| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
Correspondence and requests for reprints should be addressed to Alex A. Adjei, M.D., Ph.D., Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263. E-mail: alex.adjei{at}roswellpark.org
ABSTRACT
Over the last decade, systemic cancer therapies have evolved to exploit the growing knowledge of molecular aberrations involved in the development and progression of lung cancer. This review highlights the biological targets relevant in the treatment of non–small cell lung cancer.
Key Words: non–small cell lung cancer • vaccine • epidermal growth factor receptor • angiogenesis
The past decade marked the beginning of therapeutic approaches tailored to "suit" the molecular profiles of various malignancies. Drugs have been developed for specific biological pathways with increased specificity and reduced toxicity. Examples include imatinib in chronic myeloid leukemia and gastrointestinal stromal tumors, and trastuzumab in breast cancer. In this article, we provide a synopsis of the current status of molecular targeted therapy for lung cancer.
EPIDERMAL GROWTH FACTOR RECEPTOR
Epidermal growth factor receptor (EGFR, also known as HER1 or Erb-B1) is a member of the Erb-B family of transmembrane glycoprotein receptors that is aberrantly expressed in up to 80% of cases of non–small cell lung cancer (NSCLC), with associated worse prognosis (1). Activation of its tyrosine kinase domain upon binding of ligands, such as epidermal growth factor, transforming growth factor-
, and so on, triggers secondary signaling pathways through STAT, Ras-MAPK, and PI3 K/Akt pathways (2) that results in tumor cell growth and proliferation, apoptosis, invasion, metastasis, and angiogenesis.
Gefitinib is the first oral EGFR tyrosine kinase inhibitor to receive approval from the U.S. Food and Drug Administration (FDA) for use in chemorefractory NSCLC on the basis of encouraging phase II data. However, subsequent randomized placebo-controlled phase III study (ISEL, Iressa Survival Evaluation in Lung cancer) for 1,129 patients with NSCLC who had chemotherapy intolerance or chemorefractory disease did not show survival benefit (5.6 mo for gefitinib versus 5.1 mo for placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.77–1.02; P = 0.087) (3), in contrast with the phase III data from BR.21 study using erlotinib, another oral EGFR TKI, which demonstrated improved overall survival compared with placebo (6.7 mo versus 4.7 mo, respectively; HR, 0.70; P < 0.001) among patients with previously treated NSCLC (4). More recently, a Phase III survival study (INTEREST) interestingly demonstrated noninferiority of gefitinib compared with docetaxel, with superior safety on the gefitinib arm for patients previously treated with platinum-based chemotherapy (5). This is in striking contrast with data from S0023 evaluating the role of maintenance gefitinib versus placebo for patients with stage III NSCLC who completed chemoradiation and consolidation therapy with docetaxel. The trial was suspended before completing target accrual when an unplanned interim analysis, prompted by the negative ISEL trial, showed that median survival was 23 months for gefitinib and 35 months for placebo (P = 0.013). This difference was attributed to disease progression rather than toxicities among patients receiving gefitinib (6). While only speculative, this may be attributed to uneven distribution of negative prognostic features in the gefitinib arm, such as k-ras mutations that have been associated with worse prognosis (7).
Retrospective analyses suggest that patients who are nonsmokers, Asians, with adenocarcinoma histology, and females may have a greater benefit from EGFR TKIs. A common feature in these cases with tumor response is the presence of activating mutations that involve the ATP-binding pocket of EGFR, with in vitro data showing approximately tenfold increased sensitivity of tumors with EGFR kinase domain mutations to EGFR TKIs (8, 9). These clinical features thus prompted the design of an ongoing phase III trial in Asia, IPASS (First-line Iressa versus carboplatin/paclitaxel in Asia) evaluating progression-free survival among nonsmokers with adenocarcinoma subtype of advanced NSCLC randomized to either gefitinib monotherapy or paclitaxel/carboplatin chemotherapy as first-line treatment. Preliminary results have been reported (10), showing superior progression-free survival (PFS) with gefitinib compared with chemotherapy (HR, 0.74; 95% CI, 0.65–0.85; P < 0.0001), which exceeded the primary objective of assessing noninferiority of gefitinib in terms of PFS in comparison with chemotherapy. Tolerability profile favored gefitinib as well in this patient population. Median overall survival data are not mature, although early analysis showed similar outcomes between the two arms (18.6 mo versus 17.3 mo, respectively; HR, 0.91; 95% CI, 0.76–1.10).
