICAM levels compared with patients with high levels. The investigators concluded that baseline ICAM levels are strongly prognostic for survival and response to chemotherapy.
The AVAiL Trial
Genentech and Roche have initiated a further study, the AVAiL trial, which is exploring the combination of bevacizumab with another platinum-based chemotherapy regimen (cisplatin/gemcitabine). AVAiL is a multicenter, multinational, randomized, controlled, phase III trial with a planned enrollment of 1050 patients with previously untreated advanced NSCLC. It will evaluate the efficacy and safety of two doses of bevacizumab (7.5 or 15 mg/kg every 3 weeks) in combination with the platinum doublet chemotherapy (gemcitabine/cisplatin).
The primary objective of the AVAiL study is to demonstrate superiority in progression-free survival of both evacizumab-containing treatment arms over that in the control arm. Final AVAiL data is expected later this year, and will only then enable definitive conclusions regarding the efficacy of the two doses of bevacizumab.
David H. Johnson, MD, Director of Hematology and Oncology at Vanderbilt University, states, “First of all, we should continue to refine the use of bevacizumab. It is the only drug that has demonstrated value in random phase III trials, not just in lung cancer, but also in colon and breast cancer. Bevacizumab does what it is intended to do. We should continue to look at ways of improving the safety of bevacizumab. There are some fairly pedestrian questions that need answering, such as how long do we need to give bevacizumab, whether the dose we are giving is optimal, etc.”10
The second area is to continue to investigate drugs that impact angiogenesis through different mechanisms. In particular, if an oral drug could produce the same degree of benefit that one gets with bevacizumab—which must be given intravenously—that would be a huge advantage. Presumably oral drugs, for a variety of reasons, also would be less costly. I think we will see continued pursuit of this target by a number of companies simply because of the success of bevacizumab. It is clear that angiogenesis is an important biological target in major cancers, like breast, colon, and lung cancer, in contrast to rare cancers like chronic myelogenous leukemia.”10
Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a broad development program for bevacizumab that currently includes 130 clinical trials across 25 different types of cancer. In addition to NSCLC, bevacizumab is being evaluated in phase III clinical trials for potential use in adjuvant and metastatic colorectal, renal cell, breast, prostate, and ovarian cancers. Bevacizumab is also being evaluated in earlier-stage trials as a potential therapy in a variety of solid tumors and hematologic malignancies.
1. American Cancer Society. What are the key statistics about lung cancer? 2007. Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Are_the_Key_Statistics_About_Lung_Cancer_15.asp?sitearea=. Accessed January 20, 2007.
2. Blackhall FH, Shepherd FA, Albain KS. Improving survival and reducing toxicity with chemotherapy in advanced non-small cell lung cancer : a realistic goal? Treat Respir Med. 2005;4:71-84.
3. Chiappori A, Simon G, Williams C, et al. Phase II study of first-line sequential chemotherapy with gemcitabine-carboplatin followed by docetaxel in patients with advanced non-small cell lung cancer. Oncology. 2005;68:382-390.
4. Davies AM, Chansky K, Lau DH, et al. Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small-cell lung cancer: SWOG S9712. J Clin Oncol. 2006;24:5242-5246.
5. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005;333:328-335.
6. Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13:1845-1857.
7. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New Engl J Med. 2006;355:2542-2550.
8. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.
9. Dowlati A, Gray R, Johnson DH, Schiller JH, Brahmer J, Sandler AB. Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel ± bevacizumab in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2006;24(suppl):A7027.
10. Medscape Hematology-Oncology. Evolving data on Antiangiogenesis in NSCLC: An Expert Interview With Dr. David H. Johnson. 2006. Available at: http://www. medscape.com/viewarticle/539157. Accessed January 21,2007