|Year : 2017 | Volume
| Issue : 1 | Page : 83-88
Targeted therapy in nonsmall cell lung cancer
Senior Medical Advisor - Oncology, Eli Lilly and Company, Gurgaon, Haryana, India
|Date of Web Publication||1-Dec-2017|
Dr. T Puri
Senior Medical Advisor - Oncology, Eli Lilly and Company, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Activating mutations in the epidermal growth factor receptor gene and rearrangement of the anaplastic lymphoma kinase gene exemplify the molecular characterization of nonsmall cell lung cancer (NSCLC), particularly adenocarcinoma, and its therapeutic relevance. Several genetic alterations with prognostic and predictive role, including ROS, RET, MET, KRAS, have now been identified in adenocarcinoma and some such as DDR2 and fibroblast growth factor receptor 1 in squamous cell carcinoma. This has heralded the development of agents targeted against these aberrations. Better knowledge of tumor biology and development of targeted agents has ushered an era of personalized treatment strategies in NSCLC, leading to improvements not only in tumor control and duration of life but also in quality of life.
Keywords: Lung cancer, nonsmall cell, targeted therapy
|How to cite this article:|
Puri T. Targeted therapy in nonsmall cell lung cancer. Indian J Cancer 2017;54:83-8
| » Introduction|| |
Lung cancer has been historically divided by histology into small cell and nonsmall cell lung cancer (NSCLC), with NSCLC being further subdivided into squamous cell carcinoma (SCC), adenocarcinoma, and large cell carcinoma. Adenocarcinoma constitutes the majority of NSCLC. Despite meaningful increments in the survival of advanced NSCLC with the use of platinum-based chemotherapy, lung cancer is still the most common cause of cancer-specific mortality worldwide.
The recent years have seen a significant progress in the understanding of genetic abnormalities and protein expression; together with histology, these have paved the way for molecular classification of NSCLC., Consequent to genetic alterations, tumors can become dependent for proliferation and survival, on a single oncogene, known as “driver oncogene.” Some studies have also shown that these genetic alterations may not only be necessary for development or progression of a tumor but are also required for tumor survival, being referred to as “oncogene addiction.” This is a rational basis of the development of targeted therapies.
Mutations of epidermal growth factor receptor (EGFR) gene and rearrangement of anaplastic lymphoma kinase (ALK) gene have already been established as therapeutic targets. Drugs inhibiting these targets have shown improved clinical outcomes in patients with NSCLC whose tumors express these mutations.
Identification of new molecular targets and development of novel therapies against them are significant steps in achieving the goal of personalized therapy in lung cancer. This review focuses on some of the recently identified molecular targets in NSCLC, their therapeutic implications, and conduct of biomarker-driven research.
| » Molecular Targets in Nonsmall Cell Lung Cancer|| |
Improved outcomes have been achieved for patients with NSCLC using drugs against specific targets. The results however have been favorable in patients whose tumors have predictive markers, rather than in unselected populations. [Figure 1] denotes the triad of successful targeted therapy in oncology, namely, presence of a druggable target, development of an agent against the target, and identifying a marker that predicts favorable outcomes.
The best established oncogenic targets for management of advanced NSCLC so far are EGFR mutations and EML4-ALK translocations. However, a majority of lung cancers, especially squamous cancers, do not have druggable targets, and even if a targeted agent is developed, primary or acquired resistance develops in a number of cases.
Epidermal growth factor receptor
EGFR is a growth signal receptor that controls cell proliferation and survival. It is a member of a family of cell surface receptors that dimerize on ligand binding, thereby activating the intracellular tyrosine kinase domain and triggering downstream pathways that lead to cell proliferation, angiogenesis, and metastases. Targeting the EGFR pathway represents a novel approach to treating NSCLC.
Mutation of EGFR gene on chromosome 7 is a proven oncogenic driver mutation in NSCLC and has been the focus of extensive research since its discovery in 2004. EGFR mutation-positive lung cancer is now recognized as a unique disease entity, different from EGFR wild-type lung cancer or lung cancer with another oncogenic driver. EGFR mutations are present in approximately 10% of Caucasians and 40% of Asians, predominantly in adenocarcinoma.
Strategies to inhibit EGFR pathway include monoclonal antibodies (Mabs) or EGFR tyrosine kinase inhibitors (TKIs, including first-generation reversible inhibitors gefitinib and erlotinib and second-generation irreversible inhibitors afatinib and dacomitinib). Cetuximab is an IgG1 Mab that binds to the extracellular ligand-binding domain of EGFR, induces its internalization, thereby inhibiting downstream signaling. Phase II and Phase III studies comparing chemotherapy with or without cetuximab have shown a modest improvement in survival with the combined treatment in patients with advanced NSCLC. The FLEX study (vinorelbine and cisplatin with/without cetuximab in advanced NSCLC) showed a median overall survival (OS) of 11.3 months versus 10.1 months (hazard ratio [HR] 0.871, 95% confidence interval [CI] 0.762–0.996; P = 0.044) favoring the cetuximab arm. This improvement was however not recognized by regulatory agencies, and cetuximab has not been approved for use in lung cancer patients. In addition, while EGFR is a potential target in NSCLC, not all patients with EGFR expression benefit from therapy with cetuximab. There is however evidence from the FLEX study that high EGFR expression is a tumor biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy.
