Thoracic stereotactic body radiation therapy plus first-line tyrosine kinase inhibitors for patients with epidermal growth factor receptor-mutant polymetastatic non-small-cell lung cancer: A propensity-matched retrospective study.

ABSTRACT: The role of thoracic stereotactic body radiation therapy (SBRT) in addition to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant polymetastatic non-small-cell lung cancer (NSCLC) has not been well established. This retrospective study aimed to evaluate the efficacy and safety of EGFR-TKIs with thoracic SBRT for the treatment of this patient group.Polymetastatic NSCLC was defined as having >5 metastatic lesions. Patients with polymetastatic NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016and August 2019. Eligible patients were treated with thoracic SBRT, and TKIs were administered for the duration of SBRT and continued after SBRT until they were considered ineffective. The control group was treated with TKI monotherapy. Propensity score matching (ratio of 1:4) was used to account for differences in baseline characteristics. Progression-free survival (PFS), overall survival, and treatment safety were evaluated.In total, 136 patients were included in the study population. Among them, 120 patients received TKIs alone, and 16 patients received TKIs with thoracic SBRT. The baseline characteristics did not significantly differ between the two cohorts after propensity score matching. The median PFS was 17.8 months in the thoracic SBRT group and 10.8 months in the control group (P = .033). In the multivariate analysis, a Cox regression model showed that thoracic SBRT was an independent statistically significant positive predictor of improved survival, with a hazard ratio of 0.54 (P = .046). We recorded no severe toxic effects or grade 4 to 5 toxicities.Real-world data demonstrate that thoracic SBRT significantly extends PFS in EGFR-mutant polymetastatic NSCLC patients with tolerable toxicity. Given these results, randomized studies are warranted.

Co-delivery of EGFR and BRD4 siRNA by cell-penetrating peptides-modified redox-responsive complex in triple negative breast cancer cells.

AIMS: Triple negative breast cancer (TNBC) has drawn more and more attention due to its high mitotic indices, high metastatic rate and poor prognosis. Gene therapy, especially RNA interference (RNAi), has become a promising targeted therapy. However, improvement of transfection efficiency and discovery of target genes are major problems for the delivery of small interfering RNAs (siRNA). MATERIALS AND METHODS: In the present study, we developed GALA- and CREKA-modified PEG-SS-PEI to deliver siRNAs targeting on EGFR and BRD4 for TNBC therapy. The PEG-SS-PEI/siRNA complexes were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The release characteristic, stability, cellular uptake and intracellular localization of the complexes were also studied. The effect of the complexes on cell viability was measured in MDA-MB-231 and HUVEC cells. The in vitro anti-tumor activities of the complexes were analyzed by Transwell invasion assay and wound healing assay. The gene silencing effect was evaluated by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. KEY FINDINGS: The results revealed that the GALA- and CREKA-modified PEG-SS-PEI/siRNA complexes showed excellent transfection efficiency with redox-sensitive release profile and good biological compatibility. The complexes protected siRNA from the degradation of RNA enzymes. The complexes significantly inhibited the proliferation, invasion and migration of MDA-MB-231 cells via the synergistic inhibition of EGFR/PI3K/Akt and BRD4/c-Myc pathways. SIGNIFICANCE: Taken together, co-delivery of siEGFR and siBRD4 by GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI may provide a more effective strategy for the treatment of TNBC.

Chemotherapy should be performed in epidermal growth factor receptor mutation-positive lung adenocarcinoma patients who had progressive disease to the first epidermal growth factor receptor-tyrosine kinase inhibitor.

After the failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, some non-small cell lung cancer patients desire to receive switching with another EGFR-TKI (TKI-switching), although cytotoxic chemotherapy has been recommended as second-line therapy. It is unclear who should not receive TKI-switching in these patients. We retrospectively evaluated overall survival (OS) from the initiation of first EGFR-TKI (first-TKI) therapy in advanced lung adenocarcinoma patients with active EGFR mutations (deletion of exon 19 or L858R in exon 21) who received TKI-switching according to the best response of the first-TKI. There was no difference in the OS between patients receiving TKI-switching (n = 35) and patients receiving additional chemotherapy between the first-TKI and second-TKI therapy (n =10) (P = 0.614). Among patients receiving TKI-switching, the OS in cases with progressive disease to the first-TKI (n = 9) was shorter than that in cases with disease control to the first-TKI (n = 26) (12.7 months vs. 49.4 months, P < 0.001). Five of the nine progressive disease cases who received TKI-switching missed an opportunity to receive chemotherapy. Their OS tended to be shorter than that in patients who received chemotherapy during the whole period of anticancer therapy (12.2 months vs. 20.3 months, P = 0.060). The multivariate analysis showed that disease control to the first-TKI therapy (P = 0.005) or the presence of chemotherapy (P = 0.087) decreased the risk of mortality. Chemotherapy should be performed in patients with progressive disease to the first-TKI.

