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World J Clin Oncol. May 10, 2013; 4(2): 29-42 Published online May 10, 2013. doi: 10.5306/wjco.v4.i2.29
Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma
Soley Bayraktar, Caio M Rocha-Lima
Soley Bayraktar, Departments of Medical Oncology, Mercy Cancer Center, Ardmore, OK 73401, United States
Caio M Rocha-Lima, University of Miami and Sylvester Comprehensive Cancer Center, Miami, FL 33124, United States
Author contributions: Both authors contributed equally to this work.
Correspondence to: Soley Bayraktar, MD, MBA, Departments of Medical Oncology, Mercy Cancer Center, 1220 Hall street, Ardmore, OK 73401, United States. firstname.lastname@example.org
Telephone: +1-580-5042781 Fax: +1-580-2206118
Received: March 7, 2013 Revised: April 9, 2013 Accepted: April 17, 2013 Published online: May 10, 2013
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents.
Core tip: Targetable molecular abnormalities have not yet been identified in approximately 80% of non-small-cell lung cancer patients. In addition to anaplastic lymphoma kinase, epidermal growth factor receptor, vascular endothelial growth factor targeted therapies, the results from ongoing trials will determine if the newer targeted agents will be incorporated into clinical practice.
Citation: Bayraktar S, Rocha-Lima CM. Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma. World J Clin Oncol 2013; 4(2): 29-42
Non-small-cell lung cancer (NSCLC) remains a therapeutic challenge. Despite some progress, it remains the leading cause of cancer-related death in the United States in both men and women. The estimated incidence of NSCLC is 226160 cases with 160340 deaths in the United States in 2012. The 5-year survival rates for advanced and metastatic NSCLC are only 24% and 4%, respectively.
The core drug and backbone of treatment in locally advanced and metastatic settings of NSCLC has been a platinum agent. In a large randomized clinical trial, Schiller et al compared the efficacy of three commonly used regimens (cisplatin and gemcitabine, cisplatin and docetaxel, carboplatin and paclitaxel) with that of a reference regimen of cisplatin and paclitaxel. No significant difference in survival was observed among the four commonly used regimens, although the regimen of carboplatin and paclitaxel had a lower rate of toxic effects than the other regimens. On the basis of these results, Eastern Cooperative Oncology Group had chosen carboplatin and paclitaxel as its reference regimen for future studies; and it is still the most commonly used taxane-platinum combination in the United States which produces 15%-32% objective response rates (ORR), with 7.9-10.6 mo median overall survivals (OS)[4-6].
Further attempt at subclassification is now accepted as a standard of care; separating squamous cell carcinoma from adenocarcinoma and large-cell carcinoma as the distinction carries implications for prognosis and treatment decisions. For example, a phase III study in patients with advanced NSCLC treated with cisplatin plus pemetrexed (an inhibitor of purine and pyrimidine synthesis), showed no improvement in tumor response rate and survival over cisplatin plus gemcitabine for all histologies; however, an improvement in survival was noted in the non-squamous histology subset while a decrement in the squamous histology subset was observed. Due to safety concerns observed in the phase II trial, the addition of bevacizumab to carboplatin/taxol was subsequently studied in phase III trial and improved efficacy was observed in patients with non-squamous histology (ORR, 35%; OS, 12.3 mo).
In addition to making distinction in cytotoxic chemotherapy based on histology, over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in NSCLC tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis. Currently, detection of the presence of mutations involving the epidermal growth factor receptor (EGFR) gene and fusion of the N-terminal portion of the protein encoded by echinoderm microtubule-associated protein-like 4 (EML4) gene with the intracellular signaling portion of the receptor tyrosine kinase encoded by anaplastic lymphoma kinase (ALK) gene - that is, EML4-ALK - has become routine in many centers because patients having tumors harboring such alterations benefit from novel targeted inhibitors as part of their treatment regimen. This review describes some of the important developments and targeted agents that have been tested in clinical trials; and the potential future biologics in the treatment of advanced or metastatic NSCLC.
MOLECULARLY TARGETED THERAPIES IN ADVANCED OR METASTATIC NSCLC
EGFRs are a group of transmembrane proteins that regulate key processes in the cell, such as proliferation, division, migration, and differentiation. This family has 4 different members: EGFR (HER1 or ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4); all of which share a similar structure. Upon binding to its ligands, EGFR induces receptor homo- or hetero-dimerization and results in the activation of an intracellular tyrosine kinase domain. Receptor activation cause downstream signaling events through activation of the Ras/Raf/MEK/MAPK and PI3K/AKT/mTOR pathways that regulate cell proliferation, differentiation, and survival. The two most common EGFR mutations are short in-frame deletions of exon 19 and a point mutation in exon 21. Tumors with EGFR mutations occur at a higher frequency in East Asians than in non-Asians (30% vs 8%), in women than in men (59% vs 26%), in never-smokers than in ever-smokers (66% vs 22%), and in adenocarcinoma than in other NSCLC histologies (49% vs 2%). In the United States, activating EGFR mutations are estimated to occur in 15% of patients with primary lung adenocarcinoma.
Monoclonal antibodies against EGFR: Cetuximab is a chimeric monoclonal antibody against EGFR. One of the first phase II studies assessing combination chemotherapy with cetuximab (cisplatin or carboplatin and gemcitabine with or without cetuximab) showed an increased ORR, progression-free survival (PFS), and OS in the cetuximab group. A similar phase II study in which cisplatin and vinorelbine were administered with or without cetuximab also showed enhanced survival indices in the cetuximab arm. However a subsequent large phase III trial investigating paclitaxel or docetaxel and carboplatin, with or without cetuximab in 676 patients with NSCLC did not find any notable differences in PFS or ORR.
The recently published FLEX study demonstrated that adding cetuximab to cisplatin-based chemotherapy resulted in a small but significant improvement in median OS in patients with advanced NSCLC [11.3 mo vs 10.1 mo; hazard ratio (HR): 0.87; P = 0.04]. A retrospective analysis of FLEX data showed that 31% of patients with high EGFR expression, adding cetuximab increased the median OS from 9.6 to 12 mo (HR: 0.73; P = 0.011). Ultimately, a meta-analysis looking at the four trials in which 2018 previously untreated NSCLC patients were analyzed concluded that cetuximab improved OS and ORR regardless of the presence of EGFR mutations. In accordance with the above results, a more in-depth analysis of these subgroups in phase III trials revealed that specific activating mutations in the tyrosine kinase domain of the EGFR gene were associated with sensitivity to gefitinib but not to cetuximab. In addition, no significant cetuximab treatment-specific correlations between EGFR or K-RAS mutation status and PFS, OS, or ORR were observed in the phase III trials[20,21]. Therefore, we can conclude that EGFR or K-RAS mutations may not be useful as biomarkers in cetuximab therapy. At present, a number of clinical trials are still evaluating the efficacy of cetuximab in combination with other treatment modalities in combination with tyrosine kinase inhibitors (TKIs), and other chemotherapeutic drugs. Most of these trials are also assessing biomarker status that could be predictive or prognostic in value.
