Despite the success of the EGFR inhibitors in patients with activating mutations, who have frequent and durable responses compared to standard chemotherapy, essentially all eventually develop tumor progression. The most common mechanism of acquired resistance to EGFR TKIs is the presence of the T790M mutation in exon 20, representing approximately 50% of cases. Other causes include MET amplification, PIK3CA mutations, and transformation to small cell histology.29 Potential ways to overcome resistance include agents that bind irreversibly to EGFR or target downstream mediators of EGFR signaling; target multiple EGFR family members; and/or simultaneously inhibit EGFR, the MET pathway, and other signaling pathways. Irreversible EGFR inhibitors currently in development include dacomitinib, an inhibitor of EGFR/HER-1, HER-2, and HER-4, and afatinib (BIBW 2992), an inhibitor of EGFR/HER-1, HER-2, and HER-4.30

VEGF Vascular endothelial growth factor (VEGF) is the major regulator of angiogenesis in both normal and tumor tissues.31 Several cancers, including NSCLC, have demonstrated increased VEGF expression. Bevacizumab, a humanized monoclonal antibody to VEGF, was approved in 2006 for the first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC in combination with carboplatin and paclitaxel. The approval was based on a phase 3 trial conducted by Sandler and colleagues that demonstrated a survival benefit when bevacizumab was added to paclitaxel plus carboplatin in patients with NSCLC.32 The trial was limited to patients with non-squamous cell histology because previous clinical trial data had suggested an increased incidence of fatal hemoptysis in patients with squamous cell NSCLC.33 The median PFS was 6.2 months with bevacizumab plus chemotherapy versus 4.5 months with chemotherapy alone (HR for disease progression = 0.66; P < 0.001), and response rates were 35% and 15% (P < 0.001), respectively. In a second study, the AVAiL trial, the addition of bevacizumab to chemotherapy with cisplatin and gemcitabine prolonged PFS but not overall survival (OS).34


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Although several multitargeted VEGF TKIs have been tested in advanced NSCLC, none met the primary endpoint, although toxicity was increased.35 Thus, bevacizumab remains the only approved antiangiogenic agent in this setting.

ALK Crizotinib is a selective adenosine-5′-triphosphate (ATP)-competitive ALK and mesenchymal epithelial transition factor (MET)/hepatocyte growth factor (HGF) TKI that received accelerated FDA approval in August 2011 for the treatment of patients with locally advanced or metastatic NSCLC positive for ALK rearrangements through detection by a United States FDA-approved method. Such ALK rearrangements are estimated to occur in approximately 3% to 5% of NSCLC cases. Approval of crizotinib was based on the results of a phase 1/2 trial showing an overall response rate of 57% (47 of 82 patients), with an additional 33% (27 patients) achieving stable disease, mostly through minor responses below 30% reduction from baseline tumor size.36 At the time of study cut-off, the median PFS had not been reached, with a 72% probability of the 6-month PFS being met. In the 2011 update, the 1-year and 2-year OS rates were 77% and 64%, respectively.37 In the PROFILE 1005 study, the preliminary results with the first 439 evaluable patients showed an overall response rate (ORR) of 53% and a PFS of 8.5 months.38 Although approximately half of the patients experienced visual effects, nausea, and vomiting, adverse effects were mostly mild, and the drug was very well tolerated. Phase 3 trials of first-line crizotinib versus chemotherapy (NCT01154140) as well as second-line crizotinib monotherapy (NCT00932893) for patients with ALK-positive tumors are underway.


ADVANCES IN UNDERSTANDING OF NSCLC BIOLOGY


Treatment decisions for patients with lung cancer have historically been based on tumor histology. However, the pretreatment detection of response-predictive markers could facilitate a more personalized approach to therapy whereby the most appropriate and efficacious treatment can be selected for each patient. One such approach is treatment directed at driver mutations, such as the previously reviewed mutations in EGFR and ALK.39 Although such therapies are associated with high and prolonged responses, only a minority of such patients harbors the target mutations. Therefore, a new approach is needed for the vast majority of patients.


Molecular predictors for response to chemotherapy have recently emerged, including excision repair cross-
complementing 1 (ERCC1), regulatory subunit of ribonucleotide reductase (RRM1), breast cancer 1 (BRCA1)/receptor-associated protein 80 (RAP80), and thymidylate synthase (TS).40,41

ERCC1 The ERCC1 gene codes for the 5′ endonuclease of the nucleotide excision repair complex (NER) complex, which repairs DNA damage, thereby mediating resistance to various chemotherapies by repairing chemotherapy-induced DNA damage. ERCC1 levels can be predictive of platinum sensitivity and provide prognostic information.42,43 In the International Adjuvant Lung Trial (IALT), patients were randomized to receive cisplatin-based doublet chemotherapy or observation.44 Chemotherapy increased OS by 4%, but no benefit was observed with chemotherapy in patients with ERCC1-positive tumors. However, patients with ERCC1-positive tumors had a better overall prognosis than those with ERCC1-negative tumors, with a 5-year survival rate in the observation arm of 46% versus 39% (HR = 0.66; 95% CI, 0.49-0.90; P < 0.009). Several trials evaluating the predictive utility of ERCC1 are currently accruing patients.


RRM1 Regulatory subunit of ribonucleotide reductase (RRM1) encodes an enzyme involved in DNA repair and synthesis. As with ERCC1, expression of RRM1 has been associated with prognosis in NSCLC, with longer survival reported in patients with high expression.44 RRM1 expression is also considered to be a strong predictor of therapeutic efficacy with gemcitabine-based chemotherapy. A recent meta-analysis of 18 trials found that the response rates to gemcitabine-containing regimens were significantly higher in patients with low or negative RRM1 (odds ratio [OR] = 0.31; 95% CI, 0.21-0.45; P < 0.00001).45 These patients also had a 3.94-month longer survival (95% CI, 2.15-5.73; P < 0.0001) and a 2.64-month longer time to progression (95% CI, 0.39-4.89; P = 0.02) than those with high or positive RRM1.


BRCA1/RAP80 Another predictive biomarker is BRCA1, a tumor suppressor gene involved in the repair of DNA double-strand breaks through homologous recombination and transcription-coupled nucleotide excision repair.46,47 The associated marker RAP80 is a ubiquitin-binding protein that may specifically recognize DNA damage and help target the BRCA1 complex to these sites.48,49 Although BRCA1 mutations are linked to an increased risk of breast and ovarian cancer in women, BRCA1 has also emerged as a potential predictive biomarker for chemotherapy in NSCLC, with decreased expression associated with cisplatin sensitivity and increased expression predictive of improved outcomes with taxanes and other antimicrotubulin agents.50 In one study, 123 patients with metastatic NSCLC were selected for treatment using a customized approach based on their BRCA1 mRNA levels. Patients with low levels received cisplatin plus gemcitabine, those with intermediate levels received cisplatin plus docetaxel, and those with high levels received docetaxel alone.51 The results suggested that chemotherapy customized according to BRCA1 expression level was associated with excellent median and 2-year survival. This outcome was potentially influenced by RAP80 expression in the three BRCA1 groups; in patients with both low BRCA1 and low RAP80 levels, median survival with cisplatin plus gemcitabine treatment exceeded 26 months.