Cyto-Immuno-Therapy for Cancer: A Pathway Elicited by Tumor-Targeted, Cytotoxic Drug-Packaged Bacterially Derived Nanocells.

Immunotherapy has emerged as a powerful new chapter in the fight against cancer. However, it has yet to reach its full potential due in part to the complexity of the cancer immune response. We demonstrate that tumor-targeting EDV nanocells function as an immunotherapeutic by delivering a cytotoxin in conjunction with activation of the immune system. These nanocells polarize M1 macrophages and activate NK cells concurrently producing a Th1 cytokine response resulting in potent antitumor function. Dendritic cell maturation and antigen presentation follows, which generates tumor-specific CD8+ T cells, conferring prolonged tumor remission. The combination of cytotoxin delivery and activation of innate and adaptive antitumor immune responses results in a potent cyto-immunotherapeutic with potential in clinical oncology.

Expeditious Generation of Biparatopic Common Light Chain Antibodies via Chicken Immunization and Yeast Display Screening.

Bispecific (BsAb) and biparatopic (BpAb) antibodies emerged as promising formats for therapeutic biologics exhibiting tailor-made functional properties. Over recent years, chicken-derived antibodies have gained traction for diagnostic and therapeutic applications due to their broad epitope coverage and convenience of library generation. Here we report the first generation of a biparatopic common light chain (cLC) chicken-derived antibody by an epitope binning-based screening approach using yeast surface display. The resulting monospecific antibodies target conformational epitopes on domain II or III of the epidermal growth factor receptor (EGFR) with lower double- or single-digit nanomolar affinities, respectively. Furthermore, the domain III targeting variant was shown to interfere with epidermal growth factor (EGF) binding. Utilizing the Knob-into-Hole technology (KiH), a biparatopic antibody with subnanomolar affinity was generated that facilitates clustering of soluble and cell-bound EGFR and displayed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared to the parental antibodies. This strategy for generating cLC-based biparatopic antibodies from immunized chickens may pave the way for their further development in therapeutic settings.

Adjuvant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (TKIs) in Resected Non-Small Cell Lung Cancer (NSCLC): A Systematic Review and Meta-analysis.

The role of adjuvant tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) is not well defined. Recent randomized controlled trials showed a disease-free survival (DFS) benefit in patients harboring an epidermal growth factor receptor (EGFR) mutation. Yet, older trials on patients with any EGFR status did not demonstrate the same benefit. We aimed to assess the efficacy and safety of adjuvant TKIs in NSCLC patients. The electronic databases Medline (PubMed) and EMBASE were searched for relevant randomized controlled trials. Random effect models were used. The primary outcome was DFS measured as hazard ratio (HR). The secondary outcomes were overall survival (OS) measured as HR, 2-year DFS and toxicity expressed as risk ratio and odds ratio (OR), respectively. Subgroup analyses assessed DFS by trial design. Six trials incorporating 1860 patients were included. In patients harboring an EGFR mutation, adjuvant TKIs decreased the risk of disease recurrence by 48% (HR: 0.52, 95% confidence interval [CI]: 0.35-0.78), improved 2-year DFS (HR: 0.53, 95% CI: 0.43-0.66) but did not improve OS (HR: 0.64, 95% CI: 0.22-1.89). The risk of developing ≥grade 3 skin toxicity (OR: 6.07, 95% CI: 4.34-8.51) and diarrhea (OR: 4.05; 95% CI: 2.44-6.74) was increased. In subgroup analyses, the DFS benefit was more pronounced in trials using TKIs over chemotherapy compared with trials using TKIs postchemotherapy. In conclusion, adjuvant TKIs decrease the risk of recurrence in NSCLC patients harboring an EGFR mutation but do not improve OS. Longer follow-up is needed for a definitive assessment of OS and to define the role of adjuvant TKI for NSCLC in the clinical practice.

