Advances in anti-VEGF and anti-EGFR therapy for advanced non-small cell lung cancer

Lung Cancer 63 (2009) 1–9

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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

Advances in anti-VEGF and anti-EGFR therapy for advanced non-small cell lung cancer Martin Reck a,∗ , Lucio Crino` b a b

Department of Thoracic Oncology, Hospital Grosshansdorf, Wohrendamm 80, 22927 Grosshansdorf, Germany Department of Medical Oncology, Perugia Hospital, S. Andrea delle Fratte, 06156 Perugia, Italy

a r t i c l e

i n f o

Article history: Received 18 March 2008 Received in revised form 9 May 2008 Accepted 13 May 2008 Keywords: Epidermal growth factor receptor Non-small cell lung cancer Targeted therapies Treatment paradigms Vascular endothelial growth factor

a b s t r a c t Chemotherapy has reached a therapeutic plateau in the treatment of advanced non-small cell lung cancer (NSCLC), and effective, better-tolerated treatment strategies are needed. An improved understanding of the molecular processes underlying tumor biology has led to the development of therapies that target these processes. Intracellular signaling pathways related to the vascular endothelial growth factor and the epidermal growth factor receptor both play a central role in tumorigenesis as well as tumor growth, and are therefore rational targets for anti-cancer drug development. Various agents that target these pathways are in clinical development. Some of these have already changed treatment practice in NSCLC, most notably the monoclonal antibody, bevacizumab, in combination with chemotherapy in the first-line setting and the small-molecule tyrosine-kinase inhibitors, erlotinib and gefitinib, in the second-line setting. We will review the clinical data for various novel therapies and identify how these agents are improving outcomes in the first- and second-line treatment of advanced NSCLC. © 2008 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the most common cause of cancer death worldwide, accounting for 12% of all new cancers and 18% of cancer deaths [1]. Non-small cell lung cancer (NSCLC) represents 80% of lung cancers [2]. Late diagnosis is common; more than 60% of patients present with stage IIIB/IV disease [3]. Patients with advanced disease have a very poor prognosis: 5-year survival rates for inoperable stage IIIB disease are <10% and for stage IV disease they decrease to <2% [4]. In this paper we discuss the increasingly important role that molecular targeted agents are playing in the first- and second-line treatment of advanced NSCLC. 2. Managing first-line NSCLC: new directions 2.1. Current standard first-line options The standard of care for patients with stage IIIB NSCLC without pleural effusion is combined chemotherapy and radiotherapy; for patients with good performance status (PS), concurrent chemoradiotherapy is preferable [5,6]. For stage IIIB with pleural

∗ Corresponding author. Tel.: +49 410 260 1188; fax: +49 410 269 1317. E-mail address: [email protected] (M. Reck). 0169-5002/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2008.05.015

effusion/stage IV NSCLC, platinum-based doublet chemotherapy is the mainstay of treatment [7–9]. A meta-analysis of 65 trials in advanced NSCLC demonstrated that doublet chemotherapy regimens confer longer survival than single-agent chemotherapy [10]. Cisplatin-based therapy has been found to be superior to carboplatin-based therapy in terms of tumor response; while there was no significant difference in overall survival (OS) in the overall analysis, subgroup analyses revealed a significant survival advantage for cisplatin in combination with third-generation agents compared with carboplatin in combination with third-generation agents [11,12]. To date, cisplatin-based therapy remains the reference treatment for advanced NSCLC patients with good PS. Single-agent chemotherapy is usually recommended for elderly patients (generally defined as >70 years of age [13]) and those with reduced PS (Eastern Cooperative Oncology Group [ECOG] PS of 2) [14]. However, recent guidelines suggest that elderly patients with good PS and no comorbidities derive benefit from platinum-based doublets, without prohibitive toxicity [7]. Current data suggest that chemotherapy has reached a therapeutic plateau and that new combinations of currently available cytotoxic agents are unlikely to confer clinically relevant improvements in survival [15,16]. The use of triplet regimens is currently not supported by clinical data; a meta-analysis of 65 NSCLC trials reported a moderate but significant increase in tumor response rates with triplet versus doublet regimens, but this did not translate

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Table 1 Examples of novel agents in clinical development for advanced non-small cell lung cancer Target

Agents

Angiogenesis

AEE-788, AG-013736, AMG 706** , bevacizumab* , cediranib (AZD2171)** , CP-547632, sorafenib** , sunitinib** , vandetanib (ZD6474)** , vatalanib** Cetuximab** , erlotinib* , gefitinib* Oblimersen** Exisulind** Bexarotene** Bortezomib Dendritic cell, GM-CSF modified AP23573, everolimus (RAD-001), temsirolimus (CCI-779)

