Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Research Articles

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Abstract 3017: Using a pharmacodynamic biomarker led approach to explore and quantify the combination effect of savolitinib and osimertinib in the LG1208 NSCLC PDX model

Abstract MET-amplification has been identified as a resistance mechanism in >5% of patients with non-small cell lung cancer (NSCLC) and 25% of those that progress on 1st/2nd or 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). There are no approved therapies specifically indicated to treat EGFR mutation-positive (EGFRm)/MET amplified NSCLC patients. We report preclinical data of savolitinib (AZD6094, HMPL-504, volitinib, a potent and selective MET inhibitor) plus osimertinib (3rd generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR sensitizing mutation and EGFR T790M) in an EGFRm/MET amplified model. Combination efficacy of savolitinib and osimertinib was tested in an EGFRm (L858R) and MET-amplified LG1208 PDX model, resistant to osimertinib. As single agents, and at doses that deliver clinically relevant exposures, osimertinib (10 mg/kg) and savolitinib (15 mg/kg) showed minimal (32% tumor growth inhibition [TGI]) and moderate (81% TGI) anti-tumor activity, respectively. Upon combination, at a fixed dose of osimertinib (10 mg/kg), anti-tumor activity increased with savolitinib dose, ranging from 1 mg/kg (99.8 % TGI) to 15 mg/kg (77.9% regression). Pharmacokinetic-pharmacodynamic (PKPD) modelling was also conducted linking exposure of savolitinib to inhibition of phosphorylated MET (pMET), and osimertinib to inhibition of pEGFR. A combination effect on pEGFR was observed whereby the maximum inhibition of pEGFR increased from approximately 50% with no savolitinib to approximately 90% with 15 mg/kg of savolitinib. The exposure-dependent effect of savolitinib on pEGFR was accounted for in the PKPD model by incorporating an interaction term such that the inhibition of pEGFR is modelled as a function of savolitinib and osimertinib exposure. This PKPD model was successfully used to link to the anti-tumor activity and provide biomarker-led rationale for the combination benefit seen for efficacy in this model. Overall, the PKPD analysis describes the biomarker changes linking to efficacy and provides supporting insight into the exposure requirements for combination dosing in the clinic. Savolitinib plus osimertinib was tested in the TATTON study (NCT02143466) where patients with EGFRm, MET-amplified NSCLC with prior progression on EGFR-TKIs had encouraging responses to this combination therapy. A phase 2 trial, SAVANNAH (NCT03778229), is testing the combination of osimertinib and savolitinib in patients with EGFRm, MET-amplified NSCLC with prior progression on osimertinib only. Citation Format: Rhys Jones, Awlin Schuller, Klas Petersson, Ghada Ahmed, Stein Schalkwijk, Areya Tabatabai, Andrew Mortlock, Rana Anjum. Using a pharmacodynamic biomarker led approach to explore and quantify the combination effect of savolitinib and osimertinib in the LG1208 NSCLC PDX model [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 3017.

A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy

Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1= 30%) for the BM cohort and overall survival (OS) (H1= 5 months) for the LM cohort. The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0-16.6]; the median OS was 16.9 months [95% CI 7.9-not reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1-NR); the median PFS was 8.0 months (95% CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n= 18, P= 0.39) and LM (n= 17, P=0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P= 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2. Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Intracavitary chemotherapy with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is not superior to TKI monotherapy in controlling malignant pleural effusion recurrence in EGFR-mutated lung cancer patients.

Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients benefit from EGFR-tyrosine kinase inhibitors (TKIs) therapy. There are few studies comparing the efficacy between intrapleural chemotherapy combination with TKIs and TKIs alone in controlling re-accumulation of malignant pleural effusions (MPEs). The purpose of the study was to determine if patients with EGFR-mutated NSCLC and MPEs would benefit from intrapleural chemotherapeutics with an oral EGFR-TKI than EGFR-TKI alone. We evaluated EGFR-mutated lung cancer patients with MPEs in Zhejiang Cancer Hospital. We evaluated the efficacy. Progression-free survival (PFS) and overall survival (OS) was evaluated by Kaplan-Meier method. One hundred one NSCLC patients with MPEs at the time of diagnosis were included. We divided the patients into two groups. The overall response rate (ORR) with respect to MPE recurrence between the TKI alone and combination therapy groups was 65.5% (38/58) and 58.1% (25/43) (P=0.449). The disease control rate was 89.7% (52/58) and 86.0% (37/43) (P=0.579), respectively. The PFS in the TKI alone and TKI plus intrapleural drugs was 10.3 and 9.9 months, respectively (P=0.746). The intrapleural PFS was 11.4 and 11.0 months for the TKI alone and combination groups, respectively (P=0.188). The OS was 24.9 and 22.6 months (P=0.543), respectively. Hematologic toxicity and chest pain were more frequent in the combination therapy than TKI alone groups. Intrapleural chemotherapy with TKI did not improve the efficacy of controlling MPEs in patients with EGFR-mutated NSCLC, but may increase adverse events, which are typical side effects of chemotherapy. We could treat these patients with TKI drugs alone combined with pleural effusion drainage.