Cost-effectiveness of osimertinib in the UK for advanced EGFR-T790M non-small cell lung cancer.

AIM: This study presents the cost-utility analysis that was developed to inform the NICE health technology assessment of osimertinib vs platinum-based doublet chemotherapy (PDC) in patients with EGFR-T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS AND MATERIALS: A partitioned survival model with three health states (progression-free, progressed disease, and death) from a UK payer perspective and over lifetime (15 years) was developed. Direct costs included disease management, treatment-related (acquisition, administration, monitoring, adverse events), and T790M testing costs. Efficacy and safety data were taken from clinical trials AURA extension and AURA2 for osimertinib and IMPRESS for PDC. An adjusted indirect treatment comparison was applied to reduce the potential bias in the non-randomized comparison. Parametric functions were utilized to extrapolate survival beyond the observed period. Health state utility values were calculated from EQ-5D data collected in the trials and valued using UK tariffs. Resource use and costs were based on published sources. RESULTS: Osimertinib was associated with a gain of 1.541 quality-adjusted life-years (QALYs) at an incremental cost of £64,283 vs PDC (incremental cost-effectiveness ratio [ICER]: £41,705/QALY gained). Scenario analyses showed that none of the plausible scenarios produced an ICER above £44,000 per QALY gained, and probabilistic sensitivity analyses demonstrated a 63.4% probability that osimertinib will be cost-effective at a willingness-to-pay threshold of £50,000. LIMITATIONS: The analysis is subject to some level of uncertainty inherent to phase 2 single-arm data and the immaturity of the currently available survival data for osimertinib. CONCLUSIONS: Osimertinib may be considered a cost-effective treatment option compared with PDC in the second-line setting in patients with EGFR-T790M mutation-positive NSCLC from a UK payer perspective. Further data from the ongoing AURA clinical trial program will reduce the inherent uncertainty in the analysis.

JAK2/STAT3 pathway is involved in the protective effects of epidermal growth factor receptor activation against cerebral ischemia/reperfusion injury in rats.

Cerebral ischemia and reperfusion is a common pathophysiologic process, which is involved in stroke and brain trauma. Recent studies revealed that activating epidermal growth factor receptor (EGFR) ameliorates cerebral ischemia/reperfusion (I/R) injury, however, the precise mechanisms remain to be illuminated. In this study, the neurological behavior was evaluated by Longa score. The infarct volume was performed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and the expression of p-EGFR, p-STAT3, connexin (Cx43), Bax and Bcl-2 were detected by Western blot. The neurological behavior and infarct volume were increased in rats with cerebral I/R injury. Epidermal growth factor (EGF) pretreatment significantly decreased neurological deficit and infarct volume. However, the antagonist of EGFR, AG1478 attenuated the EGF-induced reduction of neurological deficit and infarct volume. Moreover, the inhibitor of JAK2/STAT3, AG490 undermined the protective effects stimulated by activating EGFR in rats with I/R injury. In addition, EGF pretreatment increased the expression of Bcl-2 and reduced the expression of Bax and Cx43, and the effects were abolished after using AG1478 and AG490. These findings implicate that JAK2/STAT3 pathway plays the vital role in I/R injury protection from activating EGFR. And the neuroprotective effects may associate with inhibiting the Cx43 expression and the inhibition of apoptosis.

A novel recombinant anti-epidermal growth factor receptor peptide vaccine capable of active immunization and reduction of tumor volume in a mouse model.

Over-expression of epidermal growth factor receptor (EGFR) has been reported in a number of human malignancies. Strong expression of this receptor has been associated with poor survival in many such patients. Active immunizations that elicit antibodies of the desired type could be an appealing alternative to conventional passive immunization. In this regard, a novel recombinant peptide vaccine capable of prophylactic and therapeutic effects was constructed. A novel fusion recombinant peptide base vaccine consisting of L2 domain of murine extra-cellular domain-EGFR and EGFR mimotope (EM-L2) was constructed and its prophylactic and therapeutic effects in a Lewis lung carcinoma mouse (C57/BL6) model evaluated. Constructed recombinant peptide vaccine is capable of reacting with anti-EGFR antibodies. Immunization of mice with EM-L2 peptide resulted in antibody production against EM-L2. The constructed recombinant peptide vaccine reduced tumor growth and increased the survival rate. Designing effective peptide vaccines could be an encouraging strategy in contemporary cancer immunotherapy. Investigating the efficacy of such cancer immunotherapy approaches may open exciting possibilities concerning hyperimmunization, leading to more promising effects on tumor regression and proliferation.

