Drug research and development continues to focus on regimens that select therapy according to the pathologic and molecular characteristics of the tumor.
Individualized treatment protocols for patients are becoming increasingly important in the management of NSCLC. Consequently, drug research and development continues to focus on regimens that select therapy according to the pathologic and molecular characteristics of the tumor, and thereby have the potential to enhance the poor patient outcomes currently associated with NSCLC. Treatment will increasingly focus on a genetic biomarker-based strategy to prolong patient survival, and next-generation technologies for genetic characterization of individual patients will be important to further develop a personalized treatment approach to NSCLC with molecularly targeted agents.
Histology and Predictive Biomarkers
Before 2005, chemotherapy was the standard of care for stage IV NSCLC, and typically consisted of platinum doublet chemotherapy. Subsequently, however, a major treatment paradigm shift resulted from the identification of driver mutations in genes that encode signaling protein important for cell proliferation, driving some NSCLCs. It is now the current standard of care in advanced NSCLC to assess tumors for these alterations, especially epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, both of which occur predominantly in adenocarcinomas. Consequently, histological determination of NSCLC subclasses in patients is required to identify tumors for molecular testing for these alterations or for selection of optimal therapy.1,2
More than 50% of NSCLC cases express at least one of 10 known molecular biomarkers that identify the gene mutations that drive some lung cancers.3,4 Mutations in KRAS are the most common,4,5 and these patients have few treatment options because they respond poorly to cytotoxic chemotherapy and are refractory to tyrosine kinase inhibitors (TKIs). The oral small-molecule multikinase inhibitor sorafenib targets numerous pathways, including the Ras/Raf pathway, which is involved in cell growth and survival. In a prospective study involving pretreated patients with NSCLC, patients with KRAS mutations were more likely to benefit from sorafenib. In KRAS-positive patients, the 8-week disease control rate was 79%, compared with the historical 8-week disease control rate of 30%.6 Data from another study in previously treated patients with advanced NSCLC and KRAS mutations demonstrated that sorafenib treatment resulted in median progression-free survival (PFS) of 3 months, and three partial remissions were also observed.5
EGFR mutations are the second most common, and studies have shown that patients with specific EGFR mutations benefit more from oral TKIs than patients with wild-type EGFR.7 These patients also experience a longer time to progression when treated with the oral EGFR inhibitors gefitinib or erlotinib as compared with conventional chemotherapy.8,9 Cetuximab, a monoclonal EGFR antibody, has also shown benefit in patients with NSCLC in combination with chemotherapy.10,11 Furthermore, data have demonstrated that patients with high EGFR expression levels, as indicated by immunohistochemistry, are more likely to benefit from this combination, especially in cases of adenocarcinoma.11
The ALK fusion gene is a less common oncogenic driver in NSCLC,12 and crizotinib is a selective small-molecule competitive inhibitor of this gene. One study demonstrated a complete or partial response to treatment in patients with ALK-rearranged advanced NSCLC,13 and data from a later study showed a median PFS of 9.7 months (95% CI, 7.7-12.8); the estimated overall survival (OS) at 6 and 12 months was 87.9% (95% CI, 81.3-92.3) and 74.8% (95% CI, 66.4-81.5), respectively.14
Bevacizumab is the only FDA-approved antiangiogenic agent for advanced nonsquamous forms of NSCLC, as well as being the most clinically significant one.15 It is a recombinant human monoclonal antibody that selectively binds to and neutralizes the biological activity of VEGF, thereby inhibiting angiogenesis.16-18 Bevacizumab has been shown to be effective as a first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC when combined with chemotherapy in two randomized phase III trials.19,20 Based on these results, it was subsequently approved by the FDA for first-line treatment of locally advanced, recurrent, or metastatic nonsquamous NSCLC.
Moreover, data from a meta-analysis of bevacizumab plus chemotherapy in advanced NSCLC confirmed that this regimen can be considered a standard option in selected patients with advanced NSCLC.21 Ongoing clinical trials continue to define the role of bevacizumab in the treatment of NSCLC, including its use in earlier stages of disease and in combination with other agents.22 Still, despite the success of bevacizumab, patients with advanced NSCLC who receive it will eventually experience disease progression.23
Data from two phase III trials has shown that bevacizumab combined with chemotherapy improves outcomes for patients with nonsquamous NSCLC. In patients with adenocarcinoma without EGFR mutation, median OS was 18.0 months.
In AVAPERL,24 a maintenance therapy trial, the effect of maintenance bevacizumab plus pemetrexed after first-line cisplatin/pemetrexed/bevacizumab in advanced NSCLC was investigated. All patients received the first-line, triple-combination therapy and were then randomized to maintenance bevacizumab alone or bevacizumab/pemetrexed. A 4-month improved OS was observed in patients taking the bevacizumab/ pemetrexed combination. It appears that pemetrexed clearly adds to bevacizumab, but it is not clear whether bevacizumab adds to pemetrexed.24
Clinical research remains ongoing to evaluate the role of bevacizumab in different settings, including its use as a single agent for continuation maintenance therapy in advanced NSCLC, treatment beyond disease progression, adjuvant therapy in early-stage disease, or in combination with other targeted agents.15
HER2-targeted agents have been shown to be useful in a small percentage of patients with NSCLC in which the HER2 mutation is found. In a large retrospective study involving 3800 patients, 65 (1.7%) had the HER2 mutation. All 65 cases were adenocarcinoma, and of these, most of the patients were female, and approximately half of them were never-smokers. Half of those individuals had stage IV NSCLC. Anti-HER2 drugs such as trastuzumab and afatinib were used to treat 16 patients, and some tumor shrinkage occurred after one round of treatment, with shrinkage in an additional two patients after a second round of therapy.25
Tyrosine Kinase Inhibitors
Two additional drugs that play an important role in the treatment of NSCLC are erlotinib and crizotinib. Erlotinib is an EGFR tyrosine kinase inhibitor (TKI), an orally administered small molecule that binds to the intracellular TK domain, and ultimately inhibits downstream cellular proliferation. 2 The drug originally gained FDA approval in 2004 for second-line treatment of NSCLC, as a result of data from the National Cancer Institute of Canada Clinical Trials Group Study BR.21. This investigated the efficacy of erlotinib in patients with previously treated stage IV NSCLC, and reported a 9% response rate and an OS of 6.7 months versus 4.7 months with placebo alone. The study was performed on an unselected patient population, however, and before the discovery of the sensitizing mutations in EGFR, and trials combining erlotinib and chemotherapy did not demonstrate increased benefit over chemotherapy alone. Subsequent trials, however, have demonstrated superior PFS and quality of life with initial treatment with erlotinib compared with platinum-based doublet therapy in patients with sensitizing somatic mutation.
In 2010, erlotinib was also approved for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. In a randomized, doubleblind, placebo-controlled trial of erlotinib in 889 such patients, median PFS was significantly longer with erlotinib than with placebo (12.3 weeks vs 11.1 weeks; hazard ratio [HR] = 0.71; 95% CI, 0.62-0.82; P <.0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib compared with EGFR-positive patients given placebo (median PFS, 12.3 weeks vs 11.1 weeks; HR = 0.69; 95% CI, 0.58-0.82; P <.0001).26
In May 2013, erlotinib was also approved for the first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. FDA approval was based on data from a randomized, multicenter, open-label trial comparing erlotinib to platinum-based doublet chemotherapy in such patients. Tumor samples from 134 patients were tested retrospectively by the cobs EGFR Mutation Test. The median PFS was significantly increased in patients treated with erlotinib compared with platinum-based chemotherapy (10.4 months vs 5.2 months; HR = 0.34; 95% CI, 0.23-0.49; P <.001). The median OS was also increased with erlotinib (22.9 months vs 19.5 months; HR = 0.93; 95% CI, 0.64-1.35; P =.6482), as was objective response rate (ORR) (65% vs 16%). Analysis of PFS in patients who had a positive cobas EGFR Mutation Test was also consistent with the primary analysis.27
The cobas EGFR Mutation Test, a companion diagnostic, is a real-time polymerase chain reaction-based test to detect and identify exon 19 deletion or exon 21 (L858R) substitution mutations in the EGFR gene in DNA derived from formalin-fixed, paraffin-embedded NSCLC tumor tissue. The test is to be used to identify patients whose tumors harbor these mutations.27,28
Crizotinib is an ALK TKI, an oral small-molecule ATP competitive inhibitor of ALK and c-MET. It is the only currently available ALK TKI, and was approved by the FDA in 2011, but only for use as a single agent in patients with NSCLC positive for ALK fusion.