P3.01-93 Osimertinib-Related Hematological and Pulmonary Toxicities in Advanced NSCLC Patients: Combined Analysis of Phase III Trials

In both epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitizing and EGFR T790M resistance mutations in patients with advanced non-small-cell lung cancer (NSCLC), osimertinib, a third-generation and irreversible oral EGFR-TKI, has been shown to improve survival in studies. We performed a systematic review and meta-analysis of phase III randomized controlled trials (RCT) to determine the risk of hematological and pulmonary toxicities among patients with advanced NSCLC treated with osimertinib. We undertook a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through March 2018. Phase III RCTs that mention hematological and pulmonary toxicities as adverse effects were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). A total of 971 patients with advanced NSCLC from two phase III studies were eligible for analysis. The study arm used osimertinib while the control arm utilized either chemotherapy (carboplatin/cisplatin+ pemetrexed) or standard EGFR-TKIs (gefitinib or erlotinib). The randomization ratio was 1:1 in the FLAURA study and 2:1 in the AURA3 study. Osimertinib was utilized in T790M-positive advanced NSCLC after prior first-line EGFR-TKIs in the AURA3 study (n= 556) and as first-line treatment in the FLAURA study (n= 415). The RR of all-grade side effects were as follows: anemia, 0.594 (95% CI: 0.433 – 0.814, p = 0.001); cough, 1.122 (95% CI: 0.829 – 1.520, p = 0.455); dyspnea, 1.143 (95% CI: 0.784 – 1.666; p = 0.487); and ILD, 2.378 (95% CI: 0.984 – 5.744; p = 0.054). The RR of high-grade adverse effects were as follows: anemia, 0.175 (95% CI: 0.072 – 0.425, p < 0.001); neutropenia, 0.293 (95% CI: 0.138 – 0.623; p = 0.001); thrombocytopenia, 0.183 (95% CI: 0.060 – 0.564, p = 0.003); pneumonia, 1.237 (95% CI: 0.442 – 3.459; p = 0.685); dyspnea, 0.895 (95% CI: 1.192 – 4.175; p = 0.888); and ILD, 1.238 (95% CI: 0.404 – 3.789; p = 0.708). Our meta-analysis demonstrated that patients on osimertinib experienced a significant decrease in the risk of hematological toxicities, compared to control arm. Moreover, no increase in the risk of pulmonary toxicities was noted in the osimertinib group.

Frequency of T790M mutations after progression on epidermal growth factor receptor tyrosine kinase inhibitor in metastatic non-small cell lung cancer in Indian patients: real-time data from tertiary cancer hospital.

Aim:The aim of this study is to determine the incidence of T790M mutations after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and median duration on TKI before progression on TKI.Methods:Records of Rajiv Gandhi Cancer Institute and Research Centre, of patients who were diagnosed with metastatic adenocarcinoma of the lung and progressed on oral EGFR TKIs and underwent T790M mutation analysis in the last 6 months were retrospectively reviewed. The incidence of T790M positivity, sites of progression, and median duration of TKI treatment before progression was calculated.Results:Among 31 patients, 10 patients have undergone rebiopsy, and 24 patients had undergone liquid biopsy by Droplet Digital polymerase chain reaction (ddPCR), and three patients had undergone both tests. Among all, the rate of T790M positivity was 54.8%. Among these 17 patients positive for T790M, seven patients were positive by biopsy, and 11 patients were positive by ddPCR. Among three patients who underwent both, one was positive by both. The most common site of progression among all patients is pleura, and 10% of patients progressed in brain post-TKI. Median progression-free survival on TKI before progression is 289.7 days, highest being 1290 days, and lowest 45 days.Conclusions:Exact incidence of T790M mutations after progression on TKI s in Asian population is not exactly known and requires large data, as incidence may be different than reported in the Western population. Rebiopsy and ddPCR help to determine the most common type of resistance after progression on TKI, for which effective targeted therapy is available.

