Single-agent Epidermal Growth Factor Receptor Research Articles

Epidermal growth factor receptor-mutated lung carcinomas with insufficient response to epidermal growth factor receptor inhibitors.

Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non-small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy.

Abstract 3346: BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC

Abstract Background: Activating mutations in EGFR, e.g., L858R (L) and Del19 (D), are observed in 14.1-32.3% of NSCLC worldwide and defines a druggable entity. Single agent EGFR TKI treatment was established in clinical trials. However, a treatment-emergent mutation of T790M (T) was identified as a major source of drug resistance. Irreversible 2nd and 3rd generation EGFR TKIs were shown effective. Mutant-specific inhibition by 3rd generation EGFR TKIs reduced adverse events such as skin toxicities. The emergence of a missense mutation at C797 (C), to which irreversible TKIs covalently bind, limited their efficacy. Patients harboring treatment-emergent C mutations are left with few therapeutic options. Despite anecdotal reports of efficacy from 1st generation TKIs, these complex molecular variants involving C797 are an increasing clinical concern. To prevent the emergence of drug-resistant subclones, a broad-spectrum EGFR TKI against both treatment-emergent and drug-naïve mutants is required. Such a 4th generation EGFR TKI must also enable monotherapy, allowing precise dose adjustment in case of toxicity. Method: Derived from BBT-176 which is under clinical evaluation (NCT04820023), we synthesized BBT-207 and other related molecules. Using Promega ADP-Glo™ kinase assay, we tested compounds against wild-type (WT) and mutated EGFR proteins. Ba/F3 cells harboring WT and mutated EGFR genes were created and cell viability was measured by CellTiter-Glo® and SpectraMax iD3®. In vivo anti-tumor activity was evaluated in Ba/F3 cell-derived xenograft models and an Osimertinib-resistant patient-derived xenograft model. Single dose pharmacokinetic (PK) study was performed in animals. Results: BBT-207 showed IC50 values < 10 nM against EGFR triple mutants (DTC and LTC) and comparable IC50 values against double mutants (DC and LC), while Osimertinib was ineffective in both groups. BBT-207 was also as active as Gefitinib to single mutants (D and L). Double mutants containing T790M (DT and LT) were inhibited effectively by BBT-207 and Osimertinib at similar concentrations, while not by Gefitinib. In in vivo models to which Osimertinib was inactive (LC and DTC), significant tumor growth inhibition was observed from BBT-207 alone, which was enhanced by the addition of Osimertinib. PK studies in mouse, rat, dog and monkey were consistent with high exposure and sustained drug concentrations above the IC50 values, with evidence of penetration into the central nervous system. Conclusion: BBT-207 is a reversible, mutant-specific, broad-spectrum TKI, active to clinically observed mutations of EGFR and is expected to be compatible with monotherapy of QD schedule in humans. BBT-207 is well-positioned to augment the treatment of EGFR mutated NSCLC, either for acquired drug resistance or in earlier line. Citation Format: Taiguang Jimmy Jin, Sang-Uk Kang, Chulwon Kim, Jehrod Brenneman, Mihee Song, Pavel Printsev, Bo-Bae Seo, Yong-Hee Lee, Sang-Yoon Lee. BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3346.

A Real-World Study of Patients with Advanced Non-squamous Non-small Cell Lung Cancer with EGFR Exon 20 Insertion: Clinical Characteristics and Outcomes.

In Europe, few data regarding the characteristics of EGFR exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available. Using a large real-world cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring EGFR exon 20ins. The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (EGFR) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring EGFR exon 20ins, common EGFR mutations, other EGFR mutations, and wild-type EGFR. Survival parameters were estimated by the Kaplan-Meier method in these four groups. Out of 9435 nsqNSCLC patients tested for EGFR, 1549 (16.4%) had a mutation, including 61 with EGFR exon 20ins (3.9% of all mutated EGFR). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0-1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval [CI] 22.3-32.4) months, the median real-world overall survival was 24.3 (19.1-32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6-37.5) in patients with common EGFR mutation (n = 1049) (p = 0.049) and 19.6 (95% CI 18.6-20.5) in patients with wild-type EGFR (n = 7866) (p = 0.2). This large national study in nsqNSCLC patients confirms that EGFR exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type EGFR, but worse than common EGFR mutations, highlighting the need for advancements for this rare population.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC).

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells.

Efficacy of single-agent epidermal growth factor receptor inhibition in the second-line setting for metastatic colorectal cancer with a goal towards retreatment strategies.

e16035 Background: Advances in the understanding of colorectal cancer (CRC) biology, including clonal evolution are leading to novel treatment strategies. Epidermal growth factor receptor inhibition (EGFRi) with cetuximab or panitumumab has shown significant clinical utility in KRAS/NRAS/BRAF wildtype (wt) CRC. These inhibitors are most commonly used in the third-line treatment setting in the United States. Upon the development of resistance to EGFRi, withdrawal of the EGFR inhibitor can lead to decay of resistant clones allowing for EGFR inhibitor retreatment in additional lines of treatment. Earlier-line use of single agent EGFRi could allow more patients to utilize a retreatment strategy, however no large prospective clinical trials have assessed the clinical activity of second line EGFRi in the setting of molecular selection. Here, we assess the clinical outcomes of EGFRi monotherapy for advanced KRAS wt CRC after initial progression on a single line 5FU based chemotherapy. Methods: A retrospective chart review examined patients who received single agent EGFRi in KRAS wt CRC in the second line setting. Line of therapy was defined at time of metastatic disease or recurrence within 6 months of adjuvant therapy. Clinical outcomes of overall response rate (ORR) and progression free survival (PFS) were assessed per RECIST v1.1. Results: 20 cases were identified who received single agent EGFRi (panitumumab or cetuximab) as monotherapy in the second line setting. All pts received prior 5FU based chemotherapy. Reasons for using EGFR inhibitor monotherapy in this setting included to avoid toxicities from prior chemotherapy (largely immunosuppression and GI toxicities), bridge from recent operative management, or maintain functional performance status. Patients had median age of 62 [45, 89] and majority with ECOG PS 0-1 (78.5% of those reported). Best responses included complete response 7%, partial response 21%, stable disease 64% and progressive disease 7%, and a disease control rate of 93%. The 6 and 8 month PFS were 70% and 50%, respectively. PFS ranged from 1.5 to 17.3 months with median PFS 8.2 ± 3.6 months. Conclusions: This work demonstrates preliminary efficacy data to use single agent EGFRi in the second-line setting for KRASwt patients with CRC. Future investigations will aim to prospectively validate the benefit of this treatment strategy to facilitate EGFRi retreatment and improve patient survival.

P2.06-004 A Phase 1b Study of Erlotinib and Momelotinib for EGFR TKI Naïve EGFR Mutated Metastatic Non-Small Cell Lung Cancer: Topic: Phase I Trials

Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose. Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses). MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.

The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials

Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI.

ObjectiveNon-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor (EGFR-TKI) compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients.MethodsThe data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI (gefitinib 250 mg qd or erlotinib 150 mg qd), and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan.ResultsOf the 27 patients who received EGFR-TKI retreatment, 1 (3.7%) patient was observed in complete response (CR), 8 (29.6%) patients in partial response (PR), 14 (51.9%) patients in stable disease (SD), and 4 (14.8%) patients in progressive disease (PD). The disease control rate (DCR) was 85.2% (95% CI: 62%-94%). The median progression-free survival (mPFS) was 6 months (95% CI: 1-29). Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCR was 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR, 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCR was 85.7%, and the mPFS was 9.5 months. Significant difference was found between the two groups in PFS but not in response rate or DCR.ConclusionRetreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.

Targeting EGFR and PI3K pathways in ovarian cancer

Background:The epidermal growth factor receptor (EGFR) is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. This may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway.Methods:We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the EGFR inhibitors erlotinib and gefitinib in ovarian cancer primary cell cultures.Results:The single-agent EGFR inhibitors showed little activity, although some activity was seen with the single-agent PI3K inhibitor, ZSTK474. Combinations of ZSTK474 with EGFR inhibitors showed enhanced activity with some evidence of synergy, whereas sirolimus combinations were less active. The results were not explicable on the basis of PIK3CA mutation or amplification, or PTEN loss, although one tumour with a KRAS mutation showed resistance to EGFR inhibitors. However, there was correlation of the EGFR expression with sensitivity to EGFR and resistance to PI3K active agents, and inverse correlation in the sensitivity of individual tumours to agents active against these pathways, suggesting a mechanism of action for the combination.Conclusion:Phase I/II clinical trials with these agents should include further pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.

First-Line Management of EGFR-Mutated Advanced Lung Adenocarcinoma: Recent Developments

Gefitinib and erlotinib are small-molecule reversible tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR). Objective responses have been observed frequently in patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations, the most common being deletions in exon 19 and the exon 21 L858R mutation. EGFR mutations are prevalent in female patients, those who have never smoked, those of Asian ethnicity and those who have adenocarcinoma histology. Given the efficacy of EGFR TKIs in advanced NSCLC in the salvage setting, and their favourable toxicity profile compared with conventional chemotherapy, there is considerable interest in evaluating their efficacy in the first-line treatment of advanced NSCLC. To date, there have been several phase II and phase III studies that have examined the efficacy of first-line single-agent EGFR TKIs in unselected, clinically selected or molecularly selected populations. Here we review and compare the differences in these phase III trials. Most phase III trials chose progression-free survival (PFS) rather than overall survival (OS) as their primary endpoint. PFS was prolonged but OS was not. The recent development of novel irreversible EGFR TKIs, such as afatinib and dacomitinib, is also reviewed.

Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer.

Treatment of advanced stage lung cancer is changing rapidly. With the new found knowledge on molecular targets such as the epidermal growth factor receptor (EGFR), effective therapy is now available in a selected population with the target mutation. Single-agent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for patients with activating-EGFR mutation such as base-pair deletion in exon 19 or point mutation at exon 21. At the same time, this class of drugs may be combined with chemotherapy. Studies on the concurrent combination of chemotherapy and EGFR-TKI confirmed a lack of efficacy. A phase II study on sequential intercalated combination has demonstrated an improvement in progression-free survival (PFS), but this needs to be validated by the ongoing phase III study. The third approach is to combine EGFR-TKI as maintenance therapy after tumour response or stable disease to cytotoxic chemotherapy. Two phase III studies have shown improvement in PFS, but the use of biomarkers for the selection of maintenance therapy remains debatable. Cetuximab is a monoclonal antibody against EGFR and its combination with chemotherapy was shown to improve overall survival in an unselected population. A new biomarker using the H-score will help to select patients for this combination.

Molecular Targeted Therapies for Head and Neck Cancer: A New Era in DNA-based Therapeutics

Over the past decade, the field of cancer therapeutics has slowly moved towards selective molecular targeting of oncogene addicted tumors. Inhibition of molecules overexpressed in or critical for vital mechanisms in cancer cells should theoretically induce selective tumor cell death. Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer world-wide. The front runner in molecular targets for HNSCC has been the Epidermal Growth Factor Receptor (EGFR), although other targets are also being developed in the light of low clinical outcomes using single agent EGFR inhibitors including cetuximab and erlotinib.

Abstract C35: Response of colorectal cancer cells to combination of EGFR mAbs with oxaliplatin is determined by the sequence of administration.

Abstract Monoclonal antibodies (mAb) targeting EGFR (epidermal growth factor receptor), cetuximab (Erbitux) and panitumumab (Vectibix), have been approved for the therapy of metastatic colorectal cancer (mCRC). However, the majority of the patients are primarily resistant to EGFR mAbs or become resistant during the treatment. While activating mutations in KRAS have been reported to confer resistance to EGFR mAbs, some recent randomised controlled trials with EGFR mAbs combined to oxaliplatin-based regimens have failed to demonstrate clinical effect even in patients with KRAS wild-type mCRC. We have addressed the effects of EGFR mAbs on the growth of KRAS wild-type and KRAS mutant CRC cell lines in the absence and presence of oxaliplatin. Our observations indicate that while the KRAS mutant genotype is predictive for resistance to single agent EGFR mAbs, the combination of EGFR mAb plus oxaliplatin is not superior to oxaliplatin alone regardless of the KRAS status. However, sequential administration of oxaliplatin prior to EGFR mAb results in a clear additive effect whereas a sequence of EGFR mAb prior to oxaliplatin antagonizes the effect of oxaliplatin. The opposing effects of the two different sequences seem to be independent on both KRAS and BRAF mutation status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C35.

Targeting ErbB3-mediated stromal–epithelial interactions in pancreatic ductal adenocarcinoma

Background:We sought to investigate the role of ErbB3-mediated signalling on the interaction between pancreatic cancer-associated fibroblasts (CAF) and carcinoma cells in an effort to disrupt tumourigenic pancreatic ductal adenocarcinoma (PDAC) stromal–epithelial cross-communication.Methods:Primary CAF cultures were established from human PDAC surgical specimens. AsPC-1 pancreatic cancer cell murine subcutaneous xenografts were developed in the presence and absence of CAF and were subsequently treated with epidermal growth factor receptor (EGFR) inhibitors (erlotinib) and ErbB3 inhibitors (MM-121, monoclonal ErbB3 antibody).Results:Cancer-associated fibroblasts were found to secrete neuregulin-1 (NRG-1), which promoted proliferation via phosphorylation of ErbB3 and AKT in AsPC-1 PDAC cells. This signalling cascade was effectively inhibited both in vitro and in vivo by specific ErbB3 blockade with MM-121, with greater degree of tumourigenesis inhibition when combined with erlotinib. The CAF–AsPC-1 pancreatic cancer xenografts reached significantly greater tumour volume than those xenografts lacking CAF and were resistant to the anti-tumour effects of EGFR inhibition with erlotinib.Conclusion:Cancer-associated fibroblasts-derived NRG-1 promote PDAC tumourigenesis via ErbB3-AKT signalling and overcomes single-agent EGFR inhibition. Disruption of this stromally mediated tumourigenic mechanism is best obtained through combined EGFR-ErbB3 inhibition with both erlotinib and MM-121. We have identified the NRG-1/ErbB3 axis as an attractive molecular target for the interruption of tumourigenic stromal–epithelial interactions within the PDAC microenvironment.

Future Scenarios for the Treatment of Advanced Non-Small Cell Lung Cancer: Focus on Taxane-Containing Regimens

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century--that is, two-drug combinations consisting of either cisplatin or carboplatin plus a third-generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)--remain the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin-pemetrexed over cisplatin-gemcitabine as first-line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single-agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta-analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy-naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.

Somatic EGFR Mutation and Gene Copy Gain as Predictive Biomarkers for Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer

The aim of this systematic review and meta-analysis was to characterize common EGFR molecular aberrations as potential predictive biomarkers for response to monotherapy with tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). We systematically identified articles investigating EGFR status [somatic mutational and gene copy aberrations (copy number)] in patients with NSCLC treated with TKIs. Eligible studies had to report complete and partial response rates stratified by EGFR status. We used random effects models for bivariable meta-analysis of sensitivity and specificity; positive and negative likelihood ratios (+LR and -LR, respectively) were also calculated and were considered as secondary end points. Among 222 retrieved articles, 59 were considered eligible for the somatic EGFR mutation meta-analysis (1,020 mutations among 3,101 patients) and 21 were considered eligible for the EGFR gene copy number meta-analysis (542 gene gain among 1,539 patients). EGFR mutations were predictive of response to single-agent TKIs [sensitivity, 0.78; 95% confidence interval (95% CI), 0.74-0.82; specificity, 0.86; 95% CI, 0.82-0.89; +LR, 5.6; -LR, 0.25]. EGFR gene gain was also associated with response to TKIs, albeit with lower sensitivity and specificity. In subgroup analysis, the only recognized trend was for a higher predictive value in Whites compared with East Asians for both mutation and gene copy number. This analysis provides empirical evidence that EGFR mutations are sensitive and specific predictors of response to single-agent epidermal growth factor receptor TKIs in advanced NSCLC. The diagnostic performance of mutations seems better than that of EGFR gene gain.

Clinical outcomes in non‐small‐cell lung cancer patients with EGFR mutations: pooled analysis

Non-small-cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR) is a distinct subgroup of NSCLCs that is particularly responsive to EGFR tyrosine-kinase inhibitors (TKIs). A weighted pooled analysis of available studies was performed to evaluate clinical outcome in patients with EGFR-mutated NSCLC who were treated with chemotherapy or EGFR TKIs. Median progression-free survival (PFS) times were pooled from prospective or retrospective studies that evaluated chemotherapy or single-agent EGFR TKIs (erlotinib or gefitinib) in patients with NSCLC and EGFR mutations. Among the studies identified for inclusion in the analysis, 12 evaluated erlotinib (365 patients), 39 evaluated gefitinib (1069 patients) and 9 evaluated chemotherapy (375 patients). Across all studies, the most common EGFR mutations were deletions in exon 19 and the L858R substitution in exon 21. In the weighted pooled analysis, the overall median PFS was 13.2 months with erlotinib, 9.8 months with gefitinib and 5.9 months with chemotherapy. Using a two-sided permutation, erlotinib and gefitinib produced a longer median PFS versus chemotherapy, both individually (P= 0.000 and P= 0.002, respectively) and as a combined group (EGFR TKI versus chemotherapy, P= 0.000). EGFR TKIs appear to be the most effective treatment for patients with advanced EGFR-mutant NSCLC. Ongoing prospective trials comparing the efficacy of first-line chemotherapy and EGFR TKIs in EGFR-mutant disease should provide further insight into the most appropriate way to treat this specific group of patients.

Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Ten percent of North American patients with non-small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

9000 Mutations of EGFR (mEGFR) in tumour tissue and serum DNA from stage IV non-small-cell lung cancer (NSCLC) patients (p) prospectively treated with erlotinib

Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC.We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and −LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity.Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0·21 [95% CI 0·16–0·28], specificity=0·94 [0·89–0·97]; +LR=3·52; −LR=0·84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0·47 [0·43–0·52]; specificity=0·93 [0·83–0·97]; +LR=6·82; −LR=0·57).This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high −LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.None.