Synthesis and biochemical characterization of EGF receptor in a water-soluble membrane model system.

ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) receptor tyrosine kinases are critical for tissue development and maintenance, and frequently become oncogenic when mutated or overexpressed. In vitro analysis of ErbB receptor kinases can be difficult because of their large size and poor water solubility. Here we report improved production and assembly of the correctly folded full-length EGF receptor (EGFR) into nanolipoprotein particles (NLPs). NLPs are ~10 nm in diameter discoidal cell membrane mimics composed of apolipoproteins surrounding a lipid bilayer. NLPs containing EGFR were synthesized via incubation of baculovirus-produced recombinant EGFR with apolipoprotein and phosphoplipids under conditions that favor self-assembly. The resulting EGFR-NLPs were the correct size, formed dimers and multimers, had intrinsic autophosphorylation activity, and retained the ability to interact with EGFR-targeted ligands and inhibitors consistent with previously-published in vitro binding affinities. We anticipate rapid adoption of EGFR-NLPs for structural studies of full-length receptors and drug screening, as well as for the in vitro characterization of ErbB heterodimers and disease-relevant mutants.

Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is one of the most fatal malignant tumors with increasing incidence, mortality, and insensitivity to traditional chemo-radiotherapy and targeted therapy. Chimeric antigen receptor-modified T cell (CART) immunotherapy represents a novel strategy for the management of many malignancies. However, the potential of CART therapy in treating advanced unresectable/metastatic CCA is uncharted so far. CASE PRESENTATION: In this case, a 52-year-old female who was diagnosed as advanced unresectable/metastatic CCA and resistant to the following chemotherapy and radiotherapy was treated with CART cocktail immunotherapy, which was composed of successive infusions of CART cells targeting epidermal growth factor receptor (EGFR) and CD133, respectively. The patient finally achieved an 8.5-month partial response (PR) from the CART-EGFR therapy and a 4.5-month-lasting PR from the CART133 treatment. The CART-EGFR cells induced acute infusion-related toxicities such as mild chills, fever, fatigue, vomiting and muscle soreness, and a 9-day duration of delayed lower fever, accompanied by escalation of IL-6 and C reactive protein (CRP), acute increase of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase, and grade 2 lichen striatus-like skin pathological changes. The CART133 cells induced an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release, which needed emergent medical intervention including intravenous methylprednisolone. CONCLUSIONS: This case suggests that CART cocktail immunotherapy may be feasible for the treatment of CCA as well as other solid malignancies; however, the toxicities, especially the epidermal/endothelial damages, require a further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01869166 and NCT02541370 .

Effects of Colloidal Oatmeal Lotion on Symptoms of Dermatologic Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors.

OBJECTIVE: The common adverse effects associated with targeted therapy for cancer, such as epidermal growth factor receptor inhibitors (EGFRIs), are dermatologic toxicities that cause the patient physical discomfort and affect treatment. Colloidal oatmeal lotion (COL) has been proven to help prevent dermatitis and xerosis. Evidence of its effect on EGFRI-induced dermatologic toxicities, however, is limited. The purpose of this study was to explore the effect of COL on EGFRI-induced dermatologic toxicities. DESIGN AND SETTING: This study used a 1-group pretest-posttest design with a convenience sample of 30 patients with cancer who developed EGFRI-induced dermatologic toxicities from a medical center in southern Taiwan. All participants applied topical COL 3 to 5 times a day for 4 consecutive weeks and received a pretest and 4 posttests. OUTCOME MEASURES: A generalized estimating equation was used to assess the impact of demographics, disease characteristics, and weeks of COL use on dermatologic toxicity severity, body surface area affected, and level of pruritus. MAIN RESULTS: Significant differences were found between the pretest and all posttests after using COL with regard to the severity, body surface area affected, and level of pruritus in participants who developed EGFRI-induced dermatologic toxicities (P < .05). There were no significant differences in demographics or disease characteristics on EGFRI-induced dermatologic toxicities. CONCLUSIONS: Based on the study results, COL could improve the symptoms of dermatologic toxicities in those receiving EGFRIs with no adverse effects. Therefore, the authors suggest the use of COL in clinical settings.

