EGFR-directed Tyrosine Kinase Inhibitors Research Articles

What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas-Current Status and Future Directions?

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors.

Combination of EGFR-Directed Tyrosine Kinase Inhibitors (EGFR-TKI) with Radiotherapy in Brain Metastases from Non-Small Cell Lung Cancer: A 2010-2019 Retrospective Cohort Study.

Traditionally, brain metastases have been treated with stereotactic radiosurgery (SRS), whole-brain radiation (WBRT), and/or surgical resection. Non-small cell lung cancers (NSCLC), over half of which carry EGFR mutations, are the leading cause of brain metastases. EGFR-directed tyrosine kinase inhibitors (TKI) have shown promise in NSCLC; but their utility in NSCLC brain metastases (NSCLCBM) remains unclear. This work sought to investigate whether combining EGFR-TKI with WBRT and/or SRS improves overall survival (OS) in NSCLCBM. A retrospective review of NSCLCBM patients diagnosed during 2010-2019 at a tertiary-care US center was performed and reported following the 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic and histopathological characteristics, molecular attributes, treatment strategies, and clinical outcomes were collected. Concurrent therapy was defined as the combination of EGFR-TKI and radiotherapy given within 28 days of each other. A total of 239 patients with EGFR mutations were included. Of these, 32 patients had been treated with WBRT only, 51 patients received SRS only, 36 patients received SRS and WBRT only, 18 were given EGFR-TKI and SRS, and 29 were given EGFR-TKI and WBRT. Median OS for the WBRT-only group was 3.23 months, for SRS + WBRT it was 3.17 months, for EGFR-TKI + WBRT 15.50 months, for SRS only 21.73 months, and for EGFR-TKI + SRS 23.63 months. Multivariable analysis demonstrated significantly higher OS in the SRS-only group (HR = 0.38, 95% CI 0.17-0.84, p = 0.017) compared to the WBRT reference group. There were no significant differences in overall survival for the SRS + WBRT combination cohort (HR = 1.30, 95% CI = 0.60, 2.82, p = 0.50), EGFR-TKIs and WBRT combination cohort (HR = 0.93, 95% CI = 0.41, 2.08, p = 0.85), or the EGFR-TKI + SRS cohort (HR = 0.46, 95% CI = 0.20, 1.09, p = 0.07). NSCLCBM patients treated with SRS had a significantly higher OS compared to patients treated with WBRT-only. While sample-size limitations and investigator-associated selection bias may limit the generalizability of these results, phase II/III clinicals trials are warranted to investigate synergistic efficacy of EGFR-TKI and SRS.

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010-2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following 'strengthening the reporting of observational studies in epidemiology' (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd-5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd-5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd-5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd-5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63-2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55-4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates.

Abstract 5882: Genomic correlates of differential response to EGFR-directed tyrosine kinase inhibitors

Abstract Background: Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival. TP53 mutations have been linked with worse outcomes, thought to be due to increased likelihood of small cell transformation. Methods: We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Progression free survival (PFS) on first-line EGFR TKI, overall survival (OS), and resistance mechanism were assessed. Patients were defined as TP53 mutant positive (TP53+) or wild type (TP53-). Pathogenic TP53 mutations were identified and associated with outcome and resistance mechanism. Results: We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). TP53+ patients were as likely to achieve objective radiographic response as TP53- (p=0.615), but had shorter PFS (HR 1.56, CI 1.1-2.2, p=0.011). TP53+ patients were no more likely to develop SCLC transformation (p=0.637). Among patients with T790M as their resistance mechanism, TP53+ patients still had shorter PFS compared to TP53- (HR 1.9, CI 1.2-3, p=0.003). Pre-treatment TP53 mutations were associated with a higher tumor mutational burden (p=0.017) and copy number burden (p=0.0026). Conclusion: While TP53 mutations associate with shorter PFS, there is no association with baseline TP53 mutation status and small cell transformation, and TP53+ patients also develop the T790M resistance mutation earlier than TP53- patients. Higher mutation and copy number burden in TP53+ patients suggests greater genomic instability and may act as a mechanism of earlier resistance development. Citation Format: Natalie Vokes, Tom Nguyen, Christine Lydon, Emily Chambers, Lynette Sholl, Mizuki Nishino, Eliezer Van Allen, Pasi Janne. Genomic correlates of differential response to EGFR-directed tyrosine kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5882.

