Current and Future Targeted Therapies for Non-small-cell Lung Cancers With Aberrant EGF Receptors

Shanthi Kanthala; Sandeep Pallerla; Seetharama Jois

Disclosures

Future Oncol. 2015;11(5):865-878. 

In This Article

Therapies

Traditional chemotherapeutic agents such as cisplatin have provided standard therapies for lung cancer. The treatment for metastatic NSCLC consists of a two-drug combination, including a platinum compound and a nonplatinum drug such as pemetrexed, gemcitabine and vinorelbine, or a taxane. However, clinical response is observed in only 30–40% of patients.[7] Chemotherapeutic agents are often met with resistance and, hence, targeted therapy approaches are being pursued to treat lung cancer.[46] Since EGFRs are known to play a major role in lung cancer as well as in breast and ovarian cancers, targeting EGFRs could have a significant impact on several cancer therapies.[47] Several targeted therapies are available, depending on the stage of the cancer diagnosed and the type of mutation. Therapy is given in several rounds, depending on the patient's condition. Here we have highlighted some of the widely used therapeutic agents that target EGFR in lung cancer.

TKIs

Erlotinib and gefitinib are first-generation EGFR TKIs approved for treatment of NSCLC.[48] These are orally available anilinoquinazolines that bind reversibly to the ATP binding site of the kinase domain of EGFR. In the early trials of the drugs, both erlotinib and gefitinib showed promising results for NSCLC patients.[49] However, use of these TKIs as a second and third line of therapy for advanced NSCLC patients did not yield improved results. But treatment may be further customized by EGFR genotype and pathology subtype or histology.[46,50–52] Despite encouraging responses to EGFR TKIs, most of the patients develop progression of the disease within one year, usually because of secondary or acquired resistance. It may involve, on the one hand, activation of MAPK-dependent pathways by a T790M mutation (constituting 50–60% of acquired resistance), decreasing the binding affinity to the first-generation TKIs, amplification of HER2 or MEK1, or activating of mutations in RAS or BRAF. MAPK-independent pathways, on the other hand, involve acquired PIK3CA mutations, amplification of MET proto-oncogene, which provides a bypass avenue through transactivation of HER3/PI3K signaling, or impairment of cell death mechanisms as seen with certain germline polymorphic variants of the proapoptotic molecule proapoptotic BCL-2-interacting mediator. Other documented phenomena to explain treatment resistance include epithelial-to-mesenchymal transition mediated by either AXL kinase activation or activation of TGF-β pathway through downregulation of mediator of RNA polymerase II transcription, subunit 12 (MED12) and phenotypic transformation to small-cell histology.

Second- and third-generation EGFR TKIs are being developed as part of the strategy to overcome treatment resistance to first-generation EGFR TKIs ( Table 2 ). The second-generation TKIs include the irreversible inhibitors of the ErbB family of receptors: afatinib (also known as BIBW 2992, which targets EGFR, HER2 and HER4), dacomitinib (also known as PF0299804, which targets EGFR, HER2 and HER4) and neratinib (also known as HKI272, which targets EGFR and HER2). These agents are intended to improve the efficacy of treatment in patients with activated mutant EGFR and acquired resistance to first-generation EGFR TKIs. These agents have been or are being evaluated in clinical trials, with afatinib and dacomitinib having progressed the furthest in clinical development. The FDA has recently approved afatinib for metastatic NSCLC patients with tumors harboring exon 19 deletion or exon 21 substitution mutations in EGFR gene as a first-line treatment. Afatinib is an irreversible pan inhibitor that binds to multiple kinases. Dacomitinib is in Phase III clinical studies due to its acceptable safety profile. Further development of neratinib in NSCLC is unlikely because of its low clinical activity as well as dosing limitations arising from diarrhea-related toxicities. Pelitinib (EKB-569) and canertinib (CI-1033) have also been discontinued from further clinical development.[48]