EGFR targeted thermosensitive liposomes: A novel multifunctional platform for simultaneous tumor targeted and stimulus responsive drug delivery.

The epidermal growth factor receptor (EGFR) is a promising target for anti-cancer therapy. The aim of this study was to design thermosensitive liposomes (TSL), functionalized with anti-EGFR ligands for targeted delivery and localized triggered release of chemotherapy. For targeting, EGFR specific peptide (GE11) and Fab' fragments of cetuximab were used and the effect of ligand density on in vitro tumor targeting was investigated. Ligand conjugation did not significantly change the physicochemical characteristics of liposomes. Fab'-decorated TSL (Fab'-TSL) can specifically and more efficiently bind to the EGFR overexpressed cancer cells as compared to GE11 modified TSL. Calcein labeled Fab'-TSL showed adequate stability at 37°C in serum (<4% calcein released after 1h) and a temperature dependent release at above 40°C. FACS analysis and live cell imaging showed efficient and EGFR mediated cellular association as well as dramatic intracellular cargo release upon hyperthermia. Fab'-conjugation and hyperthermia induced enhanced tumor cell cytotoxicity of doxorubicin loaded TSL. The relative cytotoxicity of Fab'-TSL was also correlated to EGFR density on the tumor cells. These results suggest that Fab'-TSL showed great potential for combinational targeted and triggered release drug delivery.

EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.

PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time.

Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, the therapeutic applicability of EVs may be limited due to a lack of cell-targeting specificity and rapid clearance of exogenous EVs from the circulation. In order to improve EV characteristics for drug delivery to tumor cells, we have developed a novel method for decorating EVs with targeting ligands conjugated to polyethylene glycol (PEG). Nanobodies specific for the epidermal growth factor receptor (EGFR) were conjugated to phospholipid (DMPE)-PEG derivatives to prepare nanobody-PEG-micelles. When micelles were mixed with EVs derived from Neuro2A cells or platelets, a temperature-dependent transfer of nanobody-PEG-lipids to the EV membranes was observed, indicative of a 'post-insertion' mechanism. This process did not affect EV morphology, size distribution, or protein composition. After introduction of PEG-conjugated control nanobodies to EVs, cellular binding was compromised due to the shielding properties of PEG. However, specific binding to EGFR-overexpressing tumor cells was dramatically increased when EGFR-specific nanobodies were employed. Moreover, whereas unmodified EVs were rapidly cleared from the circulation within 10min after intravenous injection in mice, EVs modified with nanobody-PEG-lipids were still detectable in plasma for longer than 60min post-injection. In conclusion, we propose post-insertion as a novel technique to confer targeting capacity to isolated EVs, circumventing the requirement to modify EV-secreting cells. Importantly, insertion of ligand-conjugated PEG-derivatized phospholipids in EV membranes equips EVs with improved cell specificity and prolonged circulation times, potentially increasing EV accumulation in targeted tissues and improving cargo delivery.

Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles.

The epidermal growth factor receptor deletion variant EGFRvIII is known to be expressed in a subset of patients with glioblastoma (GBM) tumors that enhances tumorigenicity and also accounts for radiation and chemotherapy resistance. Targeting the EGFRvIII deletion mutant may lead to improved GBM therapy and better patient prognosis. Multifunctional magnetic nanoparticles serve as a potential clinical tool that can provide cancer cell targeted drug delivery, imaging, and therapy. Our previous studies have shown that an EGFRvIII-specific antibody and cetuximab (an EGFR- and EGFRvIII-specific antibody), when bioconjugated to IONPs (EGFRvIII-IONPs or cetuximab-IONPs respectively), can simultaneously provide sensitive cancer cell detection by magnetic resonance imaging (MRI) and targeted therapy of experimental GBM. In this study, we investigated whether cetuximab-IONPs can additionally allow for the radiosensitivity enhancement of GBM. Cetuximab-IONPs were used in combination with single (10 Gy × 1) or multiple fractions (10 Gy × 2) of ionizing radiation (IR) for radiosensitization of EGFRvIII-overexpressing human GBM cells in vitro and in vivo after convection-enhanced delivery (CED). A significant GBM antitumor effect was observed in vitro after treatment with cetuximab-IONPs and subsequent single or fractionated IR. A significant increase in overall survival of nude mice implanted with human GBM xenografts was found after treatment by cetuximab-IONP CED and subsequent fractionated IR. Increased DNA double strands breaks (DSBs), as well as increased reactive oxygen species (ROS) formation, were felt to represent the mediators of the observed radiosensitization effect with the combination therapy of IR and cetuximab-IONPs treatment.