Whereas neither of the oral EGFR TK inhibitors erlotinib nor gefitinib demonstrated survival benefit in combination with standard chemotherapy in four phase III, well-designed trials with over 4,000 patients with advanced NSCLC combined (11–14), encouraging results were seen with cetuximab, a chimeric monoclonal antibody (mAb) against the extracellular domain of EGFR. In a multicenter randomized phase III study of cetuximab in combination with cisplatin and vinorelbine as first-line treatment for 1,125 patients with stage IIIB/IV EGFR-expressing NSCLC (FLEX; First-Line Trial for Patients with EGFR-Expressing Advanced NSCLC), overall survival was improved in patients receiving the cetuximab combination (11.3 mo versus 10.2 mo, HR, 0.871; 95% CI, 0.762–0.996; P = 0.044), with subgroup analyses suggesting a greater benefit among whites independent of histology (15). This is the first large randomized study to demonstrate a survival benefit with the addition of an anti-EGFR agent to chemotherapy in patients with advanced NSCLC. This mechanistically may be attributable in part to advantages of mAb therapy, as mAbs frequently bind to their antigens with several-fold higher affinity than the natural ligands as well as activate mechanisms to enhance antitumor effects, such as antibody-dependent complement-mediated cytotoxicity. These molecular mechanisms bestow mAbs with diverse functional capacities as agonists or antagonists of immune system signaling mediated by their target proteins . In contrast, a similarly designed open-label phase III combination study (BMS-099) of a taxane and carboplatin with or without cetixuimab as first-line treatment of 676 patients with all histologic subtypes of advanced NSCLC did not meet its primary endpoint of improvement in PFS, nor its secondary endpoint of overall survival (median 9.7 mo with cetuximab compared with 8.4 mo without cetuximab; HR, 0.89; 95% CI, 0.75–1.05; P = 0.17). This study, however, was not powered to detect improvement in overall survival (16).
ANGIOGENESIS
Angiogenesis is a tightly regulated multistep process that is implicated in tumor growth and metastasis (17). Of the multiple angiogenic factors known, vascular endothelial growth factor (VEGF; also known as vascular permeability factor) is the most potent and best characterized as the crucial regulator of both normal and pathologic angiogenesis (18). Pericytes, the primary cells that support the structure and survival of tumor microvessels, abundantly express the platelet-derived growth factor receptor (PDGFR), which actively regulates interstitial fluid pressure and, consequently, the transcapillary delivery of chemotherapy (19).
Bevacizumab, a humanized monoclonal antibody against VEGF, has shown clinical benefit in various clinical contexts for different malignancies, including NSCLC. Patients with squamous cell histology were excluded because of apparent increased risk for fatal hemoptysis observed in the phase II trial (20). Overall survival in patients with advanced NSCLC (E4599) who received first-line treatment with carboplatin/paclitaxel with bevacizumab (at 15 mg/kg dose) was improved compared with chemotherapy alone (12.3 mo versus 10.3 mo, respectively; HR, 0.80; P = 0.003) (21). The results from this trial were the basis for FDA approval of bevacizumab for use in combination with carboplatin + paclitaxel as first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic, nonsquamous NSCLC in October 2006.
In a similarly designed trial conducted in Europe called AVAiL trial (Avastin in Lung Cancer), 1,043 patients with nonsquamous NSCLC were randomly assigned to cisplatin and gemcitabine every 3 weeks, plus either bevacizumab 7.5 mg/kg, bevacizumab 15 mg/kg, or placebo on Day 1 every 3 weeks. The cisplatin plus gemcitabine was continued for a maximum of six cycles, while the bevacizumab or placebo was continued as maintenance until there was evidence of progressive disease. PFS, which was the primary endpoint, was significantly improved at 1 year with both doses of bevacizumab (14%, 14%, and 10%, for the 7.5 mg/kg, 15 mg/kg, and placebo groups, respectively). The risk of progression or death was reduced by 25% with bevacizumab 7.5 mg/kg and by 15% with bevacizumab 15 mg/kg versus placebo (HR, 0.75 [P = 0.0003] and 0.85 [P = 0.046], respectively). In addition, the objective response rate was increased with both doses of bevacizumab (34%, 30%, and 20%, for the 7.5 mg/kg, 15 mg/kg, and placebo groups, respectively). While median survival of patients in all arms of the study exceeded 1 year (13.6 mo for bevacizumab 7.5 mg/kg [HR versus placebo of 0.92; 95% CI, 0.77–1.1], 13.4 mo for bevacizumab 15 mg/kg [HR versus placebo of 1.02; 95% CI, 0.85–1.22], and 13.1 mo for placebo), there was no statistically significant difference in overall survival among the treatment arms (22). These results fanned the flames on ongoing issues regarding optimal dose of bevacizumab, which in the randomized phase II study suggested a trend toward improved survival with the higher 15 mg/kg dose that is not supported by the larger phase III AVAiL study. Moreover, while numerous phase III trials comparing various doublet combinations in NSCLC did not demonstrate the superiority of any one specific combination regimen, several trials have shown survival advantages of cisplatin-based regimens compared with carboplatin-based regimens (23, 24). Whether the choice of platinum backbone may have contributed to the differences in outcomes between the studies is plausible but remains speculative.
