New Targets and New Mechanisms in Lung Cancer

New Targets and New Mechanisms in Lung Cancer

Figure 1: Therapeutic Targets in Lung Cancer
Figure 2: Schematic of Immune Checkpoint Mechanisms—CTLA-4
Figure 3: Schematic of Immune Checkpoint Mechanisms—Anti–PD1/PD-L1
Figure 4: A Proposed Algorithm for a Personalized Systematic Approach ...

ABSTRACT: With the advent of the importance of histology in non–small-cell lung cancer (NSCLC) and the development of targeted agents that work on newly found mutations, the field of lung cancer therapy has greatly changed. In addition to new uses of chemotherapeutics and targeted agents, the possibilities of immunotherapy are also being explored. This review will describe the well-known use of vascular endothelial growth factor (VEGF) antibodies; the current uses of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors; newer agents being used against MET, fibroblast growth factor receptor (FGFR), and other intracellular targets; insights regarding the field of immunotherapy in lung cancer; and finally, newer developments in chemotherapy.


Lung cancer is the second most common form of cancer and the most common cause of cancer-related deaths in men and women, yet cure rates are significantly lower than those of other less prevalent cancers, such as cancers of the breast and colon. More than two decades ago, very few treatments were available for lung cancer; over time, however, we have made modest strides in finding new forms of chemotherapy and new treatment targets.

Especially in the last several years, significant advances have been made in personalized chemotherapy choices, based on histology and on the availability of targeted agents that are effective and less-toxic options for lung cancer patients. The first of these targeted agents was bevacizumab (Avastin), a humanized monoclonal antibody directed at vascular endothelial growth factor (VEGF), which was associated with an improvement in overall survival (OS) in non–small-cell lung cancer (NSCLC) when added to carboplatin and paclitaxel.[1] With the success of bevacizumab as a model, newer therapies are constantly being investigated, and this review aims to provide an overview of current practice, with insights into future management. (Figure 1 highlights some current and emerging targets and targeted therapies in lung cancer.)

Epidermal Growth Factor Receptor (EGFR)

The evolution of the epidermal growth factor family’s importance in malignancy and as a therapeutic target dates back to 1962, when Stanley Cohen isolated a novel protein from mice that demonstrated increased growth of incisors and eyelids in newborn animals.[2] This protein, now called epidermal growth factor, includes a family of ligands and receptors; somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are found in 15% to 20% of lung adenocarcinomas, with deletion 19 and L858R representing almost 90% of these EGFR mutations. Two classes of agents targeting EGFR have been investigated extensively in patients with NSCLC: the tyrosine kinase inhibitors (TKIs) and the monoclonal antibodies (mAbs).

Gefitinib and erlotinib (Tarceva) bind in a reversible fashion to the adenosine triphosphate (ATP) binding site of EGFR tyrosine kinase, inhibiting initiation of signaling cascades. Through numerous studies, it became clear that responses to these targeted agents did not emerge from unselected populations. Significant results were not seen just with specific patient characteristics or even EGFR amplification but instead noted in patients with specific EGFR mutations.

With this evolving knowledge, gefitinib and erlotinib were brought to the front-line treatment of patients with advanced NSCLC harboring EGFR mutations, and by December 2010, results of multiple randomized phase III trials comparing front-line erlotinib or gefitinib against platinum-based chemotherapy in patients with advanced NSCLC were reported. The Iressa Pan-Asia Study (IPASS), First-SIGNAL, the North-East Japan Study Group NEJ002 trial, and the West Japan Thoracic Oncology Group trial 3405 (WJTOG3405) are four studies that involved gefitinib, while EURTAC and OPTIMAL utilized erlotinib; all of these investigations highlighted the distinct nature of EGFR-mutated lung cancer and its selected response to TKI intervention.[3-10] In EGFR-mutated tumors, erlotinib/gefitinib consistently provided benefit across these studies in terms of progression-free survival (PFS), response rate (RR), and quality of life (QoL) compared with chemotherapy. Specifically, EURTAC randomized 165 patients between erlotinib and carboplatin/gemcitabine, and showed a PFS improvement of 8.5 months (13.1 vs 4.6 months; P < .0001); OPTIMAL randomized 173 patients between erlotinib and chemotherapy (platinum with docetaxel or gemcitabine) and showed an improvement in PFS of 4.5 months (9.7 vs 5.2 months; P < .0001).[9,10] None of the studies demonstrated an OS advantage, likely due to high rates of cross-over to the alternative therapy at the time of disease progression. The results of these trials demonstrate that testing for EGFR mutations should be a standard, to identify those who would benefit from front-line EGFR-TKI treatment.

Despite the benefits derived from treatment with gefitinib/erlotinib, acquired resistance develops. The mechanisms of resistance and means of overcoming them have become active areas of research. Amplification of MET and T790M mutations account for 20% and 50%, respectively, of these cases.[11] Irreversible EGFR inhibitors, targeted therapies against MET, and dual-pathway blockades have activity in this resistant population.

Afatinib is an irreversible ErbB family blocker that covalently binds to the cysteine residue of EGFR, providing longer inhibition of EGFR. Compelling data on afatinib from LUX-Lung 3 have been reported. In this open-label, randomized phase III study, patients with EGFR-mutated, advanced lung adenocarcinoma received front-line treatment with either afatinib or cisplatin-pemetrexed. Those treated with afatinib demonstrated a prolonged PFS (11.1 vs 6.9 months; hazard ratio [HR] = 0.58; P = .0004).[12] In the preplanned analysis, those with common mutations (Del19 or L858R) had a median PFS of 13.6 vs 6.9 months (HR = 0.47; P < .0001). The RR was significantly higher with afatinib (56.1% vs 22.6%, P < .001 in all patients; and 60.8% vs 22.1%, P < .0001 in patients with common mutations). There were also improvements in the 1-year disease-control rate, cancer-related symptoms, and QoL with afatinib. The most frequent adverse events were diarrhea and rash, although no patients discontinued afatinib because of rash. LUX-Lung 3 is the first randomized study to demonstrate benefit of an oral targeted therapy vs chemotherapy in a molecularly selected population. Afatinib has also demonstrated benefit in those previously treated with EGFR TKIs.[13] Based on these results, afatinib is currently available to those who are both TKI-naive and TKI-resistant, through an open-label expanded-access program.

Cetuximab (Erbitux), a chimeric monoclonal IgG1 antibody that blocks EGFR signaling, has been investigated in the front line in combination with platinum-based chemotherapy in advanced NSCLC through two multicenter, randomized phase III trials. The First-Line ErbituX in lung cancer (FLEX) trial and the Bristol-Myers Squibb (BMS) 099 study both revealed statistically significant increases in RR with the addition of cetuximab to chemotherapy, and both demonstrated about a 1.3-month increase in OS, although BMS 099 lacked the power to detect a statistically significant difference of this magnitude.[14,15] These results are in contrast to those found with EGFR-TKIs combined with chemotherapy, which may be attributed to the different mechanism of action of the monoclonal antibody. Despite the positive results from FLEX, cetuximab has not been approved for treatment of NSCLC.

However, cetuximab is being investigated further in combination with other targeted therapies. Bevacizumab and cetuximab have shown promising results in the Southwest Oncology Group (SWOG) 0536 trial.[16] In this safety-and-efficacy phase II single-arm study, approximately 100 patients with advanced NSCLC were treated front-line with carboplatin, paclitaxel, bevacizumab, and cetuximab. The feasibility endpoint was met, and secondary endpoints revealed an RR of 53%, PFS of 7 months, and OS of 14 months. These results have led to the ongoing phase III SWOG 0819 trial of carboplatin-paclitaxel and bevacizumab (in eligible patients), with or without cetuximab, in patients with advanced NSCLC.

Additionally, cetuximab has shown response in combination with afatinib. In a trial with combination afatinib-cetuximab in patients with EGFR mutations and disease progression on erlotinib, disease control was observed in all 22 patients treated with the 40-mg dose of afatinib, with tumor size reduction of up to 76%.[17] This is under further investigation with an ongoing expanded cohort.