Peptide vaccines and peptidomimetics of EGFR (HER-1) ligand binding domain inhibit cancer cell growth in vitro and in vivo.

Epidermal growth factor receptor (EGFR) is a validated target for several cancers including lung, colorectal, and certain subtypes of breast cancer. Cetuximab targets ligand binding of EGFR, but major problems like high cost, short t1/2, toxicity, and emergence of resistance are associated with the drug. Immunization with EGFR B cell epitopes will train the immune system to produce specific Abs that can kill cancer cells. Also, therapy with stable, less-expensive, and nontoxic EGFR peptide mimics will block EGFR signaling and inhibit cancer growth. We designed three peptides based on the contact sites between EGF and EGFR. The B cell epitopes were synthesized alone and also linked with the measles virus T cell epitope to produce a chimeric peptide vaccine. The peptide vaccines were immunogenic in both mice and rabbits and Abs raised against the vaccine specifically bound EGFR-expressing cells and recombinant human EGFR protein. The peptide mimics and the anti-peptide Abs were able to inhibit EGFR signaling pathways. Immunization with the peptide vaccine or treatment with the B cell epitopes significantly reduced tumor growth in both transplantable breast and lung cancer models. Immunohistochemical analysis also showed significant reductions in microvascular density and actively dividing cells in the tumor sections after treatment in the FVB/n breast cancer model. The 418-435 B cell epitope was the best candidate both as a vaccine or peptide mimic because it caused significant inhibition in the two mouse models. Our results show that this novel EGFR B cell epitope has great potential to be used as a vaccine or treatment option for EGFR-expressing cancers.

KRAS testing and epidermal growth factor receptor inhibitor treatment for colorectal cancer in community settings.

BACKGROUND: In metastatic colorectal cancer (mCRC), mutations in the KRAS gene predict poor response to EGF receptor (EGFR) inhibitors. Clinical treatment guidelines now recommend KRAS testing if EGFR inhibitors are considered. Our study investigates the clinical uptake and utilization of KRAS testing. METHODS: We included 1,188 patients with mCRCs diagnosed from 2004 to 2009, from seven integrated health care delivery systems with a combined membership of 5.5 million. We used electronic medical records and targeted manual chart review to capture the complexity and breadth of real-world clinical oncology care. RESULTS: Overall, 428 patients (36%) received KRAS testing during their clinical care, and 266 (22%) were treated with EGFR inhibitors. Age at diagnosis (P = 0.0034), comorbid conditions (P = 0.0316), and survival time from diagnosis (P < 0.0001) influence KRAS testing and EGFR inhibitor prescribing. The proportion who received KRAS testing increased from 7% to 97% for those treated in 2006 and 2010, respectively, and 83% of all treated patients had a KRAS wild-type genotype. Most patients with a KRAS mutation (86%) were not treated with EGFR inhibitors. The interval between mCRC diagnosis and receipt of KRAS testing decreased from 26 months (2006) to 10 months (2009). CONCLUSIONS: These findings show rapid uptake and incorporation of this predictive biomarker into clinical oncology care. IMPACT: In this delivery setting, KRAS testing is widely used to guide treatment decisions with EGFR inhibitors in patients with mCRCs. An important future research goal is to evaluate utilization of KRAS testing in other delivery settings in the United States.

Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer.

BACKGROUND: Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen. METHODS: Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended. RESULTS: The recommended phase 2 dose of celecoxib was 400 mg. Three dose-limiting toxicities included late in-field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade ≥ 3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow-up of 11 months, the 1-year locoregional control, progression-free survival, and overall survival rates were 60%, 37%, and 55%, respectively. CONCLUSIONS: Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis.

Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy.

BACKGROUND: Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes. METHODS: A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists. RESULTS: Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. CONCLUSIONS: Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified.