After a rocky start, drugs that inhibit the epidermal growth factor receptor pathway have evolved into a new treatment paradigm for patients with nonâ€“small cell lung cancer whose tumors harbor EGFR mutations.
After a rocky start, drugs that inhibit the epidermal growth factor receptor (EGFR) pathway have evolved into a new treatment paradigm for patients with non—small cell lung cancer (NSCLC) whose tumors harbor EGFR mutations. Three generations of drugs are now available, with new agents helping to overcome the significant challenge of resistance. Yet despite this tremendous progress, lung cancer is still the leader in cancer-related mortality. Many questions remain to be answered in order to achieve the best outcomes for all EGFR mutation-carrying patients.EGFR belongs to a family of four membrane receptor proteins (EGFR/ ERBB1/HER1; HER2/ERBB2; HER3/ERBB3; and HER4/ERBB4). These receptors exist as single units, but binding of their ligands prompts them to partner up with either another protein of the same type (homodimerization) or a different member of the family (heterodimerization).
This binding causes the receptor to become activated by autophosphorylation at specific tyrosine residues. In their active state, they initiate a multistep phosphorylation cascade of signaling proteins that culminates in the transcription of a distinct set of genes in the nucleus that are involved in cancer hallmark processes.
Several strategies have been developed for blocking EGFR signaling with drugs—monoclonal antibodies that bind to the extracellular domain of the receptor and block ligand binding, and small molecule inhibitors that interfere with tyrosine kinase activity. Both have been tested in patients with lung cancer and, while EGFR antibodies have had limited clinical success to date, EGFR tyrosine kinase inhibitors (TKIs) have proved to be very effective in patients with NSCLC. Initially, EGFR inhibitors were tested in all patients with NSCLC. The first-generation drugs gefitinib (Iressa) and erlotinib (Tarceva), both reversible inhibitors, received FDA approval in quick succession in 2003 and 2004, respectively, for use in patients who had progressed on first-line chemotherapy.
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Unfortunately, in the case of gefitinib, subsequent phase III confirmatory trials failed to verify the survival benefit observed in the pivotal trials upon which its accelerated approval was based. The makers of this drug voluntarily withdrew it from market in the United States in 2005. In light of the modest efficacy observed in the broad NSCLC population and the significant cost of these drugs, opinion began to sour on the entire class.In 2004, two research groups simultaneously identified the presence of mutations in the EGFR gene in NSCLC tumors. Dubbed activating mutations, they are most found in the form of exon 19 deletions and L858R point mutations in exon 21 of the EGFR gene, and result in the constitutive activation of the protein, leading to uncontrolled EGFR signaling. These types of EGFR mutations, located around the catalytic kinase domain of the receptor, are unique to lung cancer.
Prior to the discovery of EGFR mutations, a picture of typical response to an EGFR TKI had already begun to emerge. Researchers had noted a responsive phenotype: patients who responded best tended to be East Asian, nonsmokers, female, and those with adenocarcinoma NSCLC histology. As it became clear that EGFR mutations were present in around 10% of all patients with NSCLC, retrospective analyses of EGFR TKI clinical trials also presented a responsive genotype.
Confirming the observations from these retrospective analyses, numerous prospective, randomized trials have now demonstrated that, for patients with EGFR mutations, an EGFR TKI is superior to standard chemotherapy, with improved overall response rates (ORRs), disease control, symptom control, progression-free survival (PFS) and quality of life. No overall survival (OS) benefit was observed with either gefinitib or erlotinib, but this is believed to result from the extensive crossover in clinical trials.
Although the genotype and phenotype of EGFR TKI responders overlap to a large extent, it has become more apparent as researchers have tested these drugs in specific patient populations that the presence of activating EGFR mutations (genotype), rather than phenotype, should guide treatment decisions.
The key trial in EGFR-mutant patients for erlotinib was the OPTIMAL trial, in which erlotinib was compared with carboplatin and gemcitabine in 154 Chinese patients; the ORR for erlotinib was 83% compared with 36% for the chemotherapy regimen and median PFS was 13.1 months versus 4.6 months, respectively. The efficacy of erlotinib in EGFR-mutant patients was subsequently duplicated in non-Asian patients in the EURTAC trial. Among 173 patients, those treated with erlotinib had an ORR of 58% and median PFS of 9.7 months, compared with 15% and 5.2 months for gemcitabine and docetaxel. Erlotinib was approved for the treatment of EGFR-mutant patients in the first-line setting in 2013.