EGFR-Tyrosine kinase inhibitors: EGFR-TKIs are small molecules administered orally and are subdivided in reversible, gefitinib and erlotinib, and irreversible, afatinib on the basis of their straight binding with the specific site of the EGFR intracellular domain. These drugs inhibit the phosphorylation and tyrosine kinase activity of the intracellular adenosine triphosphate (ATP)-binding domain of the EGFR through competitive binding to this site, and were initially investigated in unselected patients reporting contrasting results depending on the type of population/enrolled in each study. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status. Almost all patients who respond to EGFR-TKIs have been shown to carry activating mutations usually found in exons 18 through 21 of the TK domain of EGFR, and are either point mutations or in-frame small deletions or insertions. Although more than 250 mutations of the EGFR have been described up to now, two mutations, one single point mutation in exon 21, the L858R, and a series of small in-frame deletions in exon 19 account for approximately 90% of all EGFR mutations.
Erlotinib: EGFR mutations have been defined ‘‘activating’’ and ‘‘sensitizing’’ and both definitions are correct. In fact, EGFR mutations lead to increased response of the EGFR to exogenous growth factors, thus producing a more significant and more persistent activation of intracellular signaling pathways, resulting in increased cell proliferation and survival. On the other hand, the mutant receptor is more sensitive to EGFR-TKIs as compared with wild type EGFR, since lower concentrations of drugs are required to inhibit its phosphorylation. Retrospective analyses have demonstrated that patients with EGFR mutations have high ORRs to EGFR-TKIs in any line of treatment. These findings sustain the hypothesis that tumors with EGFR mutations are addicted to the EGFR pathway, i.e. depend on these pathways for their growth. In agreement with this hypothesis, tumors with EGFR mutations have shown to homogeneously carry this molecular alteration in all tumor cells. As discussed above, erlotinib was first studied in unselected patients with NSCLC, and a subsequent analysis of the patients who had experienced dramatic tumor responses were found to have the activating mutations in the kinase domain of EGFR. The response rate was as high as 81% in patients harboring EGFR tyrosine kinase domain mutations, but less than 10% in patients with wild-type EGFR. The OPTIMAL trial was the first phase III study directly comparing erlotinib with standard chemotherapy in the first-line setting of advanced NSCLC in Chinese patients with an activating EGFR mutation. That trial showed a PFS of 13.1 mo with erlotinib compared with 4.6 mo with gemcitabine-carboplatin chemotherapy (HR: 0.16; 95%CI: 0.1-0.26; P < 0.001). An updated analysis also showed median PFS of 13.7 mo vs 4.6 mo; HR: 0.164; P < 0.0001. A second trial called EURTAC, the first to involve a Western European population, randomized patients to a platinum-based doublet chemotherapy regimen (docetaxel-gemcitabine) or to erlotinib in patients with an EGFR activating mutation. Patients treated with erlotinib experienced a PFS advantage (9.7 mo vs 5.2 mo; HR: 0.37; 95%CI: 0.25-0.54). Based on these results, erlotinib was approved as a first-line treatment in patients with advanced or metastatic NSCLC harboring the EGFR mutations.
Recent phase II/III trials have shown single agent activity of erlotinib in the second-line setting in either selected or unselected patients with metastatic NSCLC[30,31]. In the TITAN phase III trial, the efficacy and tolerability of second-line erlotinib was compared with either pemetrexed or docetaxel in 425 patients with advanced NSCLC who were treated with first-line platinum doublet chemotherapy and had disease progression during or immediately after chemotherapy. The second-line erlotinib was associated with a similar median OS duration to pemetrexed or docetaxel in patients with advanced NSCLC (5.3 mo vs 5.5 mo; HR: 0.96 in the overall population; 95%CI: 0.78-1.19). Similarly, there was no difference in OS between the treatment groups (HR: 0.85; 95%CI: 0.59-1.22) in 149 patients with EGFR wild type tumors.
The phase III SATURN trial examined erlotinib as maintenance therapy after platinum-based chemotherapy. That trial met the primary endpoint of significantly longer PFS in patients treated with erlotinib (12.3 wk) than in patients receiving placebo (11.1 wk; HR: 0.69; 95%CI: 0.58-0.82; P < 0.0001). The overall response rate was 11.9% in the erlotinib arm compared with 5.4% in the placebo arm (P = 0.0006). Importantly, the benefit of erlotinib maintenance on PFS and OS was also seen in EGFR wild-type patients (HR: 0.78, 95%CI: 0.63-0.96, P = 0.0185, and HR: 0.77, 95%CI: 0.61-0.097, P = 0.008, respectively).
Gefitinib: Two large phase III studies highlighted the role of gefitinib in tumors harboring EGFR mutations[34,35]. In IPASS trial, the efficacy of gefitinib was compared with carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma. Of 1217 enrolled patients, OS was similar for gefitinib and carboplatin/paclitaxel (HR: 0.90; 95%CI: 0.79-1.02; P = 0.109) in overall, or in EGFR mutation-positive (HR: 1.00; 95%CI: 0.76-1.33; P = 0.990) or EGFR mutation-negative (HR: 1.18; 95%CI: 0.86-1.63; P = 0.309) subgroups. Of importance, PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR: 0.48; 95%CI: 0.34-0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR: 3.85; 95%CI: 2.09-7.09). Likewise, another multicenter phase III trial demonstrated that patients with advanced-stage NSCLC containing EGFR mutations and treated with first-line gefitinib (compared with standard chemotherapy) had improved PFS. Based on these results, the American Society of Clinical Oncology recommended EGFR mutation testing for patients with advanced NSCLC who are being considered for first-line therapy with an EGFR-TKI.