EGFR Antisense oligonucleotides Apoptosis Retinoid X receptor agonist Proteasome inhibition Vaccines mTOR inhibitors

and motility [21]. Targeted agents have the potential for increased selectivity and thereby reduced toxicity compared with standard chemotherapies. 2.3. Anti-angiogenic therapy: improving survival in first-line NSCLC Bevacizumab is a recombinant humanized monoclonal antibody that binds to VEGF. A phase II trial investigating carboplatin/paclitaxel with or without bevacizumab (at a dose of 7.5 or 15 mg/kg) established the efficacy of bevacizumab-based therapy (Table 2) [22]. Bleeding was the most prominent adverse event (AE); six patients experienced life-threatening hemorrhagic incidents (9.1%). Central tumor location and squamous cell histology (four of the six patients who experienced severe bleeding had squamous carcinomas) were potentially associated with an increased risk of severe bleeding [22]. A randomized phase III trial (ECOG 4599) compared the efficacy of carboplatin/paclitaxel with or without bevacizumab (15 mg/kg) in 878 patients with previously untreated stage IIIB/IV NSCLC [23]. In view of the findings from the phase II trial, patient entry was restricted to patients with non-squamous cell histology and no baseline hemoptysis. Further exclusion criteria included central nervous system metastases (CNS; head computed tomography scan or magnetic resonance imaging performed within 4 weeks prior to enrollment to confirm absence of metastases); history of documented hemorrhagic diathesis or coagulopathy; therapeutic anticoagulation; regular use of aspirin (>325 mg/day), nonsteroidal anti-inflammatory agents or other agents known to inhibit platelet function; radiation therapy within 21 days before enrollment; major surgery within 28 days before enrollment; clinically significant cardiovascular disease; and uncontrolled hypertension. The addition of bevacizumab to carboplatin/paclitaxel significantly improved OS, progression-free survival (PFS) and response rates (Table 2). For the first time a significant increase in survival, with median OS beyond 1 year, was demonstrated for a combination of a targeted therapy and chemotherapy as first-line treatment of NSCLC compared with chemotherapy alone. Rates of bleeding, hypertension, proteinuria, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash and

* Approved for use; ** phase III trials; other agents are in phase II clinical trials. EGFR, epidermal growth factor receptor; GM-CSF, granulocyte macrophage colonystimulating factor; mTOR, mammalian target of rapamycin.

into a survival benefit [10]. Effective, better-tolerated treatment strategies for patients with advanced NSCLC are clearly needed. 2.2. A novel approach: targeted agents Improved understanding of the molecular processes involved in tumor development and growth has encouraged researchers to target cancer cells more effectively. A number of novel agents targeting different pathways involved in malignant disease are in development for the treatment of advanced NSCLC (Table 1). Inhibition of vascular endothelial growth factor (VEGF) has emerged as an effective way to manage NSCLC [17]. Angiogenesis is involved in tumor formation, growth and metastasis [18] and VEGF is a key mediator of tumor angiogenesis [19]. As such, VEGF is a rational target for new therapeutic strategies. The inhibition of the epidermal growth factor receptor (EGFR) by small molecule receptor tyrosine-kinase inhibitors (TKIs) has also attracted much attention in recent years. EGFR overexpression and/or dysregulation is observed in many solid tumors [20]. EGFR activation has been linked to processes crucial to tumor progression, including metastasis and cell survival, proliferation, adhesion, migration Table 2 Efficacy of bevacizumab-based therapy for advanced non-small cell lung cancer Trial

Phase

n

Regimen

Progression-free survival (months)

Overall survival (months)

Response rate (%)

AVF0757g [22]

II

99

Bevacizumab 7.5 mg/kg + CP Bevacizumab 15 mg/kg + CP CP alone

Median 4.3a ; p = 0.023

Median 11.6; p = 0.84

28.1

a

Median 7.4

Median 17.7; p = 0.63

31.5

Median 4.2a

Median 14.9

18.8

E4599 [23]

III

878

Bevacizumab 15 mg/kg + CP CP alone

HR = 0.66 (0.57–0.77); median 6.2 versus 4.5; p < 0.001

HR = 0.79 (0.67–0.92); median 12.3 versus 10.3; p = 0.003

35 versus 15; p < 0.001

AVAiL [25–27]

III

1043

Bevacizumab 7.5 mg/kg + CG Bevacizumab 15 mg/kg + CG Placebo + CG

HR = 0.75 (0.62–0.91); median 6.7; p = 0.0026 HR = 0.82 (0.68–0.98); median 6.5; p = 0.0301 Median 6.1

Not yet reached

34; p < 0.0001

Bevacizumab 15 mg/kg + erlotinib Bevacizumab 15 mg/kg + D or P D or P alone

HR = 0.72 (0.42–1.23); median 4.4 HR = 0.66 (0.38–1.16); median 4.8 Median 3.0

HR = 0.78 (0.46–1.31); median 13.7 HR = 0.71 (0.41–1.21); median 12.6 Median 8.6

OSI2950g [76]

II

120

CP, carboplatin/paclitaxel; CG, cisplatin/gemcitabine; D, docetaxel; HR, hazard ratio; P, pemetrexed. a Investigator assessment.

30; p = 0.0017 20 17.9 12.5 12.2

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headache were higher in the bevacizumab arm than in the chemotherapy-alone arm. The incidence of severe pulmonary bleeding (2.3%) [24] was substantially reduced compared with the phase II trial (9.1%), presumably due to the exclusion of patients with squamous cell histology and baseline hemoptysis. There were 15 treatment-related deaths in the bevacizumab arm (five attributed to pulmonary hemorrhage, five to complications of febrile neutropenia, two each to a cerebrovascular event or gastrointestinal hemorrhage and one to a probable pulmonary embolus) versus two in the chemotherapy-alone arm (gastrointestinal hemorrhage and febrile neutropenia). The safety profile of bevacizumab should be considered within the context of the significant survival advantage conferred over chemotherapy alone in this setting. To establish whether the benefits of bevacizumab extend to combination with other chemotherapy doublets, the randomized phase III trial Avastin in Lung (AVAiL; BO17704) evaluated PFS in 1043 patients who received first-line bevacizumab (7.5 or 15 mg/kg) or placebo combined with cisplatin (80 mg/m2 ) and gemcitabine (1250 mg/m2 ). Cisplatin/gemcitabine is commonly used in Europe and other parts of the world. The exclusion criteria were as outlined above for the ECOG 4599 trial, with the additional exclusion criterion of radiological evidence of tumors invading or abutting major blood vessels, as a further safety precaution. Both bevacizumab doses in combination with chemotherapy significantly improved PFS versus placebo (Table 2) [25–27]. An OS analysis is pending. Both bevacizumab doses were well tolerated; the safety profile was generally consistent with that observed in the ECOG 4599 trial. Rates of grade ≥3 pulmonary hemorrhage were slightly lower than those observed in ECOG 4599 (1.5% and 0.9% in the bevacizumab 7.5 and 15 mg/kg arms, respectively, versus 0.6% in the placebo arm). One fatal pulmonary hemorrhage event was reported in the placebo arm, versus four and three events in the bevacizumab 7.5 and 15 mg/kg arms, respectively. Bevacizumab, in combination with platinum-based chemotherapy, has received US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) approval for the first-line treatment of predominantly non-squamous advanced NSCLC. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for NSCLC also recommend bevacizumab in combination with chemotherapy as first-line therapy [28], while the ACCP Evidence-Based Clinical Practice Guidelines state that the addition of bevacizumab to carboplatin/paclitaxel should be considered a therapeutic option in a clinically selected subset of patients [7]. In view of hemorrhagic complications, bevacizumab with chemotherapy is currently considered suitable for patients with non-squamous disease, minimal baseline hemoptysis and no CNS metastases. 2.4. Targeting the EGFR pathway in first-line NSCLC 2.4.1. TKIs Erlotinib and gefitinib are orally active inhibitors of the intracellular tyrosine-kinase domain of the EGFR. Both selectively inhibit EGFR tyrosine kinase, reducing autophosphorylation and thereby disrupting EGFR signaling [29,30]. This leads to inhibition of cell proliferation, blockade of cell cycle progression and stimulation of apoptosis, with consequent inhibition of tumor growth. Erlotinib and gefitinib also potentiate the anti-tumor effects of cytotoxic chemotherapy [31,32]. Erlotinib has shown activity as monotherapy in first-line treatment of advanced NSCLC. In a phase II study (n = 53), erlotinib monotherapy in unselected patients led to a response rate of 22.7%, median OS of 13.03 months and median time to progression (TTP)

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of 2.8 months [33]. Other phase II trials indicate that various patient subgroups derive benefit from erlotinib in the first-line setting: elderly patients (median OS 10.9 months) [34]; patients with EGFR mutations (overall response rate 82% and median TTP 13.3 months) [35] and patients with good prognosis (6-month PFS rate of 56%) [36]. A recent phase II trial comparing the efficacy of firstline erlotinib versus carboplatin/paclitaxel in patients with PS 2 reported better outcomes for the chemotherapy arm and concluded that erlotinib may be considered in patients selected by clinical or molecular markers [37]. Two randomized phase III trials compared the efficacy of erlotinib (150 mg/day) or placebo combined with six cycles of chemotherapy in patients with previously untreated stage IIIB/IV NSCLC [38,39]. Patients received gemcitabine and cisplatin in the TALENT trial (n = 1172 patients), and carboplatin and paclitaxel in the TRIBUTE trial (n = 1079 patients). The addition of erlotinib to chemotherapy did not improve median OS compared with chemotherapy alone in either the TALENT (9.9 versus 10.2 months, respectively; hazard ratio [HR] 1.06; 95% confidence interval [CI]: 0.90–1.23) or the TRIBUTE (10.6 versus 10.5 months, respectively; HR 0.995; 95% CI: 0.86–1.16) trials. Two randomized phase III studies (INTACT 1 and INTACT 2) investigating the addition of gefitinib to platinum-based chemotherapy did not show any survival benefit with the addition of gefitinib [40,41]. In a phase II trial of gefitinib versus placebo in chemo-na¨ıve patients with advanced NSCLC and poor PS (INSTEP), HRs for gefitinib versus placebo were 0.82 (p = 0.2) for PFS and 0.84 (p = 0.3) for OS [42]. A phase II trial of gefitinib versus vinorelbine in chemona¨ıve elderly patients with advanced NSCLC (INVITE) did not meet its primary endpoint of demonstrating superior PFS for gefitinib relative to vinorelbine [43]. The lack of an additive effect with EGFR TKIs and chemotherapy may relate to a mechanistic interaction; for example, the antiproliferative effects of EGFR TKIs may render tumor cells less sensitive to cytotoxic agents. Preclinical data suggest that sequential or pulse dosing of erlotinib may prove more effective than concurrent administration [44]. The effectiveness of sequential administration is currently being investigated in a phase III trial (SATURN), in which patients with stage IIIB/IV NSCLC receive four cycles of a standard platinum-based doublet followed by either erlotinib or placebo.

2.4.2. Antibodies The EGFR-targeted antibody cetuximab has also demonstrated activity in the first-line setting. In the SWOG 0342 phase II trial, concurrent carboplatin/paclitaxel/cetuximab versus sequential chemotherapy followed by cetuximab both demonstrated median OS of 11 months [45]. A follow-up phase II trial (SWOG 0536) incorporating bevacizumab is ongoing. A recent phase II trial of cisplatin/gemcitabine ± cetuximab suggests that the addition of cetuximab to this doublet regimen is well tolerated and may improve clinical outcomes [46]. A phase III trial reported median PFS of 4.4 months for first-line cetuximab in combination with paclitaxel or docetaxel plus carboplatin, versus 4.24 months for chemotherapy alone [47]. In a recent phase II trial of cisplatin/vinorelbine ± cetuximab in patients with EGFR-expressing NSCLC (the Lung Cancer Cetuximab Study), the cetuximab combination showed improved outcomes compared with cisplatin/vinorelbine alone (response rate 35% versus 28%, median OS 8.3 versus 7.3 months and 2-year survival 16% versus 0%) [48]. FLEX, a phase III trial of cisplatin/vinorelbine with cetuximab in patients with EGFR-expressing NSCLC, recently met its primary endpoint (increased OS compared with chemotherapy alone); final results of this trial are awaited.

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2.5. Multi-targeted inhibition in first-line NSCLC A number of agents that target multiple pathways are also in development as first-line treatment options for advanced NSCLC. Sorafenib is a multi-targeted TKI that has received FDA and EMEA approval for the treatment of relapsed/refractory renal cell carcinoma and hepatocellular carcinoma. A phase II trial examining the activity of single-agent sorafenib in previously untreated NSCLC was closed to accrual after recruiting 25 patients because it failed to meet stage I efficacy criteria (only one confirmed partial response in the first 20 patients) [49]. Bleeding complications, including epistaxis and fatal pulmonary hemorrhage, have been observed in sorafenib-treated patients [49,50]. A recent phase III trial of firstline carboplatin/paclitaxel with or without sorafenib (ESCAPE) was stopped early after a planned interim analysis revealed that the addition of sorafenib to carboplatin/paclitaxel did not confer clinical benefit and led to a higher mortality rate in patients with squamous cell histology [51]. An ongoing randomized phase III trial (NEXUS), which was originally investigating PFS in patients with squamous and non-squamous advanced NSCLC receiving first-line gemcitabine/cisplatin (n = 350) with or without sorafenib (400 mg twice daily), has now been amended to exclude patients with squamous cell histology. The small molecule TKI sunitinib has been shown to have antitumor activity in murine xenograft models [52,53]. Ongoing phase I and II studies are evaluating sunitinib monotherapy as consolidation therapy following first-line therapy for advanced NSCLC and as first-line therapy in combination with chemotherapy. Cediranib (AZD2171), an inhibitor of VEGF receptor-1, -2 and -3 tyrosine kinase activity, has demonstrated an inhibitory effect on the growth of established tumor xenografts of various tumor types, including NSCLC. Encouraging anti-tumor activity was observed in a phase I trial of first-line cediranib plus carboplatin/paclitaxel in patients with advanced NSCLC [54]. A phase II/III trial comparing carboplatin/paclitaxel with or without cediranib in patients with stage IIIB/IV NSCLC (National Cancer Institute of Canada cooperative group) was ongoing, but will not continue into phase III due to an imbalance in toxicity noted in a planned end of phase II tolerability analysis performed by the study’s Data Safety Monitoring Committee. The efficacy of vandetanib (ZD6474), an inhibitor of VEGF receptor-2 and EGFR tyrosine kinase activity, was assessed in a phase II trial. Patients with treatment-na¨ıve locally advanced or metastatic NSCLC (n = 181) received vandetanib alone, vandetanib plus carboplatin/paclitaxel, or chemotherapy alone. The trial met its primary endpoint; vandetanib plus chemotherapy prolonged PFS versus chemotherapy alone (HR 0.76; 95% CI: 0.50–1.15, median PFS 24 and 23 weeks, respectively), but no significant improvement in OS was observed (HR 1.07; 95% CI: 0.63–1.81) [55]. Accrual to the vandetanib monotherapy arm was stopped early due to limited efficacy. Given the number of agents currently in clinical trials for the treatment of NSCLC, it seems likely that several new multi-targeted agents will soon enter the NSCLC treatment arena. As with bevacizumab, it will be important to select patients carefully when using these agents.

3. New treatment options for relapsed NSCLC 3.1. Current standard second-line chemotherapy Treatment options for patients who fail on first-line chemotherapy are fairly limited. To date, docetaxel and pemetrexed are the

only chemotherapy agents approved for use in the second-line setting, and are recommended by treatment guidelines. In a phase III trial of 155 patients, second-line docetaxel (75 mg/m2 ) significantly improved OS compared with best supportive care (BSC; 7.5 versus 4.6 months; p = 0.01) [56]. Docetaxel was associated with a high incidence of grade 3/4 toxicity, particularly myelosuppression. In another randomized trial, docetaxel (75 mg/m2 ) significantly improved 1-year survival compared with either vinorelbine or ifosfamide (32% versus 19%; p = 0.025), although OS was not different between the three groups [57]. A phase III trial compared pemetrexed (500 mg/m2 ) with docetaxel (75 mg/m2 ) in 571 patients with previously treated advanced NSCLC [58]. The primary objective was to demonstrate non-inferiority for survival time for pemetrexed compared with docetaxel, translating into an upper 95% CI bound of less than 1.11 for the HR of pemetrexed over docetaxel. Similar median OS (7.9 and 8.3 months for the docetaxel and pemetrexed arms, respectively [HR 0.99; 95% CI: 0.8–1.20]) and 1-year survival rates (29.7% for each arm) were observed. Pemetrexed was associated with significantly less toxicity than docetaxel in terms of grade 3/4 neutropenia (40.2% versus 5.3%; p < 0.001), febrile neutropenia (12.7% versus 1.9%; p < 0.001), neutropenia with infections (3.3% versus 0.0%; p = 0.004) and alopecia (37.7% versus 6.4%; p < 0.001). Following publication of these data, pemetrexed was approved on the basis of an evident clinical benefit.

3.2. Erlotinib in second-line NSCLC Erlotinib is the only EGFR TKI to have demonstrated significantly improved survival versus BSC in the second-line setting. The pivotal phase III BR.21 trial randomized 731 previously treated patients with stage IIIB/IV NSCLC to receive erlotinib (150 mg/day) or placebo in a 2:1 ratio. The trial met its primary endpoint: there was a 42.5% improvement in median OS in the erlotinib group compared with placebo (6.7 months versus 4.7 months, HR 0.70; 95% CI: 0.58–0.85; p < 0.001) [59]. The BR.21 results led to FDA and EMEA approval of erlotinib (150 mg/day) in locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Patients on erlotinib derived a survival benefit regardless of gender, age, ethnicity, smoking history, PS or disease histology. The survival benefit seen with erlotinib was not limited to those patients who had an objective tumor response. Among 571 patients with stable/progressive disease as best response, those receiving erlotinib had a median survival of 8.3 months, compared with 6.8 months for those receiving placebo (HR 0.82; 95% CI: 0.68–0.99; p = 0.037), suggesting that preventing tumor progression has clinical benefits [60]. Erlotinib significantly prolonged the median time to symptom deterioration compared with placebo for the three main lung cancer symptoms (4.9 versus 3.7 months for cough [p = 0.04], 4.7 versus 2.9 months for dyspnea [p = 0.04] and 2.8 versus 1.9 months for pain [p = 0.03]) [61]. Erlotinib was also associated with significant quality of life (QoL) benefits over placebo in terms of both global QoL and physical function domains. Head-to-head data for erlotinib versus docetaxel and pemetrexed are not yet available. The data for the different agents are summarized in Table 3. Although patients in the erlotinib trial were more likely to have a poor PS and to have received more than one line of previous therapy, the three agents appear equally effective in the second-line setting. The patient populations in these trials differed, hindering a direct comparison of efficacy; however, if the subset of patients with PS 0/1 who received one prior chemotherapy regimen is considered, median survival times are almost identical for erlotinib, docetaxel and pemetrexed.

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Table 3 Indirect comparison of efficacy data from phase III trials of erlotinib, gefitinib, docetaxel and pemetrexed Outcome

Erlotinib [59] (150 mg/day)

Response rate (%) Median duration of response (months) 1-year survival rate (%) Median overall survival (months) Median overall survival in performance status 0/1 patients with one prior regimen (months)

8.9 7.9 31 6.7 9.4

Gefitinib [66,67] (250 mg/day) 8.0–9.1 – 27–32 5.6–7.6 –

Docetaxel [56–58] (75 mg/m2 )

Pemetrexed [58] (500 mg/m2 )

7.1–8.8 5.3–9.1 30–37 5.7–7.9 9.1

9.1 4.6 30 8.3 9.4

Results cannot be compared directly because of different patient populations.

Erlotinib has a favorable toxicity profile. Rash, diarrhea and nausea (usually mild to moderate) were the most commonly reported AEs in the BR.21 trial. These events can be managed: loperamide and anti-emetics can be administered for diarrhea and nausea, respectively, while guidelines are available for the management of EGFR inhibitor-associated rash [62]. Hematological toxicities have not been reported with erlotinib. TRUST, an ongoing global phase IV trial, is providing access to erlotinib for previously treated patients with advanced inoperable NSCLC. Interim safety data from TRUST confirm the favorable safety profile of erlotinib observed in the BR.21 trial, and preliminary efficacy data are promising (disease control rate 68% and median PFS 13 weeks) [63]. Analyses of the European [64] and East/South East Asian subgroups [65] of the TRUST trial also support the safety profile observed for erlotinib in previous trials. Gefitinib was approved by the FDA in 2003 as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies, based on improved objective response rates in phase II trials. However, subsequent results from a phase III trial (ISEL) showed no significant improvement in survival for gefitinib versus placebo in patients with locally advanced or metastatic NSCLC who had failed one or more lines of chemotherapy [66]. In 2005, the FDA announced new labeling restricting the use of gefitinib to patients who are currently benefiting, or have previously benefited, from gefitinib treatment. Gefitinib is licensed in several countries in the Asia-Pacific region for the second- or third-line treatment of advanced NSCLC. However, new data on gefitinib versus chemotherapy were recently published, prompting renewed comparisons of the efficacy and tolerability of cytotoxic and non-cytotoxic therapies. INTEREST, a phase III trial, demonstrated non-inferiority for gefitinib versus docetaxel in terms of OS (7.6 and 8.0 months, respectively) in 1466 patients with previously treated locally advanced or metastatic NSCLC [67]. However, the trial did not meet its co-primary endpoint of improved OS for gefitinib compared with docetaxel in EGFR fluorescence in situ hybridization (FISH)-positive patients. Gefitinib demonstrated a more favorable tolerability profile than docetaxel (incidence of grade 3/4 AEs was 37.3% for gefitinib and 55.9% for docetaxel). In addition, significantly more gefitinib-treated patients experienced a clinically relevant improvement in QoL compared with those receiving docetaxel. The V15-32 trial, which also examined gefitinib versus docetaxel in 489 previously treated Japanese patients, did not achieve its primary objective of non-inferiority. The median OS for the gefitinib and docetaxel arms was 11.5 and 14.0 months, respectively (HR 1.12; 95% CI: 0.89–1.40) [68]. However, it should be noted that the influence of post-progression therapy may have confounded the OS outcome; patients originally randomized to docetaxel could cross over to receive gefitinib as post-study treatment. The INTEREST trial data suggest that chemotherapy agents are not inherently more effective than