In an expanded phase I trial involving 82 patients with advanced ALK-positive disease, most of whom were previously treated and had received two or more therapies, results showed a 57% overall response, with 33% of patients achieving stable disease. In a later study involving 143 ALK-positive NSCLC patients with advanced disease, an ORR was observed in 61% (95% CI, 52-69%) of patients treated with crizotinib. The median duration of response was 49 weeks, and the median PFS was 9.7 months. Six- and 12-month survival were 88% and 75%, respectively. Similar survival results were reported in a retrospective study, in which survival of 56 ALK-positive patients treated with crizotinib was similar (median survival time [MST] not reached) to 63 ALK-negative, EGFR-positive patients treated with an EGFR TKI (MST, 24 months), and superior to ALK-positive controls who did not receive crizotinib (MST, 20 months).2
All patients with EGFR mutations eventually acquire resistance to frontline treatment with TKIs. Studies have shown that the most common mechanism for this, accounting for up to 60% of cases, involves the T790M mutation. This secondary point mutation substitutes methionine for threonine at amino acid position 790.2
Overcoming Drug Resistance
The problem of resistance to the EGFR TKIs led to the development of second- and even third-generation EGFR TKIs, as well as the use of combination therapy involving EGFR inhibitors with other targeted agents.29
Afatinib, approved by the FDA in July 2013, is a secondgeneration TKI that irreversibly binds both HER2 and EGFR. Afatinib is approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test concurrently approved with the therapy, the therascreen EGFR RGQ PCR Kit.30
Afatinib broadly blocks the molecular pathways involved in cancer growth, contributing to its enhanced potency compared with other therapies. Data from the pivotal phase III LUX-Lung 6 trial demonstrated that afatinib was more effective than standard chemotherapy (gemcitabine plus cisplatin) for patients with locally advanced or metastatic NSCLC with an EGFR mutation. Afatinib increased PFS by 11.1 months, significantly better than the 6.9-month increase achieved with pemetrexed and cisplatin.30,31
“LUX-Lung 6 and LUX-Lung 3 together represent the largest clinical trial program in EGFR mutation-positive NSCLC patients,” noted Professor James Chih-Hsin Yang, director of the Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan. “The results of both trials have shown us that afatinib could offer lung cancer patients with EGFR mutations a significant delay in tumor growth, and a better quality of life, compared to current standard of care chemotherapies.”
Nintedanib is an investigational triple angiokinase inhibitor that targets three receptor tyrosine kinases involved in the regulation of angiogenesis: VEGFR, fibroblast growth factor (FGF) receptor, and platelet-derived growth factor (PDGF) receptor. In the LUME-Lung 2 clinical trial, nintedanib plus pemetrexed was compared with pemetrexed plus placebo in patients with advanced NSCLC who relapsed after first-line chemotherapy. The trial was halted prematurely but showed a significant improvement in PFS, and patients treated with nintedanib plus pemetrexed lived for a median of 4.4 months before tumor growth resumed, compared with 3.6 months with pemetrexed and placebo (HR = 0.83; P=.04).31
“The results of the LUME-Lung 1 trial are particularly exciting because we have not seen any advances in overall survival for NSCLC patients receiving second-line treatment in nearly 10 years. Additionally, this is the first time an antiangiogenic treatment has shown a real benefit for NSCLC patients after initial chemotherapy has failed,” said Martin Reck, MD, PhD, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, and principal investigator of the LUME-Lung 1 trial. “It is important to understand that NSCLC patients have a very poor prognosis as their tumor will inevitably progress after first-line treatment. Nintedanib may therefore provide a muchneeded new option for treatment.”
LDK378, a selective ALK inhibitor, is another investigational drug in clinical trials. In a phase I study involving 78 patients, there was a 60% overall response rate in patients with ALK-positive NSCLC who had experienced disease progression after crizotinib treatment. Phase II clinical trials are currently under way to further investigate this response, and several phase III studies are planned for later this year, with first regulatory filing anticipated by early 2014.32,33
“These results confirm that LDK378 has activity in patients with ALK-positive NSCLC, including those who have progressed on crizotinib, as well as those who haven’t taken crizotinib,” said lead investigator Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer Center, Boston. “LDK378 may become another standard targeted therapy for these ALK-positive patients.”
The effectiveness of immunotherapy using monoclonal antiprogrammed death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies has been demonstrated in metastatic NSCLC. In a recent phase I trial of the anti-PD-L1 monoclonal antibody nivolumab (BMS 936558), 129 patients with previously treated advanced NSCLC were treated with three different dosages: 1 mg/kg, 3 mg/kg, and 10 mg/kg. Of the 75 patients with NSCLC, 49 were evaluable for response. Objective response was seen in five of the 49 patients. Tumor response was seen in squamous (1 of 13 patients; 8%) and nonsquamous (4 of 36 patients; 11%) histologies. An additional six patients (12%) had stable disease for at least 6 months.34 These results further support previous findings and suggest that PD-1 inhibition may be a feasible strategy in NSCLC.