Two phase III clinical trials suggested that gefitinib was more efficacious and less toxic than docetaxel as a second-line treatment in patients with previously-treated advanced NSCLC[36,37]. In the ISTANA trial, the primary endpoint of PFS was longer with gefitinib than docetaxel (HR: 0.729; 90%CI: 0.533-0.998; P = 0.0441), and the secondary endpoints showed superior ORR (28.1% vs 7.6%; P = 0.0007), good tolerability, and similar quality-of-life (QoL) improvement rates for gefitinib compared to docetaxel. In the INTEREST trial, of 1433 patients analyzed (723 in gefitinib group and 710 in docetaxel group), non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 events vs 576 events; HR: 1.020, 95%CI: 0.905-1.150). Interestingly, superiority of gefitinib in patients with high EGFR-gene-copy number was not proven (72 vs 71 events; HR: 1.09, 95%CI: 0.78-1.51; P = 0.62; median survival 8.4 mo vs 7.5 mo). Table 1 summarizes the selected phase III and randomized phase II trials comparing EGFR-TKIs and chemotherapy as first-line therapy in patients with advanced NSCLC.
Table 1 Selected phase III and randomized phase II trials comparing epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy as first-line therapy in patients with advanced non-small cell lung cancer.
3By independent review. PC: Paclitaxel and carboplatin; Cis: Cisplatin; C: Carboplatin; G: Gemcitabine; D: Docetaxel; P: Pemetrexed; OS: Overall survival; HR: Hazard ratio; NM: Not yet mature; NA: Not available; PFS: Progression-free survival; ORR: Objective response rate; n: Number of patients enrolled in the study.
Vascular endothelial growth factor inhibition
Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), was approved by Food and Drug Administration for the treatment of NSCLC in 2006. The combination of bevacizumab with carboplatin and paclitaxel was shown to prolong OS compared with chemotherapy alone (median OS, 12.3 vs 10.3 mo, respectively) in patients with nonsquamous advanced NSCLC. Bevacizumab has also been combined with gemcitabine and cisplatin, with a modest benefit observed in PFS but no differences seen in OS. Many other antiangiogenic agents have been under development.
Triple angiokinase inhibitors, which inhibit VEGF, platelet derived growth factor and/or fibroblast derived growth factor were thought to have the potential to improve the therapeutic outcomes for patients with NSCLC. Clinical trials have been ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, vandetanib, cediranib, nintedanib, sunitinib, pazopanib, brivanib, linifinib, axitinib, and motesanib (http://www.clinicaltrials.gov ). To date, none of these agents in combination with chemotherapy have resulted in improvements in OS for patients with advanced NSCLC. Moreover, in a phase II trial (ESCAPE), patients with squamous histology treated with chemotherapy plus sorafenib had a shorter OS than those receiving chemotherapy plus placebo (HR: 1.85; 95%CI: 1.22-2.81). A recent meta-analysis comparing the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC showed that chemotherapy plus a TKI significantly increased the ORR (HR: 1.71, 95%CI: 1.43-2.05) and PFS (HR: 0.83, 95%CI: 0.76-0.90], but not OS (HR: 0.93, 95%CI: 0.83-1.03). The toxicity was comparable between the two therapies. Table 2 summarizes the phase III clinical trials testing antiangiogenic TKIs in combination with chemotherapy in NSCLC.
Table 2 Phase III clinical trials testing antiangiogenic tyrosine kinase inhibitors in combination with chemotherapy in non-small cell lung cancer.
There is evidence from the 3 phase II clinical trials supporting the potential use of sorafenib as a monotherapy in chemotherapy refractory NSCLC[26,27]. Particularly, the BATTLE trial showed a promising response rate (8-wk disease control rate in 58% of patients) in heavily pretreated patients with single agent sorafenib. More impressively, in patients whose tumor harbored a KRAS mutation, sorafenib had a disease control rate of 79% while on a separate phase II trial in NSCLC, the response rate to erlotinib was only 14% (P = 0.016). This indicates that the significant disease control rate in KRAS mutant NSCLC patients may be due to sorafenib’s effects on KRAS downstream pathways such as Raf inhibition rather than its antiangiogenic effects. The randomized, placebo-controlled, multicenter international phase III trial (NCT00863746 MISSION Trial) is currently underway to evaluate single agent sorafenib as third- or fourth-line therapy in patients with NSCLC. The enrollment for MISSION Trial has been concluded and data should be available later this year.
Rearrangements of the ALK gene are felt to be mutually exclusive of EGFR and KRAS mutations and occur in approximately 4% of NSCLC. The ALK mutations are more common in adenocarcinomas and in light smokers or non-smokers. The phase I trial of the ALK-inhibitor crizotinib in advanced ALK-positive NSCLC revealed a response rate of 57% (95%CI: 46%-68%) and an estimated 6-mo PFS probability of 72% (95%CI: 61%-83%). A retrospective review of 82 ALK-positive patients (including patients who had received multiple lines of therapy) treated with crizotinib revealed an impressive 1-year survival of 74% (95%CI: 63%-82%) and 2-year survival of 54% (95%CI: 40%-66%). Crizotinib was approved in the United States in 2011, primarily based on response rates of 50% on the first 136 patients with ALK-rearranged NSCLC enrolled on PROFILE 1005 and secondarily on a response rate of 61% from the first 119 patients with ALK-rearranged NSCLC enrolled on PROFILE 1001. Table 3 lists the major ongoing trials with crizotinib for advanced NSCLC.
Table 3 Major ongoing clinical trials with crizotinib for advanced non-small cell lung cancer1.
Key entry criteria
PROFILE 1007 (NCT00932893)
Crizotinib vs Pem or Doc as second-line
ALK(+) and 1 prior platinum-based chemo
PROFILE 1014 (NCT01154140)
Crizotinib + Pem + Cis/Carbo vs Pem + Cis/Carbo as first-line
ALK(+) and chemotherapy-naive
PROFILE 1005 (NCT00932451)
Crizotinib vs placebo as third-line
ALK(+) and PD in arm B of study PROFILE 1007
PROFILE 1001 (NCT00965731)
Crizotinib + erlotinib vs erlotinib as second or third-line
New ALK inhibitors are under investigation, with phase I trials of LDK378 (not yet recruiting) and AP26113 (currently recruiting). NCT01449461, a phase I trial of AP26113, will be conducted in two parts, with the second part including expansion cohorts. The 4 cohorts include ALK mutations with no previous exposure to ALK inhibitors, ALK mutation with resistance to an ALK inhibitor, EGFR mutation with resistance to EGFR inhibitors, and non-lung malignancies with ALK mutations.