MA09.05 Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors

MA09.05 Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors

RN765C, a low affinity EGFR antibody drug conjugate with potent anti-tumor activity in preclinical solid tumor models

Epidermal growth factor receptor (EGFR) is a clinically validated target and often overexpressed in some solid tumors. Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies have been approved for treatment of NSCLC, head and neck cancers and colorectal cancers. However, clinical response is limited and often accompanied by significant toxicities due to normal tissue expression. To improve the effectiveness of targeting EGFR while minimizing the toxicities on normal tissues, we developed a low-affinity anti-EGFR antibody drug conjugate (ADC), RN765C. Potent in vitro cytotoxicity of RN765C, with nanomolar to subnanomolar EC50, was observed on a panel of cancer cell lines expressing moderate to high level of EGFR. In contrast, RN765C was less effective in killing normal human keratinocytes, presumably due to its lower receptor expression. Mechanistically, RN765C has multiple modes of action: inducing payload mediated mitotic arrest and cell death, blocking EGFR pathway signal and mediating antibody dependent cell cytotoxicity. In preclinical studies, a single dose of RN765C at 1.5-3 mg/kg was generally sufficient to induce tumor regression in multiple cell line and patient-derived xenograft models, including those that are resistant to EGFR-directed tyrosine kinase inhibitors. Our data support further investigation of RN765C in the clinic to treat EGFR expressing solid tumors.

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFR-directed tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs. Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.

Abstract 5260: Identification of substrates of lung cancer-specific mutant EGFR kinases.

Abstract Among various cancers, lung cancer is the leading cause of cancer-related mortality in both men and women in the US. The major driver mutations in lung cancer are in KRAS and EGFR. Mutations in EGFR account for 10-30% of lung adenocarcinoma. Somatic activating mutations in the kinase domain of EGFR occur in a subset of patients with lung adenocarcinoma and are associated with sensitivity to EGFR-directed tyrosine kinase inhibitors (TKIs). Unfortunately, all patients who respond dramatically to TKIs (gefitinib and erlotinib) eventually develop secondary resistance. A mutation in the gatekeeper residue in the ATP binding pocket of EGFR (T790M) occurs in around 50% of such patients. We hypothesized that mutant EGFR kinases have altered substrate specificities in vivo; these substrates play intermediary roles in transducing mutant EGFR signaling to downstream components to promote tumorigenesis. We have employed a screening method using an in vitro kinase assay on protein arrays containing around 17,000 proteins to compare the substrate specificity of the kinase domains of wild type EGFR, L858R EGFR (the most common activating mutant), and the EGFR harboring both the L858R and T790M mutations (TKI resistant mutant). We have identified several potential substrates such as Crk, Crk-like protein, Grb2, Stat3, Nck1, PIK3R3, etc., which have altered phosphorylation status in response to mutant EGFR kinase activity. We also performed a SILAC (Stable isotope labeling by amino acids in cell culture)-based global phosphoproteomic analysis in human lung adenocarcinoma cells using mass spectrometry and observed that phosphorylation of some of the potential substrates is modulated by EGF stimulation and TKI inhibition. We are currently validating promising substrates from the above assay by performing in vitro kinase assays in presence or absence of TKIs. Furthermore, to identify specific phosphorylation sites of the validated targets in vivo, we have adapted a SILAC-based mass spectrometry approach to immunoprecipitate specific substrates from isogenic human bronchial epithelial cells expressing various EGFR mutants followed by identification and quantification of phosphorylation. We have used siRNA-mediated gene silencing to interrogate the role of several of these substrates in survival of human lung adenocarcinoma cells. Finally, we are examining the phosphorylation status of identified substrates in tumor samples from patients of lung adenocarcinoma to correlate phosphorylation with EGFR mutation status. Citation Format: Tapan K. Maity, Hee-Sool Rho, Natalya Belinka, Zhi Xie, Xu Zhang, Abhilash Venugopalan, Romi Biswas, Constance Cultraro, Heng Zhu, Udayan Guha. Identification of substrates of lung cancer-specific mutant EGFR kinases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5260. doi:10.1158/1538-7445.AM2013-5260

Abstract 725: In vivo imaging and quantitative proteomics to study responsiveness to EGFR targeted therapy.