Oral inhibitors of VEGF receptor tyrosine kinase have also been evaluated in the treatment of NSCLC. Both sorafenib and sunitinib are multiple kinase inhibitors against VEGF-R, PDGFR, c-kit, and Flt-3 that are approved for the treatment of renal cell carcinoma. Sorafenib was initially developed as a raf kinase inhibitor, but subsequently was shown to have potent antitumor activity based on its antiangiogenic mechanism of action. In a randomized discontinuation phase II study for 342 patients with advanced NSCLC progressing after two prior chemotherapy regimens, patients randomized to sorafenib who had stable disease as best response upon a 2-month run-in period with sorafenib had a twofold increase in PFS (3.6 mo versus 1.9 mo, P = 0.01) and a larger proportion of patients maintained stable disease (29% versus 5%, P = 0.002) compared with patients randomized to placebo. There is also a trend toward improvement in overall survival, but this is not statistically significant. Patients randomized to placebo were allowed to crossover to sorafenib on disease progression (25). Sunitinib as a single-agent therapy also showed promising antitumor activity for patients with previously treated advanced NSCLC in a single-arm one-stage phase II trial design. Patients who previously received antiangiogenic agents were excluded. Overall response rate was 11.1%, and median duration of stable disease was 22 weeks. While overall well tolerated with no cases of febrile neutropenia, it is to be noted that 5% of patients had grade 
3 neutropenia (26).
Because of the role of pericytes in tumor vasculature and interstitial fluid pressure, dual targeting of PDGFR and VEGFR may represent a synergistic and more effective antiangiogenic strategy than anti-VEGF therapy alone in combination with chemotherapy. This concept was tested in the ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC) trial, a phase III study comparing first-line treatment using carboplatin/paclitaxel with or without sorafenib in patients with unresectable NSCLC. Unfortunately, the study failed to meet its primary endpoint of improved survival. Moreover, fatal pulmonary hemorrhages predominated in patients with squamous cell histology, and subset analysis suggested a detrimental effect to patients with squamous cell carcinoma who received sorafenib (27). Based on these results, a similarly designed trial (NEXUS) using gemcitabine and cisplatin as the backbone chemotherapy regimen was amended to exclude patients with squamous histology.
Since sunitinib as a single agent has a higher toxicity profile with some degree of myelosuppression compared with sorafenib, there are concerns with using it in combination with agents or combinations that have high rates of neutropenia, particularly in light of results from ESCAPE trial. Consequently, sunitinib is currently being evaluated as a maintenance agent compared with placebo in patients with IIIB/IV NSCLC who have nonprogressing disease after four cycles of platinum-based chemotherapy with or without bevacizumab (CALGB 30607). It is also being tested in a three-arm randomized phase 2 trial against pemetrexed versus the combination of sunitinib plus pemetrexed in the second-line setting. The primary endpoint for both these trials is PFS.
IGF/PI3K/AKT/mTOR PATHWAY
Phosphatidylinositol 3 kinase (PI3K) is one of the most relevant oncogenic pathways, with estimates suggesting that activating mutation in the p110 catalytic subunit occurs in up to 30% of all human cancer, though this is uncommon in NSCLC (28). The most common mechanism of its aberrant activation, though, is the loss of the regulatory PTEN lipid phosphatase, which occurs frequently in NSCLC (29). PI3K is activated by Ras and receptor tyrosine kinases such as EGFR, c-met, and insulin-like growth factor (IGF) receptor pathway. Autocrine production of IGF as well as overexpression of its cognate receptor, IGF-1R, are well documented in NSCLC (30, 31), with downstream signaling chiefly mediated by the PI3K–Akt pathway (32).
Regardless of the mechanism of its dysregulation, Akt is the chief mediator of downstream signaling through various targets, one of which is the mammalian target of rapamycin (mTOR), a serine/threonine kinase that serves as a key component regulating transcriptional and translational proteins that control cell growth, angiogenesis, apoptosis, and amino acid and glucose metabolism (33). This pathway has been implicated in mediating chemoresistance as well as resistance to novel agents such as EGFR TKIs (34, 35).