Dacomitinib (PF-00299804) is a pan-HER inhibitor that binds irreversibly to the ATP domain of EGFR, HER2, and HER4 and has demonstrated EGFR inhibition in cell lines harboring L858R and T790M mutations.[18,19] In a global phase II study, 188 patients were randomized to dacomitinib or erlotinib after progression on chemotherapy. PFS (primary endpoint) was improved with dacomitinib (2.86 vs 1.91 months; HR = 0.66; P = .012), suggesting that dacomitinib is another potential treatment option.[20]

KD019/XL647 is a small-molecule TKI that targets EGFR, VEGFR-2, HER2, and Ephrin type B receptor 4. In a phase II study evaluating two dosing regimens, the RR was 20% and the PFS was 5.3 months. In patients with EGFR mutations, the RR was 57% and the PFS was 9.3 months.[21] This is a compound that will continue to undergo clinical evaluation.

A number of agents targeting parallel and downstream signaling of the EGFR pathway are under development for the treatment of NSCLC, including MET inhibitors. The rationale for dual inhibition of EGFR and MET for treatment of NSCLC is based on evidence that MET is associated with resistance to erlotinib and gefitinib, and preclinical and clinical data suggest that this combination has additive or synergistic antitumor activity which may overcome resistance.[22-24]

Tivantinib (ARQ 197) is an oral, selective, non–ATP-competitive inhibitor of MET receptor tyrosine kinase. A global randomized, double-blind, placebo-controlled phase II trial compared erlotinib plus ARQ 197 vs erlotinib plus placebo in EGFR inhibitor–naive patients with advanced NSCLC. In this 167-patient trial, median PFS (primary endpoint) was prolonged with combination therapy (16.1 vs 9.7 weeks; HR = 0.81; 95% confidence interval [CI], 0.57–1.15; P = .23).[25] Based on these promising data, the MARQUEE (Met inhibitor ARQ 197 plus Erlotinib vs Erlotinib plus placebo in NSCLC) trial was designed as a phase III, randomized, double-blind study of tivantinib plus erlotinib vs placebo plus erlotinib in previously treated patients with advanced non-squamous NSCLC, with a primary endpoint of OS.[26]

The agent onartuzumab/MetMAb (OAM4558) inhibits hepatocyte growth factor/scatter factor (HGF/SF)—a tissue-derived cytokine—from binding to MET, while its monovalent structure prevents dimerization/activation of the MET signaling pathway.[27] Studies have shown that the activation of MET by the binding of HGF/SF in tumors may lead to cell proliferation, increased cell survival, and induction of motility and invasion via modification of cell-to-cell adhesion, thus leading to poor prognosis, especially in lung cancer.[28,29] A global randomized, double-blind, placebo-controlled phase II study compared erlotinib plus onartuzumab vs erlotinib plus placebo in the second- or third-line management of advanced NSCLC. The addition of MetMAb to erlotinib significantly improved PFS and OS in patients who had high expression of MET in their tumors, resulting in a near two-fold reduction in the risk of disease progression and a three-fold reduction in the risk of death.[30] This is being followed by the MetLung study, a randomized, phase III, multicenter, double-blind, placebo-controlled study in patients with advanced NSCLC and MET-positive tumors who have failed at least one line but no more than two prior lines of platinum-based chemotherapy; the primary endpoint is OS.[31]

In conclusion, targeting the EGFR pathway for treatment of NSCLC continues to expand from the reversible EGFR TKIs to the irreversible EGFR TKIs and other monoclonal antibodies that, used as single agents and in combination with other novel therapies, remain a backbone of management for those who harbor EGFR mutations.

Anaplastic Lymphoma Kinase (ALK)

ALK was originally identified in patients with anaplastic large cell lymphoma, a subset of B-cell non-Hodgkin lymphoma.[32] The ALK gene also plays a key role in the pathogenesis of inflammatory myofibroblastic tumors and in neuroblastoma, but it was never observed to be important in lung cancer until two groups discovered ALK rearrangement in NSCLC in 2007.[33,34] The potential driver mutation is a fusion of an intrachromosomal inversion on the short arm of chromosome 2 that joins exons 1–13 of the Echinoderm microtubule-associated-protein like 4 gene (EML4) to exons 21–29 of ALK.[33-35] The resulting EML4-ALK is a fusion of the N-terminal portion of the protein encoded by EML4, with the intracellular signaling portion of the receptor tyrosine kinase encoded by the ALK gene.[33,34] This EML4-ALK fusion gene seems novel to NSCLC.

Generally, the incidence of ALK-rearranged NSCLC is 3% to 5%.[35-37] One study showed a 13% incidence in metastatic NSCLC in Western populations and a 22% incidence in never/light smokers.[35] In Asian patients negative for EGFR and KRAS mutations, ALK fusion was seen in 17%.[38] Clinical signs of ALK rearrangement in NSCLC are unclear; hence, molecular testing is necessary. There are three methods of detecting ALK rearrangement: a fluorescence in situ hybridization (FISH) break apart assay, immunohistochemistry (IHC), and reverse-transcriptase polymerase chain reaction (RT-PCR). FISH is the current gold standard and is the companion diagnostic test (Vysis ALK break apart FISH probe kit; Abbott Molecular Inc) approved by the US Food and Drug Administration (FDA) in conjunction with conditioned approval of crizotinib (Xalkori) in the United States.[35,39-41]

Crizotinib is an oral, small-molecule competitive ATP inhibitor, primarily of MET, and it also has selective ALK inhibition.[35,36,39] It was first studied in humans in 2006 in the PROFILE 1001 study, using an initial standard dose-escalation pharmacokinetic schema followed by a clinical efficacy evaluation. After two patients in this phase I study had a dramatic response (coinciding with the discovery of ALK gene rearrangements in patients with NSCLC), an expanded prospective cohort was enrolled, with testing for ALK rearrangement.[42] Updated results from September 2012 showed a 60% RR (3 complete responses, 84 partial responses), a median time to first documented objective response of 8 weeks, and a median duration of response of 49 weeks. Overall survival data are not yet mature, but estimated 6- and 12-month OS rates are 87.9% and 74.8%, respectively.[43]

Response to crizotinib is independent of age, sex, performance status, and prior treatment.[43] Upon the initial results of PROFILE 1001, a multicenter open-label phase II study (PROFILE 1005) was initiated. Recent data from this study showed a response rate of 60%; the median PFS was 8.1 months and the median response duration was 46 weeks, with responses appearing at 6 weeks.[44]

Crizotinib gained FDA approval in August 2011 for locally advanced or metastatic NSCLC that is ALK-positive, based on the previously described studies reporting response rates alone. Preliminary results of the prospective randomized phase III trial (PROFILE 1007) comparing crizotinib and either pemetrexed (Alimta) or docetaxel in the second-line setting were recently presented in Vienna at the 2012 meeting of the European Society for Medical Oncology (ESMO). The primary endpoint of PFS was 7.7 months in the crizotinib arm and 3 months in the chemotherapy arm. The RRs were 65% and 20%, respectively. Interim OS data showed no difference, but OS may be skewed secondary to patient crossover.[45]

Currently, the National Comprehensive Cancer Network (NCCN) guidelines give a category 2A recommendation for the ALK inhibitor crizotinib in the first-line setting in patients with locally advanced or metastatic NSCLC who have the ALK gene rearrangement.[46] The NCCN also recommends FISH as the standard diagnostic test until further evidence regarding use of RT-PCR and IHC for assessing ALK status becomes available.

ALK-rearranged NSCLC has developed resistance to crizotinib. Some mechanisms of resistance include acquired or secondary resistance via mutations in six amino acid residues in ALK, coactivation of EGFR signaling, secondary point mutations in the ALK TKI domain, ALK gene amplification, and loss of the ALK fusion gene and the activation of other kinases.[47]

Several other ALK inhibitors are in the development pipeline, with investigative goals aiming for more selective ALK inhibition and the overcoming of crizotinib resistance. Some are selective ALK inhibitors like AP26113, CH5424802, LDK378, ASP3026, and X396. AP26113 is ALK/EGFR-specific, hence it has the potential to overcome crizotinib resistance mediated by EGFR activation. Recently, the FDA granted “breakthrough therapy” designation to LDK378, allowing expedited development of the drug (of note, this designation is distinct from that of priority review or that of accelerated approval.)[48] Two heat shock protein 90 (HSP90) inhibitors, retaspimycin and ganetespib, have demonstrated clinical activity in patients with ALK-rearranged NSCLC. HSP90 is a chaperone protein, and its inhibition leads to rapid degradation of EML4-ALK, resulting in tumor regression and cell death.[35,36]


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