non-cytotoxic options and that, as a class, EGFR TKIs are no less effective than standard chemotherapy agents. 3.3. Multi-targeted inhibition in second-line NSCLC Several multi-targeted agents are at phase II/III clinical development for the second-line treatment of NSCLC. Two phase II trials of second-line sorafenib monotherapy (400 mg/day) suggested that this agent is well tolerated and active against relapsed NSCLC, achieving a median PFS of 2.7 months and median OS of 6.7 months [50,69]. Single-agent sunitinib (37.5 mg/day) demonstrated an acceptable safety profile and preliminary evidence of activity (overall response rate = 2.1%, median PFS 12.3 weeks and median OS 37.1 weeks) in 47 previously treated patients with advanced NSCLC [70]. In a phase I/II trial of patients with platinum-refractory NSCLC, erlotinib in combination with sunitinib demonstrated a favorable safety profile; efficacy results are still awaited [71]. In a phase II trial (GOAL) vatalanib monotherapy in 56 patients with relapsed or refractory NSCLC was generally well tolerated, and demonstrated a disease control rate of 33%, median OS of 7.2 months and median PFS of 2.4 months [72]. Two phase II trials have demonstrated that vandetanib has activity both as monotherapy and in combination with docetaxel in patients with pre-treated NSCLC. Four phase III trials of vandetanib in relapsed NSCLC are ongoing: vandetanib (100 mg/day) plus docetaxel versus docetaxel alone after failure of first-line treatment; vandetanib (300 mg/day) versus erlotinib (150 mg/day) after failure of no more than two prior regimens; vandetanib (300 mg/day) versus placebo as third/fourth-line treatment in patients for whom chemotherapy and EGFR TKI therapy has failed; and vandetanib (100 mg/day) plus pemetrexed versus pemetrexed after failure of first-line treatment. An ongoing phase II study is evaluating the role of cediranib in recurrent NSCLC. The results of these trials will help to determine whether these agents will add to the therapeutic options in this setting. 4. Future prospects: changing treatment paradigms The phase III trials reviewed here provide compelling evidence that targeted therapies can provide valuable improvements in outcomes in both the first- and second-line treatment settings. Ongoing trials will determine how these agents may modify current treatment paradigms. 4.1. Planned and ongoing trials to realize the potential of novel therapies in the treatment of advanced NSCLC A number of large trials are being conducted to determine the future role of novel agents in the therapeutic landscape for advanced NSCLC (Table 4). A large ongoing trial (MO19390; SAiL), involving approximately 2000 patients from 400 centers worldwide, is assessing the safety

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M. Reck, L. Crin` o / Lung Cancer 63 (2009) 1–9

Table 4 Planned and ongoing trials of bevacizumab and erlotinib as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC) Trial name

Setting

Patient population

Treatment arms

Primary endpoint

MO19390 (SAiL) (n = 2000)

First-line

First-line

≤6 cycles of standard of care first-line chemotherapy + bevacizumab (7.5 or 15 mg/kg) 2 cycles of carboplatin/paclitaxel

Safety

AVF3744g (BRIDGE) (n = 40)

Locally advanced, metastatic or recurrent non-squamous NSCLC Stage IIIB/IV or recurrent squamous NSCLC

AVF3752g (PASSPORT) (n = 110)

First- and second-line

Metastatic non-squamous NSCLC with previously treated brain metastases

TORCH (n = 900)

First-line

Stage IIIB/IV NSCLC

SATURN (n = 1700)

First-line

Stage IIIB/IV NSCLC

AVF3671g (ATLAS) (n = 1150)

First-line

Stage IIIB/IV non-squamous cell NSCLC

OSI3364g (BeTa Lung) (n = 650)

Second-line

Advanced NSCLC

4 cycles of carboplatin/paclitaxel + bevacizumab (15 mg/kg) q3w Chemotherapy or erlotinib + bevacizumab (15 mg/kg) q3w

Rate of grade ≥3 pulmonary hemorrhage

Rate of grade ≥2 symptomatic central nervous system hemorrhage

Erlotinib (150 mg/d) followed by gemcitabine/cisplatin × 6 Gemcitabine/cisplatin × 6 followed by erlotinib (150 mg/d) 4 cycles of first-line platinum-based chemotherapy Stratify for HER1/EGFR± Erlotinib (150 mg/d) or placebo

Overall survival

Bevacizumab (15 mg/kg) q3w + chemotherapy (carboplatin/paclitaxel, cisplatin/gemcitabine or carboplatin/docetaxel) Non-progressive disease patients receive either: bevacizumab (15 mg/kg) q3w + erlotinib (150 mg/d) OR bevacizumab (15 mg/kg) q3w + placebo Erlotinib (150 mg/d) + placebo Erlotinib (150 mg/d) + bevacizumab (15 mg/kg) q3w

PFS

PFS in overall population and in EGFR +ve population

Overall survival

CNS, central nervous system; HER1/EGFR, human epidermal receptor-1/epidermal growth factor receptor; PFS, progression-free survival; q3w, every 3 weeks.

profile of up to six 3-weekly cycles of bevacizumab (7.5 or 15 mg/kg) in combination with first-line standard chemotherapy regimens followed by bevacizumab maintenance therapy until disease progression. Preliminary safety results support the well-characterized safety profile of bevacizumab-based therapy; an analysis of 513 patients (intent-to-treat [ITT] population) indicates a similar safety profile to that observed in the phase III trials of bevacizumab in NSCLC [73,74]. In view of the potential functional antagonism between erlotinib and some chemotherapy agents, two phase III trials are investigating the efficacy of sequential doublet chemotherapy and erlotinib administration in the first-line setting. The TORCH trial will assess OS in patients receiving erlotinib (150 mg/day) or gemcitabine/cisplatin with a crossover design, while the SATURN trial compares the use of erlotinib (150 mg/day) or placebo as maintenance therapy in patients whose disease has not progressed on four cycles of a first-line standard platinum-based doublet.

and 12.6 months median OS [75]. Treatment was well tolerated: grade 3/4 toxicities were rash (6%) and infection (7.5%). In a threearm phase II trial, 120 patients received bevacizumab (15 mg/kg) with erlotinib (150 mg/day) or single-agent chemotherapy (docetaxel [75 mg/m2 ] or pemetrexed [500 mg/m2 ]), or chemotherapy alone. The addition of bevacizumab to either chemotherapy or erlotinib conferred longer PFS and OS than chemotherapy alone (Table 2) [76]. The overall safety profile favored the bevacizumab plus erlotinib arm because this combination avoids the toxicities of standard chemotherapy; fewer patients (13%) in the bevacizumab plus erlotinib arm discontinued the study due to AEs compared with patients receiving chemotherapy alone (24%) or bevacizumab plus chemotherapy (28%). Definitive randomized phase III trials are ongoing to investigate the efficacy of this combination. A randomized phase III trial (ATLAS) will evaluate the efficacy of bevacizumab with or without erlotinib, administered after bevacizumab plus chemotherapy, while the BeTa Lung trial will assess the efficacy of erlotinib with or without bevacizumab in the second-line setting (Table 4).

4.2. Promising data from combinations of biological therapies Combining biological agents with different molecular targets provides the opportunity to simultaneously disrupt a number of pathways involved in tumor development and progression, thereby potentially increasing efficacy beyond that achieved with a single agent. Unlike combinations of cytotoxic agents, which are often limited by additive toxicities, targeted agents generally have nonoverlapping toxicities. The combination of bevacizumab and erlotinib in patients with recurrent NSCLC has shown promising efficacy and tolerability. In a phase I/II study in 40 patients, erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 3 weeks) led to a response rate of 20%

4.3. Customizing patient care Other novel approaches may also have potential in advanced NSCLC. There is growing interest in pharmacogenomics – the optimization of chemotherapy that takes the tumor genome into account – to better select patients whose disease will respond to treatment and thereby improve the therapeutic index [77]. For example, ongoing research aims to generate predictive genomic signatures for chemotherapy response. Molecular biological studies have already identified genetic aberrations that are potentially useful for customizing treatment; mRNA transcripts involved in DNA

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repair pathways, such as ERCC1 and BRCA1, have been shown to confer selective resistance to cisplatin or taxanes [78,79]. There is great interest in whether biomarkers can be used to predict which patients will benefit most from treatment with EGFRTKIs. Retrospective evidence comes from the BR.21 trial, in which tumor biopsy samples were used to investigate whether response and survival with erlotinib was associated with EGFR expression, EGFR gene amplification and mutations [80,81]. The presence of an EGFR mutation may increase tumor responsiveness to erlotinib, but there was no evidence of an effect of mutation status on survival (patients with wild-type and mutated EGFR both had prolonged survival). Patients with EGFR-positive tumors and tumors with a high EGFR gene copy number may benefit most from erlotinib in terms of survival, but prospective validation of the biomarkers is required before the tests can be used in routine clinical practice. Of note, the INTEREST trial failed to achieve its co-primary endpoint of demonstrating an OS benefit for gefitinib versus docetaxel in patients with high EGFR gene copy number (HR 1.09; 95% CI: 0.78–1.51; p = 0.62; ITT population); there was no evidence that EGFR FISH-positive patients have superior OS on gefitinib compared with docetaxel [67]. The analysis of FISH-positive patients was based on small sample sizes: 85 and 89 patients in the gefitinib and docetaxel arms, respectively. This highlights the need for large, robust, prospective placebo-controlled trials in order to definitively identify potential biomarkers. MERIT, a trial investigating potential relationships between tumor biomarkers and clinical benefit from erlotinib, is the largest prospective genomic profiling trial conducted to date in advanced NSCLC. In baseline tumor biopsy samples of 264 patients, no binary markers for clinical benefit were identified. However, exploratory Affymetrix analysis identified three candidate markers of response on chromosome 7: EGFR, phosphoserine phosphatase and RAPGEF5 (which encodes guanine nucleotide exchange factor) [82,83]. Largescale prospective studies (such as SATURN) are now underway, to determine whether any of the prospective biomarkers reliably predicts for response and, more importantly, survival with erlotinib. Tailored chemotherapy on the basis of tumor pharmacogenomics may also represent a promising novel approach for treating NSCLC. In a recent large randomized trial, chemo-na¨ıve patients with locally advanced or metastatic NSCLC experienced similar median OS with pemetrexed/cisplatin and gemcitabine/cisplatin overall (10.3 months in each arm), but in a pre-planned analysis patients with adenocarcinoma or large cell carcinoma treated with pemetrexed/cisplatin experienced significantly improved OS compared with those receiving gemcitabine/cisplatin [84]. In contrast, patients with squamous cell histology did not experience improved OS with pemetrexed/cisplatin. These findings could be explained by the lower expression of thymidylate synthase, the pemetrexedspecific target, in adenocarcinoma compared with squamous cell carcinoma [85]. This is the first evidence of survival differences between platinum doublets according to tumor histology. The results of pharmacogenomics research are preliminary to date, and the clinical applications of this research remain to be demonstrated. Nevertheless, any advances in this field promise the advent of “tailored treatment” for patients with NSCLC.

5. Conclusions Since the introduction of third-generation cytotoxic drugs, manipulation of chemotherapy-based regimens has led to only small improvements in the survival of patients with advanced NSCLC. The plateau in what can be achieved with currently available cytotoxic therapy highlights the need for novel approaches to improve the outcome of patients with advanced disease.

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The introduction of targeted agents, with different modes of action and toxicity profiles to chemotherapy, represents a real breakthrough in the treatment of NSCLC. In the first-line setting, bevacizumab-based therapy is the first treatment in more than a decade to show a survival benefit beyond that achieved with standard chemotherapy. Erlotinib significantly prolongs survival and improves the QoL of patients who have relapsed during prior therapy for advanced disease, while gefitinib has recently demonstrated similar efficacy to chemotherapy in the second-line setting. Ongoing and planned randomized trials are investigating a range of other agents. It is likely that future treatment paradigms will be shaped by the data emerging from randomized trials investigating targeted therapy-based treatment regimens. Conflict of interest statement Lucio Crino` has no conflict of interest to declare. Martin Reck has received honoraria as a speaker and consultant as well as a fee for organizing an educational event from F. Hoffmann-La Roche. Travel to a recent ASCO congress was also funded by F. Hoffmann-La Roche. Acknowledgments The authors would like to acknowledge medical writing support provided by Gardiner-Caldwell Communications; this support was funded by F. Hoffmann-La Roche. References [1] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin 2005;55:74–108. [2] Cartman ML, Hatfield AC, Muers MF, Peake MD, Haward RA, Forman D. Lung cancer: district active treatment rates affect survival. J Epidemiol Community Health 2002;56:424–9. [3] Makitaro R, Paakko P, Huhti E, Bloigu R, Kinnula VL. Prospective populationbased study on the survival of patients with lung cancer. Eur Respir J 2002;19:1087–92. [4] Ginsberg RJ, Vokes EE, Rosenzweig K. Non-small cell lung cancer. In: DeVita JV, Hellman S, Rosenberg SA, editors. Cancer-principles and practice of oncology. Philadelphia, PA: JB Lippincott Co.; 2001. p. 925–82. [5] Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigmgeneral principles. Nat Clin Pract Oncol 2007;4:86–100. [6] Jett JR, Schild SE, Keith RL, Kesler KA. Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (second edition). Chest 2007;132(3 Suppl.):266S–76S. [7] Socinski MA, Crowell R, Hensing TE, Langer CJ, Lilenbaum R, Sandler AB, et al. Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (second edition). Chest 2007;132(3 Suppl.):S277–89. [8] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker J, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330–53. [9] Felip E, Stahel RA, Pavlidis N. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol 2005;16(Suppl. 1):28–9. [10] Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. JAMA 2004;292:470–84. [11] Ardizzoni A, Tiseo M, Boni L, Rosell R, Fossella FV, Schiller JH, et al. CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24(June 20 Suppl.):366s [abstract 7011]. [12] Tiseo M, Ardizzoni A. Cisplatin or carboplatin in the treatment of non-small cell lung cancer: a comprehensive review. Oncol Rev 2007;1:162–9. [13] Gridelli C, Shepherd FA. Chemotherapy for elderly patients with non-small cell lung cancer: a review of the evidence. Chest 2005;128:947–57. [14] Cheong KA, Chrystal K, Harper PG. The management of PS2 patients with advanced non-small cell lung cancer. Int J Clin Pract 2006;60:1493–6. [15] 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;346:92–8. [16] Gronberg BH, Bremnes R, Aasebo U, Brunsvig P, Flotten O, Hjelde H, et al. Pemetrexed + carboplatin versus gemcitabine + carboplatin in the treatment of stage IIIB/IV non-small cell lung cancer (NSCLC). J Clin Oncol 2007;25(June 20 Suppl.):388s [abstract 7517].

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