An indirect method of inhibition of the IGF-1 pathway is with the use of growth hormone–releasing hormone antagonists (GHRHa), agents that are being developed to treat growth hormone excess conditions such as acromegaly. These agents inhibit the pituitary secretion of growth hormone, resulting in reduction in IGF-1 levels and inhibition of the PI3K–Akt signaling pathway (36, 37). A more direct approach is with the use of monoclonal antibody therapies. CP-751,871, a fully humanized monoclonal antibody to IGF-1 receptor, has been tested in a randomized phase II study in combination with paclitaxel and carboplatin versus chemotherapy alone as first-line treatment for advanced NSCLC. There was an increased response rate among patients receiving CP-751871, with apparent dose–response and a trend toward improved PFS (38). Several randomized phase III studies of this agent with chemotherapy and with erlotinib are on the way or already implemented.
CCI-779 (temsirolimus) is an mTOR inhibitor that has been evaluated as front-line treatment for advanced NSCLC in a two-stage phase II design. With a median PFS of 2.3 months and response rate of 8%, the study did not meet criteria to complete patient accrual to the second stage, although it had a favorable toxicity profile (39). Everolimus, an oral mTOR inhibitor, has also been studied in a phase II setting for patients with previously treated NSCLC, with similar PFS and response rate of 2.6 months and 4.8% as seen on the aforementioned front-line study (40).
SRC
Src nonreceptor tyrosine family kinases are key regulators of multiple cellular events. Src is the best known representative of this family of nonreceptor tyrosine kinases, and its increased activity up-regulates multiple signaling pathways leading to increased cell proliferation, survival, invasion, and migration (41). It mediates the phenomenon of epithelial–mesenchymal transition (EMT), which has been implicated with tumor invasion and metastasis (42). Down-regulation of E-cadherin is a key event in EMT that can be observed with Src activation (42). The loss of E-cadherin has been correlated with resistance to EGFR TKIs; restoration of E-cadherin expression, on the other hand, improves sensitivity to this class of drugs (43).
Increased expression of Src has been reported in 60 to 80% of adenocarcinomas and bronchioloalveolar cancers and in 50% of squamous cell carcinomas (44). It mediates the effects of EGFR-dependent and VEGF-dependent pathways via activation of STAT-3 (signal traunsducer and activor of transcription-3) (45–47). Dasatinib, currently approved for the treatment of CML and gastrointestinal stromal tumors, is a multitargeted oral inhibitor of Src family kinases, Bcr-Abl, Kit, platelet-derived growth factor receptor (PDGFR)β, and Eph receptors that possess anti-apoptotic activity in EGFR-dependent NSCLC cell lines (48). Other orally active dual Src/Abl inhibitors that have shown preclinical and early clinical evidence of potential efficacy in NSCLC include AZD0530 and SKI-606 (bosutinib) and are currently undergoing further investigations (49).
c-MET
c-Met is a transmembrane tyrosine kinase receptor that is activated by its natural ligand hepatocyte growth factor (HGF, also called scatter factor). c-Met overexpression, gene amplification, or activating mutations are found in a variety of primary human cancers including NSCLC, the dysregulation of which results in cell proliferation, anti-apoptosis, angiogenesis, aletered cytoskeletal function, and metastasis (50, 51). MET gene amplification has been implicated as a mechanism of drug resistance to EGFR TKIs through the activation of HER3, which in turn signals through the PI3K/Akt pathway (52). Still another mechanism of resistance to EGFR TKIs can be mediated through c-Met activation of Src, which causes down-regulation of E-cadherin (53, 54). This leads to disruption of cell–cell adhesion, increased cell motility, and tumor invasion characteristic of EMT. Current direct therapeutic approaches in early clinical development include small molecule inhibitors such as PHA665752 and PF-2341066 and antibodies that bind HGF.
VACCINE TARGETS
Corralling the immune system in the treatment of cancer was popularized by Williams Coley, of "Coley's toxins" fame, from his observations of an apparent temporal association between infection and cancer remission (55), which predated the current enthusiasm to develop therapeutic cancer-specific vaccines. Lung cancer is traditionally thought to be poorly immunogenic, in contrast to melanoma or renal cell cancer, due in part to its immunosuppressive microenvironment (56). To overcome this important obstacle, some methods include administration of systemic chemotherapy such as cyclophosphamide to reduce suppressor T cell activity (57) or conjugation of the vaccine with nonspecific immune stimulants known as "adjuvants" to induce detectable antibody and T cell responses (58). The setbacks from negative clinical trials of yesteryears provided important learning points that, with improved technology and identification of new antigenic targets, have led to new vaccine designs that have recently regenerated much interest in this field.