Abstract Lung cancer is the leading cause of cancer related mortality in the United States and is the most common cancer worldwide. Somatic mutations in the kinase domain of EGFR such as in-frame deletion of LREA amino acids in exon 19 and L858R point mutation in exon 21 largely account for 15-30% of lung adenocarcinoma. Although lung cancer patients carrying either of these mutations respond dramatically to EGFR-directed tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, acquired resistance to these drugs has been the main obstacle in treating these patients for the long term. Secondary mutation at the gatekeeper residue of the kinase domain (T790M) of EGFR accounts for drug resistance in about 50% of patients. We have used doxycycline inducible mutant EGFR transgenic mice to model human lung adenocarcinoma that is sensitive and resistant to TKIs. Our overall goal is to examine the treatment response to EGFR-directed TKIs in lung adenocarcinoma harboring various EGFR mutants. Our approach is aimed to identify imaging surrogates and proteomics profile of treatment response in mouse models of mutant EGFR-driven lung tumorigenesis. In this study, we have used transgenic mice that express exon 19 deletion mutant, L858R mutant, and L858R/T790M double mutant in type II pneumocytes upon doxycycline induction. Tumor burden in these mice was monitored by serial MRI imaging. Each group of mice with significant tumor burden was treated with erlotinib, a reversible EGFR inhibitor, BIBW-2992, an irreversible EGFR/ERBB2 dual inhibitor, or a combination of BIBW-2992 and cetuximab, an antibody directed against EGFR followed by 2[18F]Fluoro-2-deoxy-d-glucose (FDG)-PET imaging to assess any tumor regression. We observed a significant reduction of 18FDG uptake by tumors after the treatment with erlotinib in L858R mutant mice. However, in L858R/T790M mutant mice, no significant reduction of 18FDG uptake was observed upon treatment with erlotinib and BIBW-2992 had only mild effect. We are currently designing rational combination treatments based on the response in 18FDG-PET imaging. Finally, we are performing global phosphoproteomic analysis using quantitative mass spectrometry and immunohistochemistry with phospho-specific antibodies on tumor tissue before and after various treatments and correlating with the response in PET imaging. Results from these experiments will help us identify potential biomarkers (imaging and proteomic) of treatment response in lung adenocarcinoma driven by both TKI-sensitizing and resistant mutants of EGFR. Citation Format: Abhilash Venugopalan, Niu Gang, Jinxia Guo, Tapan Maity, Xu Zhang, Constance Cultraro, Xiaoyuan Chen, Udayan Guha. In vivo imaging and quantitative proteomics to study responsiveness to EGFR targeted therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 725. doi:10.1158/1538-7445.AM2013-725

EJ-3 - Targeting the her Family in Head and Neck Cancer: A Road with Hurdles

ABSTRACT The epidermal growth factor receptor (EGFR) is playing a role in the multistep carcinogenesis of squamous cell carcinoma of the head and neck (SCCHN) and its signaling promotes SCCHN growth and progression. EGFR is over expressed in the vast majority (>90%) of H&N cases and a high expression is associated with an unfavorable prognosis. Therefore, EGFR is a rational therapeutic target. In practice, both monoclonal antibodies (MAbs), which bind to the outer domain, and small molecule oral tyrosine kinase inhibitors (TKIs) that target the intracellular catalytic domain of the EGFR are being used. Cetuximab (Cet) is the only targeted agent that got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease in association with radiation (RT) and in recurrent/metastatic disease in combination with platinum/5-FU-based chemotherapy (in United States also as single agent in second line) and is still under active investigation in this disease. Unfortunately, several important questions are still unanswered (e.g. is RT + Cet equal in efficacy to RT + cisplatin (P)?, is maintenance therapy essential and for how long?, what are the adequate markers to predict response to Cet?, etc). Moreover, some results have been disappointing (e.g. PRT + Cet is not superior to PRT alone) and some applications are still investigational (e.g. Cet + induction chemotherapy and Cet in the postoperative setting). Interestingly, the results of trials involving other EGFR-directed MAbs, i.e. zalutumumab, panitumumab and nimotuzumab, so far have been consistent with the cetuximab data, but failed their primary end points. The results with EGFR-directed TKIs overall have been disappointing. Dual TKIs of both EGFR and HER/2 (the preferred dimerization partner of EGFR) have shown some promise, as well as newer irreversible HER-family blockers, such as afatinib and PF-299804. Both afatinib and PF-299804 have also demonstrated preclinical activity against tumor cells bearing a truncated EGFR protein, lacking the extracellular ligand-binding domain (EGFR variant III). Despite the hurdles, targeting the HER has a place in SCCHN treatment.

Biologic therapy in head and neck cancer: a road with hurdles.

The epidermal growth factor receptor (EGFR) is overexpressed in the vast majority of cases of squamous cell carcinoma of the head and neck (SCCHN). A high EGFR expression is associated with an unfavorable prognosis. Cetuximab is a chimeric human/murine IgG1 antibody which binds with high affinity to the EGFR. It is the only targeted agent which got approval for the treatment of SCCHN from the regulatory agencies of Europe and the United States, both in locoregionally advanced disease, in association with radiation, and in recurrent/metastatic disease. The outcome of trials involving other EGFR-directed monoclonal antibodies, that is, zalutumumab and panitumumab, was consistent with the results with cetuximab. However these trials failed to meet their primary endpoint. The results with EGFR-directed tyrosine kinase inhibitors have been disappointing. Other potential targets for treatment in SCCHN include the entire ErbB family, the vascular endothelial growth factor (VEGF) and its receptor (VEGFR), the insulin-like growth factor 1 receptor (IGF-1R), the insulin receptor (IR), histone deacetylases (HDAC), the mammalian target of rapamycin (mTOR), the platelet-derived growth factor receptor (PDGFR), heat-shock protein 90 (HSP90), nuclear factor-kappa B (NF-κB), aurora A or B, and phosphatidylinositol 3-kinase (PIK3CA).

A Phase II Trial of Erlotinib As Front-Line Treatment in Clinically Selected Patients With Non–Small-Cell Lung Cancer

BackgroundThe purpose of this study was to evaluate the efficacy of erlotinib as front-line treatment in clinically selected patients with non–small-cell lung cancer (NSCLC). Patients and MethodsForty-nine previously untreated white patients who had stage IIIB/IV pulmonary adenocarcinoma or bronchoalveolar carcinoma and who were nonsmokers or former light smokers were treated with erlotinib 150 mg daily, irrespective of the EGFR mutation status. ResultsIn an intention-to-treat analysis, the overall response rate (ORR) was 24.5%. The median progression-free survival (PFS) was 6.7 months, the median overall survival (OS) was 15.5 months, and the 1-year survival rate was 61.3%. Among the 36 patients for whom tumor material was available, 9 (25%) had activating EGFR mutations. The ORR was 66.7% in patients with activating EGFR mutations and 14.8% in patients with wild-type EGFR (2P = .006). In patients with activating EGFR mutations, the OS has not been reached, whereas it was 12.9 months in patients with EGFR wild type (2P = .045). Twenty-four patients had a PFS of > 6 months; 11 (45.8%) of them had EGFR wild type and 7 (29.1%) had EGFR mutation. ConclusionsThe selection of patients for treatment with EGFR-directed tyrosine kinase inhibitors (TKIs) should be based on mutation testing. However use of clinical (smoking status) and pathologic (adenocarcinoma) criteria may identify a subgroup of patients with advanced/metastatic NSCLC who can benefit from front-line treatment with erlotinib when mutation testing is not feasible.

Fcγ Receptor Polymorphisms as Biomarkers for Epidermal Growth Factor Receptor Antibodies

TO THE EDITOR: With great interest I read the editorial by Shepherd and Tsao on epidermal growth factor receptor (EGFR) biomarkers in non–small-cell lung cancer (NSCLC). In this article, the authors comment on the biomarker analyses of the BMS099 trial, which appear in the same issue of Journal of Clinical Oncology, and similar results from the First-Line Erbitux in Lung Cancer (FLEX) study, which have only been published in abstract form so far. Interestingly, validated biomarkers for EGFR-directed tyrosine kinase inhibitors in NSCLC, such as EGFR or KRAS mutations, were not predictive for responses to EGFR antibodies, suggesting fundamental differences in the therapeutic modes of action between these two classes of EGFR inhibitors. In contrast to tyrosine kinase inhibitors, EGFR antibodies, including the immunoglobulin G2 antibody panitumumab, recruit effector cells for antibody-dependent cellular cytotoxicity (ADCC). In vitro, in vivo, and clinical data, demonstrating an association between functional Fc receptor polymorphisms and response to antibody therapy, have suggested ADCC as a major effector mechanism of other therapeutic antibodies. For cetuximab, two studies reported correlations between Fc receptor polymorphisms and clinical responses in colorectal cancer, suggesting that blockade of signaling is not the only mechanism of action of cetuximab in vivo. Pending data on the impact of these Fc receptor polymorphisms for the outcome of antibody therapy in NSCLC may trigger novel approaches to enhance antibody efficacy in this difficult-to-treat tumor entity because the interactions between Fc receptors and therapeutic antibodies are amenable to antibody engineering. For example, Fc-engineered EGFR antibodies triggered killing of KRAS-mutated tumor cells that were resistant to growth inhibition and ADCC by wild-type EGFR antibodies.

Integrating Epidermal Growth Factor Receptor–Targeted Therapies into Platinum-Based Chemotherapy Regimens for Newly Diagnosed Non–Small-Cell Lung Cancer

Cytotoxic chemotherapy treatment for patients with advanced non-small-cell lung cancer (NSCLC) has reached a plateau, but further improvements are expected with integration of targeted therapies. Epidermal growth factor receptor (EGFR)-directed therapies are of particular interest because the EGFR is frequently expressed in tumors and associated with poorer outcome. Thus, blockade of the EGFR should improve outcome. Blockade can be achieved by tyrosine kinase inhibitors (TKIs) or monoclonal antibodies (MoAbs). Both approaches have been evaluated in advanced NSCLC. As single agents, EGFR-directed TKIs have demonstrated efficacy in patients previously treated with chemotherapy. When combined with first-line platinum-based chemotherapy, TKIs failed to improve the outcome. In contrast, MoAbs in combination with platinum-based first-line chemotherapy showed promising efficacy in phase II trials. Two phase III trials with chemotherapy with or without cetuximab have been performed in patients with advanced NSCLC. Other EGFR-directed MoAbs and TKIs are in earlier stages of clinical development.