KRAS and BRAF mutations and MEK inhibition
Mutations in KRAS have been found in 15%-30% of patients with NSCLC and are considered to be one of the more frequent mutations in these tumors[44,45]. Approximately 97% of K-RAS mutations in NSCLC involve codons 12 or 13. As with EGFR mutations, KRAS mutations are detected mainly in lung adenocarcinomas and are less frequently observed in squamous cell carcinomas of the lung[47,48]. In contrast with lung adenocarcinomas harboring EGFR mutations, tumors having KRAS mutations are seen at a higher frequency (20%-30%) in Caucasian patients than in East Asian patients (5%). Also, compared with EGFR mutations, KRAS mutations are more common in current or former smokers than in never-smokers.
Although the value of KRAS status as a prognostic and predictive biomarker for anti-EGFR therapy is less clear in NSCLC, several studies have demonstrated that KRAS mutations are a factor correlated with poor survival in patients with NSCLC[51-53]. A recent prospective biomarker-driven phase III trial conducted in 889 patients comparing placebo with sequential erlotinib maintenance in unresectable NSCLC (SATURN, BO18192) showed that the presence of KRAS mutations was not predictive for erlotinib efficacy and was prognostic significantly associated with reduced PFS. The predictive significance of KRAS mutation status is being further evaluated in BATTLE-2 clinical trial.
BRAF encodes a non-receptor serine/threonine kinase that is a member of the Ras/MAPK signaling pathway downstream of Ras protein. Upon activation, BRAF directly phosphorylates MEK, which in turns phosphorylates ERK, thereby regulating cellular responses to growth signals. BRAF mutations were first identified in melanoma cells, with 80% of mutations involving the Val600 residue in the kinase domain. By contrast, BRAF mutations account for only 1%-3% of NSCLC and they are mostly non-Val600Glu mutations including Gly468Ala and Leu596Val[56,57]. BRAF mutations were shown to be mutually exclusive with EGFR mutations within exons 18-21, KRAS codon 12 mutations, ERBB2 codon 20 mutations, and translocations in ALK. Furthermore, V600E mutated NSCLCs showed a more aggressive tumor histology characterized by micropapillary features and were associated with poor prognosis.
A number of studies are currently examining the effect of MEK inhibitors on BRAF or KRAS-mutated solid tumors. As a downstream effector of the EGFR pathway that signals through K-RAS, MEK inhibition has also been suggested to play a role in patients who become resistant to EGFR inhibitors. A number of trials to examine MEK inhibitors alone or in combination with other targeted treatments are currently recruiting. The NCT00888134 phase II trial is examining the effects of MEK inhibitor AZD6244 in patients with metastatic malignancy and a BRAF mutation. Dasatinib was shown to selectively induce senescence in NSCLC cells with inactivating BRAF mutations. The NCT01514864 phase II trial is now recruiting patients to examine the effect of dasatinib in patients with NSCLC or melanoma harboring a BRAF mutation (Clinicaltrials.gov).
GSK2118436 is a potent MEK inhibitor that has been shown to have preclinical activity in BRAF mutant NSCLC and melanoma. A phase II trial (NCT01336634) is currently recruiting patients with previous exposure to platinum chemotherapy, and will examine GSK2118436 in advanced NSCLC patients with a BRAF mutation. The primary outcome will be ORR, and the trial is expected to be completed in late 2013. A phase I trial (NCT01324258) of GSK1120212, another potent MEK inhibitor, in combination with gemcitabine is currently recruiting patients with solid tumors in Japan. An Open-Label, Phase I/Ib Dose Escalation Study to assess the safety and tolerability of GSK1120212 in combination with docetaxel, erlotinib, pemetrexed, pemetrexed + carboplatin, pemetrexed + cisplatin, or nab-paclitaxel in patients with advanced metastatic lung and/or pancreatic cancers is currently recruiting patients (NCT01192165). A number of phase I trials are currently examining the combination of MEK162, a MEK1/2 inhibitor, with PI3K (BYL719) or Raf (Raf265) inhibitors in advanced solid tumors with documented KRAS or BRAF mutations (NCT01449058, and NCT01352273). Selumetinib (AZD6244, a potent MEK inhibitor) is being investigated in NSCLC patients with tumors harboring KRAS mutations. Table 4 lists the ongoing clinical trials involving targeted agents for patients with advanced or metastatic NSCLC.
Table 4 Ongoing phase II/III clinical trials involving targeted agents for patients with advanced or metastatic non-small cell lung cancer.
Clinical trial ID
Key entry criteria
Erlotinib vs docetaxel
WT EGFR, prior platinum chemo, no prior taxanes
Erlotinib vs pazopanib
Active, not recruiting
1 prior chemo
Erlotinib + OSI-906
EGFR mutation (+), chemotherapy-naive
Erlotinib + ARQ197
WT EGFR, prior platinum-based chemo
Erlotinib + ARQ197
2 prior lines of chemo
Erlotinib + PC + Bev
Active, not recruiting
Active, not recruiting
Stable disease after chemo, EGFR unknown, never or light smokers
Gefitinib vs Pem
WT EGFR, prior platinum-based chemo
Active, not recruiting
EGFR mutation (+)
Active, not recruiting
Prior platinum-based chemo, progressed after erlotinib or gefitinib
1 prior chemo
PF00299804 vs erlotinib
1 prior chemo
AZD6244 + erlotinib
KRAS WT or KRAS mutant
Tumors harboring DDR2 mutation or inactivating B-RAF mutation
OVERCOMING ACQUIRED DRUG RESISTANCE TO EGFR TARGETED THERAPIES IN NSCLC
Despite the significant improvement in outcomes for these highly selected patients, treatment failures secondary to resistance have been described since 2005. Known mechanisms of resistance include secondary EGFR mutations (T790M mutant) or persistent phosphorylation of EGFR that reduces the inhibitory ability of gefitinib or erlotinib, and MET amplification with subsequent activation of downstream pathways[61,62]. The discovery of resistance to the EGFR-TKIs has led to the development of second-generation EGFR-TKIs, or the use of combination of EGFR inhibitors with other targeted therapies. Moreover, a third generation of EGFR-TKIs is now entering clinical trials; these compounds bind covalently to the ATP-binding cleft of mutant EGFR and appear to have selective activity against the T790M mutant.
Many trials have studied intensification of EGFR inhibition through use of second-generation TKIs such as neratinib, afatinib, and dacomitinib. These inhibitors are different from erlotinib and gefitinib in 2 main ways: each forms a covalent, irreversible bond with the EGFR protein, and each also inhibits other members of the ERBB family of kinases.