The dominant resistance mechanism developed to EGFR-directed therapy is a kinase-activating mutation T790M. Third-generation EGFR inhibitors designed to inhibit the EGFR T790M mutant include HM781–36B, WZ4002, CO-1686 and AZD9291. Poziotinib (HM781–36B) is a new potent irreversible inhibitor of EGFR, HER2, HER4 and the TEC family of kinase inhibitors (Bruton's tyrosine kinase, B lymphocyte kinase and BMX). In preclinical studies, it demonstrated efficacy against T790M mutant at a dose eightfold lower than that for afatinib, and is presently being evaluated in Phase II clinical studies. Another new agent, AZD9291, showed promising results in clinical Phase I trials – tumor shrinkage was observed in 64% of 205 patients with mutant EGFR. Similarly, treatment with CO-1686, a covalent inhibitor of mutant EGFR, was well-tolerated and showed tumor shrinkage in 58% of 72 patients with T790M mutations. Currently, both of these agents are subjects of Phase II as well as Phase III clinical studies and have received a special 'breakthrough status' from the FDA for expediting the approval process. Icotinib is another candidate with an acceptable adverse effect profile that is under investigation for activity in NSCLC patients harboring EGFR mutations.[48,71]

Possible mechanisms of acquired resistance to these next-generation TKIs are increased extracellular signal-regulated kinase activation by increased MEK1 signaling or downregulation of negative regulators of extracellular signal-regulated kinase signaling, which may be overcome by the use of MEK inhibitors. Findings from recent studies suggest that the combination of WZ4002 and an MEK inhibitor appears to be preclinically effective in treating drug-resistant tumors as well as in delaying the emergence of tertiary drug-resistant clones. The multitargeted EGFR/HER2/VEGFR/Ephref-4 inhibitor XL547 and the dual reversible ALK/EGFR inhibitor AP26113 also demonstrated preclinical activity against EGFR T790M mutant tumors. Early clinical phase data on XL647 and AP26113 suggested a preliminary hint of modest clinical activity in patients with resistance to other EGFR TKIs.[11] The FDA recently approved crizotinib, which is an ALK and c-ros oncogene 1 (ROS1) inhibitor, for lung cancer treatment.

Monoclonal Antibodies

Cetuximab (erbitux) is an immunoglobulin G chimeric mAb against EGFR. It competitively inhibits ligand binding and has been investigated in combination with chemotherapy in Phase III trials (ErbituX in lung cancer [FLEX] study) of molecularly unselected NSCLC patients.[72] A FISH assay to determine EGFR gene copy number had demonstrated potential promise as a predictive marker of response to cetuximab in a small study.[15,73] However, no biomarker was found to consistently correlate with the benefit from cetuximab in the concluded Phase III clinical studies for NSCLC, including EGFR, FISH or KRAS mutation status. Other mAbs against EGFR under investigation in trials for NSCLC include necitumumab, panitumumab, nimotuzumab, matuzumab and zalutumumab (Table 2).

A different approach in addressing EGFR TKI resistance involves the use of combination regimens. For the first time, a combination of afatinib and cetuximab was reported to be very promising in terms of an overall response rate of 29% even in mutant T790M cases. Other combinations of erlotinib with cetuximab and erlotinib with MM-121, a fully human mAb that targets HER3, in patients with acquired resistance to EGFR TKI did not show sufficient clinical activity for further investigation. Also, the combination of anti-Erbref-3 antibodies with EGFR TKIs synergistically affected cell proliferation in vitro, caused cell cycle arrest, upregulated p21 expression and inhibited tumor growth in mouse xenografts.[28] An approach using chemotherapies, antibodies and immunotherapy seems to show shrinkage of tumors with a T790M mutation. Such methods of blocking at both intracellular and extracellular levels, called 'vertical blockade', could improve the therapeutic outcomes for EGFR-TKI resistant tumors.[74,75]

Novel agents like dual-targeting antibodies that bind to two antigens or tumor marker proteins are also under development.[76] Encouraging results were observed with a combination of the HER2 dimerization inhibitor pertuzumab and EGFR TKI erlotinib in NSCLC patients in Phase Ib clinical trials.[67] However, the tolerance levels were poor, with adverse effects such as pneumatosis intestinalis.[68] Scheuer et al. studied the effectiveness of a combination of trastuzumab and pertuzumab in the inhibition of HER2-overexpressed tumor growth. They concluded that this combination has a synergistic antitumor effect on NSCLC (Calu-3) and breast cancer xenograft models. Moreover, it was shown to reduce the metastasis of breast cancer to lung tissues. Initially, clinical trials in HER2-positive NSCLC patients undergoing chemotherapy failed to show any benefit from adjuvant therapy with the anti-HER2 antibody trastuzumab. However, in later studies HER2 mutations were shown to play a more significant role in lung carcinogenesis than overexpression of HER2 protein in patients with HER2-mutant NSCLC.[20,70]

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