The game-changing data for gefitinib came from the IPASS trial, in which the drug was compared with cisplatin and gemcitabine in previously untreated East Asian patients with advanced disease. The ORR was 71.2% versus 47.3% and median PFS was 9.6 months versus 6.3 months in the gefitinib and chemotherapy arms, respectively. Gefitinib was approved in Europe in 2009, partly on the basis of this trial. Several smaller trials of gefitinib were also carried out in Korean and Japanese patients with EGFR mutations (First-SIGNAL, WJTOG3405, and NEJ 002) and demonstrated similar trends.
In the United States, the phase IV IFUM trial was carried out to address the fact that the majority of patients in the IPASS trial were Asian. The efficacy of gefitinib in patients with EGFR mutations was confirmed in a Caucasian population. Among 106 patients, the ORR was 69.8% and the median PFS was 9.7 months. These data were further supported by a retrospective subgroup analysis of 186 EGFR mutation-positive patients from the IPASS trial, which demonstrated an ORR of 67% for gefitinib versus 41% for chemotherapy and a median PFS of 10.9 months versus 7.4 months, respectively. The FDA approved gefitinib in frontline settings for EGFR-positive patients in July 2015.
Although most patients with EGFR-mutant NSCLC harbor aberrations targeted by these drugs, up to 10% of patients may exhibit rarer mutations in other exons of the EGFR gene. However, the clinical significance and optimal management of patients with these mutations is less clear. Some mutations are associated with response to EGFR TKIs (eg, exon 18 G719X and exon 21 L861Q), others with resistance (eg, exon 20 insertion), and others have unknown clinical significance. In addition to unraveling the distinct epidemiological features and disease outcomes that may be associated with these different types of mutations, clinical trials evaluating EGFR TKIs in patients with these mutations are ongoing.Despite dramatic responses to EGFR TKI therapy in EGFR-mutant patients, virtually all will develop resistance, typically after around a year. Understanding acquired resistance to these drugs has become an area of intensive research aimed at developing new, smarter drugs that could help clinicians stay one step ahead of the disease.
Several mechanisms of resistance have been uncovered in recent years. Most common is the development of secondary mutations in the EGFR gene, in particular the gatekeeper mutation (T790M), which occurs in at least 50% of patients. EGFR TKIs are designed to bind to a conserved threonine residue on EGFR, which controls access to the ATP kinase pocket, hence acting as the “gatekeeper.” The T790M mutation changes the threonine to a bulkier amino acid and disrupts the TKI’s ability to bind EGFR; it also increases the affinity of the mutant kinase for ATP and outcompetes the EGFR TKI.