Dacomitinib (PF0299804): PF0299804 is an oral irreversible inhibitor of the EGFR/HER1, HER2, and HER4 tyrosine kinases. Preclinical data showed activity for PF0299804 against EGFR mutations and T790M[61,65]. Two phase II studies highlighted the agent’s clinical antitumor effect, both in first-line therapy and in treatment-refractory settings. In the first of the studies, PF0299804 was compared with erlotinib. That trial enrolled a range of molecular subgroups, including a group of patients with wild-type KRAS. In all subgroups, PF0299804 showed a PFS advantage (12.4 wk vs 8.3 wk; HR: 0.704; P = 0.030). In the second phase II trial, dacomitinib demonstrated significantly improved PFS over erlotinib (2.86 mo for patients treated with dacomitinib and 1.91 mo for patients treated with erlotinib, HR: 0.66; 95%CI: 0.47-0.91; P = 0.012), with an acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.
Afatinib: Afatinib has been shown to suppress the kinase activity of wild-type and activated EGFR, including erlotinib-resistant isoforms with the T790M mutation. The phase IIb/III LUX-Lung 1 randomized, double-blind trial examined best supportive care plus afatinib or placebo in patients in whom chemotherapy and a reversible EGFR inhibitor had failed. No difference in OS was observed; however, PFS was significantly improved with afatinib (3.3 mo vs 1.1 mo; HR: 0.38; 95%CI: 0.306-0.475; P < 0.001), as were tumor-related symptoms and QoL. The most exciting clinical trial of afatinib in the acquired-resistance setting was a phase Ib study in the United States and Netherlands. Patients who had progressed on erlotinib or gefitinib were given afatinib and cetuximab. Approximately 94% of patients, regardless of T790M mutation status, had a partial response or stable disease.
A number of phase II trials continue to examine the safety and efficacy of afatinib as a second-line therapy. LUX-Lung 2 phase II trial (NCT00525148) has completed enrollment of patients with activating EGFR mutations in whom first-line chemotherapy has failed. Similarly, LUX-Lung 4 phase I/II Japanese trial (NCT00711594) has completed accrual; results are awaited from this group of patients with first generation EGFR-TKI-resistant advanced NSCLC.
The phase III LUX-Lung 3 trial reported the efficacy and safety data of first-line afatinib vs cisplatin and pemetrexed (PC) in patients with EGFR mutation-positive tumors. Treatment with afatinib led to a significantly prolonged PFS vs PC (median 11.1 mo vs 6.9 mo; HR: 0.58; 95%CI: 0.43-0.78; P = 0.0004). In 308 patients with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mo, respectively (HR: 0.47; 95%CI: 0.34-0.65; P < 0.0001). ORR was significantly higher with afatinib (56% vs 23%; P < 0.0001). Significant delay in time to deterioration of cancer-related symptoms of cough (HR: 0.60, P = 0.0072) and dyspnea (HR: 0.68, P = 0.0145) was seen with afatinib vs PC. Drug-related adverse events led to discontinuation in 8% (afatinib; 1% due to diarrhea) and 12% of patients (PC). Given the promising results of this pivotal trial, afatinib is now being compared with gefitinib as first-line treatment in patients with stage IIIB/IV lung adenocarcinoma with EGFR activating mutations (LUX-Lung 7; NCT01466660).
Increasing evidence has suggested that solid tumors have multiple salvage and resistance pathways that allow them to circumvent inhibition of a single signaling pathway. In fact, EGFR is known to regulate the production of VEGF and other proangiogenic factors, and increased VEGF expression has been associated with resistance to EGFR inhibition in a human tumor xenograft model of NSCLC. Thus, it is likely that blocking only one of these pathways will be insufficient for providing any meaningful therapeutic outcomes. Based on the logical strategy for improving anti-tumor efficacy by inhibition of multiple signaling pathways, a number of clinical trials are currently dual-inhibition strategies [e.g. mTOR, c-MET, PIK3CA, insulin-like growth factor 1 receptor (IGF-1R) or histone deacetylase (HDAC) inhibitor plus EGFR inhibitor].
Combination of EGFR and VEGF inhibitors: There have been promising results from combination of sorafenib with erlotinib. The combination has shown encouraging disease stabilizing effects with tolerable toxicity profiles[73-75]. In a randomized, double-blind, placebo controlled, phase II trial in 168 patients with previously treated advanced NSCLC, sorafenib plus erlotinib was compared with erlotinib plus placebo. Overall, there were no significant differences in OS, PFS, or ORR between these two groups. However, in 67 patients with tumors bearing wild-type EGFR, sorafenib/erlotinib group showed a superior median PFS (3.38 mo in sorafenib/ erlotinib group vs 1.77 mo in placebo/erlotinib group; P = 0.018) and a superior mean OS (8 mo for sorafenib/erlotinib vs 4.5 mo for placebo/erlotinib; P = 0.019). Another phase II study evaluated sorafenib in combination with gemcitabine or erlotinib in 60 elderly patients with previously untreated advanced NSCLC. ORR and median OS were 6.5% and 6.5 mo with sorafenib plus gemcitabine, and 10.3% and 12.6 mo with sorafenib plus erlotinib. Similarly designed randomized phase II/IIItrials failed to show any improvement in OS from the addition of sunitinib to erlotinib (9.0 mo vs 8.5 mo with placebo plus erlotinib; HR: 0.922; 95%CI: 0.797-1.067). In a phase III trial, the addition of bevacizumab to erlotinib suggested a non-significant OS benefit with the combined inhibition therapy in patients with EGFR-mutant tumors (median OS: 18 mo for bevacizumab plus erlotinib vs 12 mo for erlotinib; HR: 0.44; 95%CI: 0.11-1.67).
A recent meta-analysis evaluated the safety and efficacy of the combined inhibition of the VEGFR and EGFR signaling pathways with single-targeted therapy. Patients receiving combined inhibition therapy had a significant longer PFS than the group with single-targeted therapy (HR: 0.80; 95%CI: 0.67-0.95; P = 0.011). The combined therapy was associated with a non-significant 3% improvement in OS (HR: 0.97; 95%CI: 0.89-1.05; P = 0.472) confirming the previous studies. Also, no difference in the ORR between the study groups were detected (HR: 1.44; 95%CI: 0.95-2.18; P = 0.085). Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS in the expense of increased toxicity in combined inhibition therapy. Currently, there is no evidence to support the use of combined inhibition of the VEGFR and EGFR signaling pathways in unselected patients with advanced NSCLC. Nonetheless, combined inhibition therapy may have a potential advantage in the treatment of advanced NSCLC compared with single inhibition therapy if the subsets of patients who may benefit from this treatment are well identified.
MET inhibitors: Investigation of resistance to current EGFR inhibitors has highlighted the role of the c MET/ALK pathway. MET amplification leads to EGFR-independent activation of the PI3K/Akt pathway through the activation of erbB3-dependent signaling and thereby could lead to EGFR inhibitor resistance[78,79]. Thus, combinations of EGFR and c-MET/ALK inhibitors hold potential for overcoming resistance.
The addition of c-MET inhibitor to erlotinib has demonstrated promising clinical activity in phase II studies[81,82] when compared with erlotinib alone, particularly among patients with MET overexpression and non-squamous histology. The subset analyses of the trial by Spigel et al suggested that METMab plus erlotinib was associated with increased PFS and OS as compared with erlotinib alone in patients with MET overexpression. In the study comparing ARQ 197-209 (c-MET inhibitor) plus erlotinib vs erlotinib alone, a statistically significant improvement in OS was also found in non-squamous patients favoring ARQ 197-209 and erlotinib combination. In another randomized phase II study investigating second-line erlotinib with or without ARQ-197 in patients with advanced NSCLC, primary objective of the trial (PFS) was met in 167 patients (HR: 0.68, 95%CI: 0.47 to 0.98; P < 0.05) and the phase III trial is ongoing. Furthermore, albeit in a small subgroup of patients, that trial showed an advantage in terms of PFS for the combination of erlotinib and ARQ-197 in K-RAS-mutated, EGFR wild-type and c-MET amplified subjects.
HDAC inhibitors: The HDACs act to tighten the bond between histones and DNA, thus inhibiting gene transcription by blocking binding sites on promoters. Inhibition of HDAC leads to induction of apoptosis in malignant cells. Vorinostat is currently the furthest along in the development. A phase I trial (NCT00702572) with carboplatin, paclitaxel, bevacizumab and vorinostat for patients with advanced NSCLC is recruiting patients. A number of other phase I clinical trials to examine the effect of vorinostat with other targeted treatments including inhibitors of EGFR, mTOR, and a proteasome inhibitor, NP10052 are ongoing.
PI3K-AKT-mTOR inhibitors: One downstream mutation that has been described in lung cancers with acquired resistance to TKIs is in PIK3CA, a gene encoding a protein in the PI3K/AKT/mTOR pathway. The PI3K/AKT pathway up-regulates mTOR in response to stimulation by growth factors. Loss of inactivating mutations of phosphatase and tensin homolog (PTEN) results in a gain in function of the PI3KCA gene. Phosphorylated AKT overexpression and loss of PTEN expression in NSCLC was shown to confer poor prognosis. Phase II study of everolimus (an oral mTOR inhibitor) plus erlotinib in previously treated patients with advanced NSCLC yielded a 11% difference in disease-control rate at 3 mo favoring the combination but did not meet the prespecified threshold to support a phase III study. Preclinical trials of PI3K inhibitors have shown efficacy, and research is ongoing[90,91]. A phase Ib trial is going to evaluate the combination of BYL719 (a selective inhibitor of PI3Kα) and the MEK inhibitor (MEK162). This international multicenter trial is not recruiting patients yet, but is expected to be completed by 2014 (NCT01449058).
IGF-1R inhibitors: Activation of the IGF-1R pathway has been noted as a consequence of EGFR inhibition in a variety of NSCLC cell lines, leading to cellular proliferation and evasion of apoptosis. Studies have also documented heterodimerization of EGFR and IGF-1R in response to stimulation with either EGF or IGF-1, the ligands for the two receptors. In a preclinical study, coinhibition of EGFR and IGF-1R resulted in synergistic growth inhibition of H1299NSCLCxenografts in vivo compared with treatment with erlotinib alone.
Unfortunately, the clinical studies have not been promising. A randomized phase II study of erlotinib in combination with R1507 (a recombinant monoclonal antibody against IGF-1R) did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. The absence of therapeutic benefit with EGFR inhibitor in combination with an IGF-1R-targeted agent was further substantiated by other phase III clinical trials[95,96]. The study evaluating the use of OSI-906 (IGF-1R TKI) in combination with erlotinib in patients with advanced NSCLC with activating mutations of the EGFR is ongoing but not actively recruiting patients (NCT01221077).
Recent research in NSCLC has focused on understanding the molecular abnormalities associated with NSCLC cell growth and proliferation and their impact on response to treatment and survival. In addition to histology, testing EGFR mutation and ALK rearrangement has now become the standard of care for treatment selection in NSCLC patients. However, only 20% of Western NSCLC patients have an activating EGFR mutation or ALK translocation. Targetable molecular abnormalities have not yet been identified in approximately 80% of NSCLC patients. Multiple targeted agents, including monoclonal antibodies and receptor TKIs, are at various stages of development and hold promise. The results from ongoing trials will determine if the newer targeted agents will be incorporated into clinical practice.
P- Reviewers Cadena MP, Vetvicka V S- Editor Wen LL L- Editor A E- Editor Xiong L
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002;346:92-98.
Jett JR, Schild SE, Keith RL, Kesler KA. Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (2nd edition).Chest. 2007;132:266S-276S.
Kelly K, Crowley J, Bunn PA, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.J Clin Oncol. 2001;19:3210-3218.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006;355:2542-2550.
Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer.J Clin Oncol. 2010;28:1835-1842.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol. 2008;26:3543-3551.
Zhang Y, Banerjee S, Wang Z, Xu H, Zhang L, Mohammad R, Aboukameel A, Adsay NV, Che M, Abbruzzese JL. Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer.Cancer Res. 2006;66:1025-1032.
Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS. Epidermal growth factor receptor (EGFR) signaling in cancer.Gene. 2006;366:2-16.
Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond.Mod Pathol. 2008;21 Suppl 2:S16-S22.
Bell DW, Brannigan BW, Matsuo K, Finkelstein DM, Sordella R, Settleman J, Mitsudomi T, Haber DA. Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms.Clin Cancer Res. 2008;14:4079-4084.
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, Milton DT, Strawn JR, Wakelee HA, Giaccone G. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) Mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy.J Clin Oncol. 2011;29:2121-2127.
Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer.J Clin Oncol. 2007;25:5777-5784.
Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, Pfeifer W, O’Byrne KJ, Welte T, Kolb R. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.Ann Oncol. 2008;19:362-369.
Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.J Clin Oncol. 2010;28:911-917.
Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.Lancet. 2009;373:1525-1531.
Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt WE, Paz-Ares L, Störkel S. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study.Lancet Oncol. 2012;13:33-42.
Lin H, Jiang J, Liang X, Zhou X, Huang R. Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: a systematic review and meta-analysis.Lung Cancer. 2010;70:57-62.
Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J, Tsuchihashi Z, Cantley LC. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations.J Natl Cancer Inst. 2005;97:1185-1194.
Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, Dakhil S, Hermann RC, Lynch TJ, Weber MR. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer.J Clin Oncol. 2010;28:918-927.
O’Byrne KJ, Gatzemeier U, Bondarenko I, Barrios C, Eschbach C, Martens UM, Hotko Y, Kortsik C, Paz-Ares L, Pereira JR. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study.Lancet Oncol. 2011;12:795-805.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer.Nat Rev Cancer. 2007;7:169-181.
Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer.J Clin Oncol. 2007;25:587-595.
Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma.J Clin Oncol. 2011;29:2972-2977.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004;350:2129-2139.
Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer.Clin Cancer Res. 2006;12:7232-7241.
Zhou C, Wu Y, Chen C, Chen G, Feng J, Liu X, Wang C, Zhang S, Wang J, Zhou S. Efficacy results from the randomised phase III optimal (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (gem), in chinese advanced nonsmall-cell lung cancer (NSCLC) patients (PTS) with egfr activating mutation.Ann Oncol. 2010;21:viii6.
Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC).Ann Oncol. 2013;Mar 1 [Epub ahead of print].
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2012;13:239-246.
Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, Jung SH, Park YH, Ahn JS, Park K. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy.Lung Cancer. 2012;75:82-88.
Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).Ann Oncol. 2013;24:993-999.
Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.Lancet Oncol. 2012;13:300-308.
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.Lancet Oncol. 2010;11:521-529.
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).J Clin Oncol. 2011;29:2866-2874.
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.N Engl J Med. 2010;362:2380-2388.
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.Lancet. 2008;372:1809-1818.
Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, Ahn MJ, Ahn JS, Suh C, Kim SW. Randomized Phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy.Clin Cancer Res. 2010;16:1307-1314.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL).Ann Oncol. 2010;21:1804-1809.
Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.J Clin Oncol. 2009;27:4247-4253.
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010;363:1693-1703.
Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol. 2011;12:1004-1012.
Crin L, Kim D, Riely GJ, Janne PA, Blackhall FH, Camidge DR, Hirsh V, Mok T, Solomon BJ, Park K. Initial phase 2 results with crizotinib in advanced ALK-positive nonsmall cell lung cancer (NSCLC): PROFILE 1005.J Clin Oncol. 2011;29:abstr 7514.
Camidge DR, Bang Y, Kwak EL, Shaw AT, Iafrate AJ, Maki RG, Solomon BJ, Ou SI, Salgia R, Wilner KD. Progression- free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive nonsmall cell lung cancer (NSCLC).J Clin Oncol. 2011;29:2501.
Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A. BRAF and RAS mutations in human lung cancer and melanoma.Cancer Res. 2002;62:6997-7000.
Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy?J Clin Oncol. 2010;28:4769-4777.
Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A, Flanagan A, Teague J, Wooster R, Futreal PA. COSMIC 2005.Br J Cancer. 2006;94:318-322.
Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, Atkins JN, Dakhil SR, Albain KS, Kim ES. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342.J Clin Oncol. 2010;28:4747-4754.
Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, Lamb ML, Kohman LJ, Poiesz BJ. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer.J Clin Oncol. 1999;17:668-675.
Li M, Liu L, Liu Z, Yue S, Zhou L, Zhang Q, Cheng S, Li RW, Smith PN, Lu S. The status of KRAS mutations in patients with non-small cell lung cancers from mainland China.Oncol Rep. 2009;22:1013-1020.
Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, Nafa K, Riedel ER, Hsu M, Pao W. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.Clin Cancer Res. 2008;14:5731-5734.
Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, Wagenaar SS, Vanderschueren RG, van Zandwijk N, Mooi WJ. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung.N Engl J Med. 1990;323:561-565.
Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis.Br J Cancer. 2005;92:131-139.
Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome.J Natl Cancer Inst. 2012;104:228-239.
Brugger W, Triller N, Blasinska-Morawiec M, Curescu S, Sakalauskas R, Manikhas GM, Mazieres J, Whittom R, Ward C, Mayne K. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer.J Clin Oncol. 2011;29:4113-4120.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.Cell. 2004;116:855-867.
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB. Somatic mutations affect key pathways in lung adenocarcinoma.Nature. 2008;455:1069-1075.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W. Mutations of the BRAF gene in human cancer.Nature. 2002;417:949-954.
Kobayashi M, Sonobe M, Takahashi T, Yoshizawa A, Ishikawa M, Kikuchi R, Okubo K, Huang CL, Date H. Clinical significance of BRAF gene mutations in patients with non-small cell lung cancer.Anticancer Res. 2011;31:4619-4623.
Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, Viola P, Pullara C, Mucilli F, Buttitta F. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations.J Clin Oncol. 2011;29:3574-3579.
Sen B, Peng S, Tang X, Erickson HS, Galindo H, Mazumdar T, Stewart DJ, Wistuba I, Johnson FM. Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib.Sci Transl Med. 2012;4:136ra70.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.PLoS Med. 2005;2:e73.
Hirsch FR, Varella-Garcia M, Bunn PA, Di Maria MV, Veve R, Bremmes RM, Barón AE, Zeng C, Franklin WA. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis.J Clin Oncol. 2003;21:3798-3807.
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.Nature. 2009;462:1070-1074.
Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer.Clin Cancer Res. 2011;17:5530-5537.
Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib.Cancer Res. 2007;67:11924-11932.
Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.J Clin Oncol. 2012;30:3337-3344.
Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.Lancet Oncol. 2012;13:528-538.
Horn L, Groen HJ, Smit EF, Janjigian YY, Fu Y, Wang F, Shahidi M, Denis L, Pao W, Miller VA. Activity and tolerability of combined EGFR targeting with afatinib (BIBW 2992) and cetuximab in T790M non-small cell lung cancer patients. 14th World Conference on Lung Cancer; 2011 Jul 3-7; Amsterdam, Netherlands. New York: Millennium Medical Publishing Inc.; 2011;.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Science. 2007;316:1039-1043.
Ciardiello F, Troiani T, Bianco R, Orditura M, Morgillo F, Martinelli E, Morelli MP, Cascone T, Tortora G. Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy.Ann Oncol. 2006;17 Suppl 7:vii109-vii114.
Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, Lifshits E, Byers LA, Xu L, Wu HK. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.Clin Cancer Res. 2009;15:3484-3494.
Lind JS, Dingemans AM, Groen HJ, Thunnissen FB, Bekers O, Heideman DA, Honeywell RJ, Giovannetti E, Peters GJ, Postmus PE. A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer.Clin Cancer Res. 2010;16:3078-3087.
Spigel DR, Burris HA, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, Whorf RC, Mitchell RB, Daniel DB, Zangmeister J. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer.J Clin Oncol. 2011;29:2582-2589.
Gridelli C, Morgillo F, Favaretto A, de Marinis F, Chella A, Cerea G, Mattioli R, Tortora G, Rossi A, Fasano M. Sorafenib in combination with erlotinib or with gemcitabine in elderly patients with advanced non-small-cell lung cancer: a randomized phase II study.Ann Oncol. 2011;22:1528-1534.
Miller VA, O'ConnorP , Soh C, Kabbinavar F. A randomized, doubleblind, 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. 2009;27:abstr LBA8002.
Zhang X, Li Y, Li H, Qin Y, Bai C, Xu F, Zhu T, Xu J, Wu M, Wang C. Combined EGFR and VEGFR versus single EGFR signaling pathways inhibition therapy for NSCLC: a systematic review and meta-analysis.PLoS One. 2012;7:e40178.
Kim ES, Salgia R. MET pathway as a therapeutic target.J Thorac Oncol. 2009;4:444-447.
Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, Del Grammastro M, Sciarrotta MG, Buttitta F, Incarbone M. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients.J Clin Oncol. 2009;27:1667-1674.
Ou SI, Salgia R, Clark JW. Comparison of crizotinib (PF-02341066) pharmacokinetics between Asian and non- Asian patients with advanced malignancies.J Thorac Oncol. 2010;5:S382.
Schiller JH, Akerley WL, Brugger W, Ferrari D, Garmey EG, Gerber DE, Orlov SV, Ramlau R. Von Pawel J, Seuist LV. Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC).J Clin Oncol. 2010;28:abstract LBA7502.
Spigel DR, Ramlau R, Daniel DB, Goldschmidt JH Jr, Blumenschein GR, Krzakowski MJ, Robinet G, Clement-Duchene C, Barlesi F, Govindan R. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC.J Clin Oncol. 2011;29:abstr 7505.
Sequist LV, von Pawel J, Garmey EG, Akerley WL, Brugger W, Ferrari D, Chen Y, Costa DB, Gerber DE, Orlov S. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer.J Clin Oncol. 2011;29:3307-3315.
Sandler A, Schiller JH, Hirsh V, Sequist LV, Soria J, Von Pawel J, Wang Q, Pande AU, Schwartz BE, Garmey EG. A phase III, randomized, double-blind, placebo-controlled study of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small cell lung cancer (NSCLC).J Clin Oncol. 2011;29:abstr TPS217.
Steele NL, Plumb JA, Vidal L, Tjørnelund J, Knoblauch P, Rasmussen A, Ooi CE, Buhl-Jensen P, Brown R, Evans TR. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors.Clin Cancer Res. 2008;14:804-810.
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications.Curr Cancer Drug Targets. 2008;8:187-198.
Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis.Lung Cancer. 2006;51:181-191.
Leighl NB, Soria J, Bennouna J, Blais N, Traynor AM, Papadimitrakopoulou V, Klimovsky J, Jappe A, Jehl V, Johnson BE. Phase II study of everolimus plus erlotinib in previously treated patients with advanced non-small cell lung cancer (NSCLC).J Clin Oncol. 2010;28:abstr 7524.
Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, Cappuzzo F, Sharma S, Gross SH, Dimitrijevic S. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors.Ann Oncol. 2009;20:1674-1681.
Ihle NT, Lemos R, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance.Cancer Res. 2009;69:143-150.
Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib.Clin Cancer Res. 2007;13:2795-2803.
Morgillo F, Woo JK, Kim ES, Hong WK, Lee HY. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib.Cancer Res. 2006;66:10100-10111.
Ramalingam SS, Spigel DR, Chen D, Steins MB, Engelman JA, Schneider CP, Novello S, Eberhardt WE, Crino L, Habben K. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer.J Clin Oncol. 2011;29:4574-4580.
Reidy DL, Vakiani E, Fakih MG, Saif MW, Hecht JR, Goodman-Davis N, Hollywood E, Shia J, Schwartz J, Chandrawansa K. Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer.J Clin Oncol. 2010;28:4240-4246.
Pao W, Girard N. New driver mutations in non-small-cell lung cancer.Lancet Oncol. 2011;12:175-180.
Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung.J Clin Oncol. 2012;30:1122-1128.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, Satouchi M, Tada H, Hirashima T, Asami K. Updated overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harbouring mutations of the epidermal growth factor receptor (EGFR).J Clin Oncol. 2012;30:abstr 7521.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).Ann Oncol. 2013;24:54-59.
Yang JCH, Schuler MH, Yamamoto N, O¡¯Byrne KJ, Hirsh V, Mok T, Geater SL, Orlov SV, Tsai CM, Boyer MJ, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah RNH, Massey D, Lorence RM, Shahidi M, Sequist LV. LUX-Lung 3: a randomized, openlabel, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations (abstract LBA7500). 2012 annual meeting of the American Society of Clinical Oncology; 2012 Jun 1-5; Chicago, IL.
Jänne PA, Wang X, Socinski MA, Crawford J, Stinchcombe TE, Gu L, Capelletti M, Edelman MJ, Villalona-Calero MA, Kratzke R. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial.J Clin Oncol. 2012;30:2063-2069.
de Boer RH, Arrieta Ó, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2011;29:1067-1074.
Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer.J Clin Oncol. 2011;29:1059-1066.
Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial.Lancet Oncol. 2010;11:619-626.
Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, Chen YM, Emerson L, Langmuir P, Manegold C. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR).J Clin Oncol. 2012;30:1114-1121.
Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer.J Clin Oncol. 2012;30:3084-3092.