Early development of the EGFR TKIs focused on patients with clinical characteristics, specifically, Asian ethnicity, female gender, never/light smokers, and adenocarcinoma. Only subsequently, it was discovered that these characteristics enriched the population for activating EGFR mutations. The predictive power of an EGFR mutation was confirmed in the Iressa Pan Asian Study which was a randomized Phase III study comparing first-line gefitinib with standard chemotherapy (paclitaxel and carboplatin) in 1217 Asian nonsmokers/light smokers with pulmonary adenocarcinoma. A subgroup analysis of 417 patients with known EGFR mutations showed improvement in progression-free survival (PFS) in patients receiving gefitinib in the presence of activating EGFR mutations (HR 0.48, 95% CI 0.36-0.64) while there was a detrimental effect in patients with EGFR wild-type tumors (HR 2.87, 95% CI 2.05–3.98). The interaction between treatment and EGFR mutation with respect to PFS was statistically significant (P<0.001).
Thus far, eight randomized Phase III trials on first- and second-generation TKIs, including gefitinib, erlotinib, and afatinib, have shown similar improvements in response rates and PFS [Table 1]. None of these studies has however shown an improvement in OS owing to crossover of chemotherapy-treated patients to a TKI on progression.
|Table 1: Randomized trials comparing epidermal growth factor receptor tyrosine kinase inhibitor with chemotherapy in patients with activating epidermal growth factor receptor mutations|
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The combination of chemotherapy and EGFR TKIs has been the subject of research for more than a decade. Before the discovery of EGFR mutation, four randomized studies comparing chemotherapy alone or with TKIs in unselected populations failed to demonstrate any benefit.,,, This may have been due to inclusion of a large number of patients with EGFR wild-type tumors who are now known to derive minimal benefit with an EGFR TKI. Preclinical studies in NSCLC cell lines have shown that pharmacodynamic separation, by administering chemotherapy before the EGFR TKI, may be an appropriate strategy to combine the two modalities. This has been researched in the FASTACT 2 study, which compared an intercalated combination of chemotherapy (gemcitabine and cisplatin) and erlotinib with chemotherapy alone, in unselected patients with advanced NSCLC. The median PFS was 7.6 versus 6.0 months (HR 0.57, 95% CI 0.47–0.69) and OS was 18.3 versus 15.2 months favoring the combination arm.
Most patients develop resistance to EGFR TKIs over the course of treatment. Resistance may be due to acquired gatekeeper mutations (e.g., T790M), activation of bypass tracks (e.g., cMET amplification), or histologic transformation to small cell lung cancer. While chemotherapy remains the standard treatment after progression on EGFR TKI, postprogression TKI (to avoid flare) along with standard treatment is the subject of ongoing research.
Second-generation EGFR TKIs such as afatinib or dacomitinib irreversibly inhibit the EGFR tyrosine kinase by forming covalent bonds with the ATP-binding sites of the enzyme. They may also inhibit tumors with T790M mutations, thereby having a role in delaying or treating acquired resistance to first-generation TKIs. The irreversible pan-ERBB inhibitor, afatinib, has an extensive LUX lung program and has shown evidence of clinical activity in EGFR-mutant NSCLC in both first-line setting and in patients pretreated with chemotherapy and erlotinib/gefitinib, as well as in heavily pretreated NSCLC with unknown EGFR status, and pulmonary squamous cell cancer. Afatinib is now approved as a first-line treatment option for patients with EGFR mutations. Dacomitinib has been researched both in unselected population as well as in patients with known EGFR mutations.
Anaplastic lymphoma kinase
ALK is a transmembrane tyrosine kinase receptor that is normally expressed in the small intestine, testes, and brain, but not in the lung. ALK signaling is activated in NSCLC by creation of oncogenic fusions of the ALK gene on chromosome 2 with an upstream partner, EML4. The chimeric protein is a potent oncogenic driver involved in mitogenic signaling, cell differentiation, and survival. EML4-ALK rearrangements occur in 2%–7% of NSCLC patients, usually in never-smokers with adenocarcinoma. The companion diagnostic biomarkers for this oncogene are the standard break-apart fluorescent in situ hybridization or immunohistochemistry (IHC) with anti-ALK Mabs. A high correlation rate between the two biomarkers has been reported.