Other mechanisms of resistance include the activation of other components of the EGFR pathway downstream of the receptor or of other signaling pathways. MET amplification and PIK3CA mutations are present in around 5% of patients, while HER2 amplification has been found in up to 12%-13% of patients. Additionally, the histological transformation of NSCLC into small cell lung cancer has been noted. Thus far, the focus has been on the T790M mutation, and the first strategy was to develop irreversible EGFR inhibitors to restore their competitive advantage over ATP. Several different drugs were developed but showed limited efficacy in T790M-positive patients, possibly because these drugs still target wild-type as well as mutant EGFR and, in order to achieve the concentration required to reverse resistance, the side effects of targeting wild-type EGFR become intolerable.Fortuitously, as a result of this EGFR wild-type activity, the second-generation inhibitor afatinib (Gilotrif) showed significant efficacy in patients with activating EGFR mutations and has added an additional option to the arsenal of EGFR-targeting drugs available in the first-line setting, following its initial 2013 approval by the FDA. Afatinib was approved on the basis of the LUXLung 3 (afatinib vs cisplatin and pemetrexed) and LUX-Lung 6 (afatinib vs cisplatin and gemcitabine in Asian patients) trials, which both demonstrated a significant increase in PFS for afatinib compared with chemotherapy. More recently, afatinib also became the first EGFR TKI to demonstrate an improvement in OS, although only in patients with exon 19 deletions. Direct head-to-head comparisons of first- and second-generation inhibitors have been limited thus far, but indirect comparisons suggest gefitinib and erlotinib may be better tolerated, with no difference in ORR, but afatinib may provide superior PFS. The largest head-to-head comparison performed to date is the LUX-Lung 8 trial; recently reported results showed the superiority of afatinib over erlotinib in the second-line setting in patients with squamous cell NSCLC. Among 795 patients randomized to treatment with either agent, those treated with afatinib demonstrated median PFS of 2.6 months and OS of 7.9 months compared with 1.9 months and 6.8 months, respectively, with erlotinib.A number of third-generation inhibitors have now been designed that specifically target T790M-mutant EGFR. In November 2015, osimertinib (Tagrisso), which the FDA had designated as a breathrough therapy, became the first to cross the regulatory finish line when the agency approved its use for patients with advanced EGFR T790M-mutant NSCLC following progression on a prior EGFR TKI. The accelerated approval, which is contingent upon the outcome of confirmatory phase III clinical data, is the first for a treatment following a rebiopsy and molecular testing, marking a significant milestone in the move toward precision medicine.
The approval for osimertinib, formerly known as AZD9291, was based on the multicenter, single- arm, AURA extension and AURA trials in a total of 411 patients, in which the ORR was 71% and 61%, respectively, according to updated data presented at the 2015 World Conference on Lung Cancer.A new drug application for rociletinib (CO-1686), which also gained a breakthrough therapy designation, is under review. In November 2015, Clovis Oncology disclosed that the FDA requested additional data that is likely to delay the regulatory decision. The application is based on data from the ongoing TIGER-X trial. In November, the company said an intent-to-treat analysis showed the confirmed response rate was 28% among 79 patients who received rociletinib at 500 mg and 34% among the 170 patients in the 625-mg group.The new agents also have generated responses in patients with T790M-negative disease, albeit with lower ORRs, and they have improved tolerability compared with the first- and second-generation inhibitors. Thus, the possibility that agents developed to address resistance could be employed in the frontline setting is also being explored. Meanwhile, frontline inhibitors in patients with acquired resistance have shown promise in combination with other targeted therapies. The combination of erlotinib and bevacizumab demonstrated a 1-year PFS rate of 72% in patients with T790M mutations in the phase II BELIEF trial, as reported at the 2015 European Cancer Congress, but combined toxicities could limit clinical implementation. In addition to ongoing clinical trials evaluating combinations of EGFR TKIs with drugs targeting other mechanisms of resistance, such as MET and PI3K inhibitors, studies have also suggested that acquired resistance mutations may be lost following a TKI-free period and alternate dosing schedules are also being investigated.Since a patient’s EGFR mutation status impacts treatment outcomes, it is essential to confirm whether the aberrations are present prior to treatment with EGFR TKIs, reflected by the fact that EGFR mutation testing is now incorporated into treatment guidelines. The FDA labels also specify the use of companion diagnostics in the indication of each of the four approved inhibitors.
Erlotinib was approved for use in conjunction with the cobas EGFR Mutation Test, while gefitinib and afatinib are paired with the therascreen EGFR RGQ PCR kit. Osimertinib is indicated for use with the cobas EGFR Mutation Test v2, which is the first diagnostic test to detect the T790M mutation. It is also important to reassess mutation status during treatment to guide therapeutic decisions following development of resistance, researchers have found.
Currently, the standard for detecting EGFR mutations is biopsy and tissue analysis. However, surgical biopsies are unavailable in the majority of patients. Therefore, small biopsies and cytological samples are typically used, but are limited by the amount and quality of DNA available.
The use of surrogate sources of tumor DNA is being investigated, such as blood, serum and plasma samples that may contain circulating tumor cells or cell-free DNA that can be used for tumor genotyping. These liquid biopsies offer several advantages; they are noninvasive, permit serial evaluation of the tumor at different timepoints, and allow evaluation of the entire, heterogeneous tumor landscape.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.