Mucin 1 (MUC1) is a surface-expressed transmembrane protein that is overexpressed or aberrantly glycosylated in tumor cells, including NSCLC, compared with normal cells (59). L-BL25(Stimuvax) is a liposomal vaccine against the extracellular core peptide of MUC1. A phase II trial in patients with stage III/IV NSCLC who had objective tumor response or stable disease after first-line systemic chemotherapy showed that, in a post hoc subgroup analysis, that patients with stage IIIB randomized to the vaccination arm showed a favorable, albeit non–statistically significant, improved survival trend, with a median survival of 30.6 months compared with 13.3 months in patients receiving best supportive care alone (60). This intriguing result has led to the ongoing international randomized phase III trial of L-BLP25 vaccine versus placebo, named START (Stimulating Targeted Antigenic Responses To NSCLC), which opened in February 2007, that is expected to enroll approximately 1,300 patients with unresectable stage IIIA/III NSCLC who have objective tumor response or stable disease after at least two cycles of platinum-based chemoradiotherapy.
Cancer/testis (CT) antigens are tumor-specific antigens not expressed in normal adult tissues except in the testis (61). The melanoma-associated antigen A3 (MAGE-A3) protein is the most commonly expressed among CT antigens, and its expression is increased in various malignant tissues types, including approximately 35% of NSCLC (62, 63), with expression increasing proportionally with disease stage (64). A phase II randomized trial in 182 patients with completely resected stage IB or II MAGE-A3–positive NSCLC demonstrated a trend toward improved survival in patients randomized to receiving the vaccine compared with the placebo group (63). On the basis of such data, a randomized controlled Phase III efficacy and safety trial (MAGRIT) had been launched to evaluate MAGE-A3 ASCI as adjuvant therapy in approximately 2,270 MAGE-A3–positive patients with completely resected stage IB, II, or IIIA NSCLC upon completing standard adjuvant chemotherapy.
Another vaccine approach uses whole tumor cells such that the host immune system is exposed to the full gamut of tumor cell antigens, either patient-specific (autologous) or derived from lung cancer cell lines (allogeneic). Belagenpumatucel-L (Lucanix ) is an allogeneic vaccine derived from NSCLC cell lines genetically modified by nonviral methods to secrete the TFG-β2 antisense oligonucleotide to increase the immunogeneicity of this vaccine (65). A randomized phase II trial involving 75 patients was completed and demonstrated a survival advantage to patients receiving the higher doses of belagenpumatucel-L. An international, multicenter, randomized, double-blinded, placebo-controlled Phase III trial of this vaccine started recruitment in March 2008 for approximately 700 patients with stage III/IV NSCLC with objective tumor response or stable disease after first-line platinum-based chemotherapy.
More recently, a randomized phase II study using a human recombinant EGF vaccine named CimaVax-EGF (conjugated to a carrier recombinant P64K protein derived from Neisseria meningitides and expressed in E. coli) administered to 80 patients with stage IIIB/IV NSCLC who completed first-line chemotherapy showed a trend favoring survival among vaccinated patients, with statistically significant survival advantage in the subgroup of vaccinated patients less than 60 years old compared with control subjects (1-yr survival rate of 75% versus 25%, respectively). Moreover, the ability to develop a robust anti-EGF antibody response was strongly correlated with survival (66). The vaccine and its early phase clinical trials were developed in Cuba, where it received registration approval in June 2008, making it the first approved vaccine in the world for the treatment of lung cancer.
CONCLUSIONS
These are exciting times in drug discovery and development. Biological and clinical rationale is available to support combinatorial regimens, such as anti-VEGF with anti-EGFR approaches, anti-EGFR with mTOR inhibitors, and so on that are currently being tested in various phase II and phase III settings. Despite a better understanding of the molecular heterogeneity of tumors and the complex multidirectional interactions between signaling pathways, the challenge remains to establish optimal combinations of novel agents with each other or with standard chemotherapeutic agents that are effective and well tolerated. While still simplistic, there is progress in the identification of biomarkers that predict drug sensitivity or resistance that enable a personalized approach to cancer treatment, such as lack of clinical benefit of anti-EGFR therapies in metastatic colorectal cancer that harbor k-ras mutations (67). Moreover, because of manageable toxicity profile overall, long-term maintenance therapy with these novel agents, either adjuvantly or after standard chemotherapy in the advanced stages, will represent a growing proportion of future clinical investigations.
FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 31, 2008; accepted in final form November 19, 2008)
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