The first in class ALK inhibitor, crizotinib (which also inhibits ROS1 and MET), was approved by the FDA for treatment of ALK-positive advanced NSCLC based on the results of Phase I/II trials. A randomized Phase III trial, PROFILE 1007, compared crizotinib with single-agent chemotherapy with either pemetrexed or docetaxel in 347 patients with advanced or metastatic ALK-positive NSCLC who had received one prior platinum-based regimen. The median PFS was 7.7 versus 3.0 months for crizotinib versus chemotherapy (HR 0.49, 95% CI 0.37–0.64). Although ALK-positive NSCLC responds dramatically to crizotinib, no patient is cured and a majority of patients progress after a median of ~10 months. Resistance to crizotinib may occur through somatic kinase domain mutations, ALK gene fusion copy number gain, and emergence of separate oncogenic drivers. Several compounds including ALK inhibitors such as ceritinib and heat shock protein 90 inhibitors such as ganetespib are under investigation for crizotinib refractory tumors. In a Phase I dose escalation study of ceritinib in ALK-positive NSCLC, the response rate was 56% in patients previously treated with crizotinib and 62% in patients who had not received crizotinib.
ROS1 is a receptor tyrosine kinase with homology to the insulin receptor superfamily. Rearrangements of ROS1 gene on chromosome 6 are known oncogenic drivers in NSCLC, and several fusion partners have been identified. ROS1 fusions are present in ~ 2% of NSCLC, predominantly in young never-smokers having adenocarcinoma. ROS1 rearrangements are typically mutually exclusive with EGFR, ALK, or KRAS alterations. At present, crizotinib is the only agent that has shown efficacy in ROS1 translocated NSCLC. In an update of the PROFILE 1001 study, crizotinib demonstrated excellent antitumor activity with 56% response rate in ROS1-positive tumors.
RET is a receptor tyrosine kinase coded by a gene on chromosome 10 (10q11), with a clear role in endocrine cancers. RET is involved in cell proliferation, migration, differentiation, and neuronal migration. RET fusion genes have been identified in about 1.7% of adenocarcinomas with identifiable clinicopathologic characteristics, namely, young never-smokers having solid subtype pathology. RET can be targeted with TKIs including sunitinib, sorafenib, vandetanib, and cabozantinib.
The mesenchymal-epidermal transition (MET) proto-oncogene codes for a transmembrane tyrosine kinase heterodimer receptor. Binding of MET to its ligand, the hepatocyte growth factor (HGF) activates multiple signaling pathways leading to cancer cell migration, invasion, proliferation, metastases, and neoangiogenesis. Several pathways can lead to dysregulation of the MET/HGF pathway in a variety of tumors including NSCLC. These include rare MET mutations; high MET gene copy number seen in 1%–11% of cases, which is associated with high MET protein expression and poor prognosis; and MET amplifications seen in about 20% cases which are linked to secondary resistance to EGFR TKIs in patients with EGFR mutation-positive NSCLC., A variety of targeted agents inhibiting the MET/HGF pathway are in clinical development. These include agents interfering with HGF binding such as ficlatuzumab and rilotumumab; anti-MET Mabs including onartuzumab and small molecules such as tivantinib that have MET kinase or downstream inhibition activity.
Mutations in KRAS gene on chromosome 12 are detected in approximately 20% of NSCLC, mainly adenocarcinoma, and more frequently in smokers with Caucasian ethnicity. KRAS mutations are mutually exclusive with EGFR, HER2, or BRAF mutations and ALK rearrangements. KRAS-mutated tumors are intrinsically resistant to EGFR-directed therapies. A potential strategy for inhibition of KRAS-mutant NSCLC is the inhibition of effector protein of the MAPK pathway, which converges at the MEK1 and MEK2 kinases. Selumetinib is a selective non-ATP competitive inhibitor of MEK1/MEK2 kinase. A Phase II study comparing docetaxel with or without selumetinib as the second-line treatment for KRAS-mutant NSCLC showed a significant improvement in PFS (5.3 vs. 2.1 months, P = 0.014) and objective response (37% vs. 0%, P < 0.0001) for the combination, though the primary end-point of OS was not significantly different (9.4 vs. 5.2 months, P = 0.21). Selumetinib is currently undergoing Phase III research.
Squamous cell carcinoma
Fibroblast growth factor receptor 1
Fibroblast growth factor receptor 1 (FGFR1) is a member of the FGFR family. Its activation leads to downstream signaling through PI3K/AKT, RAS/MAPK pathways, leading to tumor growth, migration, and angiogenesis.
FGFR1 amplification is seen more commonly in SCC (21%) than adenocarcinoma (3%). Several small molecule FGFR TKIs such as ponatinib and dovitinib are currently under clinical development in Phase I/II studies.
In many cancers including NSCLC, angiogenic pathways have been established as important therapeutic targets because they are essential for tumor growth, progression, and metastases. One of the best characterized proangiogenic pathways is the vascular endothelial growth factor (VEGF) pathway, which comprises six growth factor ligands (VEGF A–E and placental growth factor) and three receptors (VEGFR 1–3). The prominent role of VEGF signaling pathway in tumor angiogenesis has prompted the development of antiangiogenic strategies that include Mabs that block the function of the ligand or the receptor and small molecule TKIs that directly inhibit VEGFRs and their signaling pathways.
Bevacizumab, an antibody against VEGF ligand A, is the only approved agent in the first-line treatment of advanced NSCLC; its use is however restricted to tumors with nonsquamous histology. Bevacizumab was approved based on the results of two pivotal studies., In the ECOG 4599 study, 878 patients with nonsquamous NSCLC were randomized to receive paclitaxel and carboplatin with or without bevacizumab (15 mg/kg). Bevacizumab was associated with significant prolongation of both OS (12.3 vs. 10.3 months; P = 0.0003) and PFS (6.2 vs. 4.5 months; P < 0.001). In the AVAiL study, 1043 patients with nonsquamous NSCLC were randomized to receive gemcitabine and cisplatin with or without bevacizumab (7.5 or 15 mg/kg). PFS was significantly prolonged with both doses of bevacizumab (6.7 vs. 6.1 months for 7.5 mg/kg, P = 0.003 and 6.5 vs. 6.1 months for 15 mg/kg for 15 mg/kg, P = 0.03). OS was however not prolonged. There is however no biomarker for prediction of response to bevacizumab.
Phase III trials with small molecule orally administered multitargeted antiangiogenic TKIs, such as cediranib, sorafenib, or motesanib, in patients with NSCLC have however not yielded survival benefits. There could be various reasons behind the high failure rate of antiangiogenic agents in NSCLC. Agents may not effectively combat redundancy of antiangiogenic pathways, they may not completely inhibit signaling via their target receptors, and finally validated biomarkers for prediction of response have not been identified.
Antiangiogenic agents, both Mabs and TKIs, are associated with class-specific adverse events, including hypertension, hemorrhage, and venous thromboembolism, which may preclude treatment in some patients. In addition to development of predictive biomarkers for response, it is also important for research to focus on identification of factors that predict the risk of adverse events to optimize the therapeutic ratio.
| » Locally Advanced Nonsmall Cell Lung Cancer|| |
The outcomes of patients with locally advanced NSCLC are suboptimal, and the recurrence rates are high. Many of these patients have a distant failure, which suggests that systemic disease control needs to be more effective. The results of molecular targeted therapies in locally advanced cancer have been quite disappointing. These studies have however been conducted in molecularly unselected groups of patients. The success of EGFR TKIs in EGFR mutation-positive advanced NSCLC and of the ALK inhibitor in ALK-translocated advanced NSCLC suggests that these agents may be researched in molecularly selected patients with locally advanced NSCLC. The National Cancer Institute in the USA has approved a randomized Phase II study of individualized combined modality therapy for stage III NSCLC. The study involves screening for EGFR and ALK mutations, and in the presence of the mutations, patients are randomized to receive induction TKI followed by chemoradiation versus standard chemoradiation.
| » Clinical Trial Design|| |
The advent of targeted agents in NSCLC has also triggered discussion about appropriate clinical trial methodology, and it is vital to pay as much attention to clinical trial methodology as to discovery of drugs. Phase II studies should be characterized by high predictive value, both to avoid wasting resources in subsequent Phase III trials with agents that are not efficacious and to avoid discarding active agents.
Previous clinical trials were restricted to enrollment of patients with a known single mutation and were not designed adequately for testing multiple molecular targets. Evaluating combinations of biomarkers or overlap between gene expression, mutations, and IHC can pave the way for rational drug combinations or sequencing trials in future. Ethical considerations are also important in the design of trials with biomarker-selected patients.
| » Future Directions and Conclusions|| |
Appropriate patient selection, identification of druggable targets, and development of drugs with activities specific to these targets have resulted in significant improvement of outcomes for patients with advanced lung cancer. There are now a number of regulatory approved agents that can be used for patients with advanced NSCLC [Table 2]. New strategies in personalized diagnostics, including whole genome sequencing, may change the treatment approach toward lung cancer.
|Table 2: Targeted agents approved for treatment of advanced nonsmall-cell lung cancer|
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While the future looks encouraging, there are challenges that need to be addressed and opportunities to be tapped. One of the foremost challenges is to collect adequate tumor tissue and facilitate broad and rapid testing for molecular markers, expanding the testing capability, and containing the cost of these tests to increase outreach. In addition, incorporation of biomarker analysis in clinical trial design, early identification of resistance to targeted therapies and development of therapeutic interventions to overcome resistance are integral to improved outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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