Phase II trial of capecitabine +/- erlotinib in advanced colorectal cancer, with retrospective KRAS and primary tumor site analysis.

781 Background: Palliative capecitabine (X) monotherapy for advanced colorectal colorectal cancer (aCRC) is generally well tolerated by elderly or frail pts. Epidermal growth factor receptor (EGFR) monoclonal antibodies improve efficacy when added to combination chemotherapy for mCRC. Erlotinib (E), an oral EGFR tyrosine kinase inhibitor (TKI) may add benefit when added to X. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of X and E in aCRC. Methods: Pts with untreated aCRC who were either deemed unfit for, or chose against, combination chemotherapy were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), and safety. Tumours were designated as left-sided if there were distal to the transverse colon. KRAS status was retrospectively analyzed for 72 of 82 pts. Results: From 2004 to 2008, 82 pts were randomized to X alone (40 pts) or XE (42 pts). TTP was not different between X and XE (7.9 m vs. 9.2 m; p = 0.890), however, KRAS subgroup analysis revealed pts with KRAS mutations did significantly worse when treated with XE compared to X alone (1.9m vs 7.4m; HR = 2.63; P = 0.038). Pts with KRAS wild-type (WT) treated with XE had an improved TTP compared to those treated with X (11.7m vs. 8.4m, HR = 0.73; Wilcoxon P = 0.061). KRAS-WT pts treated with XE with left-sided disease had an improved OS compared to pts with right-sided disease (16m vs. 12.1m, not significant). KRAS-WT pts with left-sided primaries treated with XE had a non-significant improvement in TTP compared to pts treated with X alone (11.7m vs 8.4m). XE was well tolerated but had significantly higher rates of diarrhea and acneform skin rash. Conclusions: The addition of E to X is generally well tolerated but associated with additional toxicities. E may benefit pts with KRAS-wild-type CRC, specifically those with left-sided primary tumours, and likely harms those with KRAS-mutated CRC. Further study of oral EGFR-TKIs in left-sided KRAS-wild-type aCRC is warranted.

Abstract B20: Combination of Ganoderma lucidum extract and erlotinib decreases IBC progression

Abstract Inflammatory breast cancer (IBC) is a rare, and the most lethal and aggressive type of advanced breast cancer. Despite many efforts to increase IBC treatment efficacy, prognosis of this cancer is very grim. IBC cells and tissues overexpress epidermal growth factor receptor (EGFR), and this is a poor prognostic factor in this disease. Erlotinib is a small oral EGFR tyrosine kinase inhibitor that causes reverse inhibition of the EGFR tyrosine kinase domain. However, Erlotinib resistance can reduce the efficacy of this treatment. Our published results demonstrate that the extract of medicinal mushroom, Ganoderma lucidum (GLE), selectively decreases IBC cell viability. Our hypothesis is that the combination of GLE and Erlotinib will be more effective than their treatments alone, in reducing cancer cell viability and tumor progression via the EGFR signaling pathway. The IBC cell line, SUM149, was treated with Erlotinib and GLE at different concentrations for 72hrs to examine cell viability. To determine tumor progression, severe combined immunodeficient (SCID) mice were injected with SUM149 cells and then treated with Erlotinib alone, and in combination with GLE for 13 weeks. The expression of extracellular signal-regulated kinase (ERK)-1/2 and serine/threonine-specific protein kinase (AKT) of tumor samples were studied by Western Blot analysis, as the interaction of these signaling pathways are important in drug resistance effects and tumorigenesis. Our results show that SUM149 cells treated with Erlotinib and/or GLE decrease their viability in a dose-dependent manner. Moreover, using both treatments in combination at lower dosages than those alone results in reduced viability. In vivo results show that during weeks 8 to 13 of treatment, tumor volume in Erlotinib plus GLE treated mice was significantly lower when compared to tumor volume in Erlotinib treated mice. Also, Erlotinib alone and Erlotinib plus GLE treated mice displayed significantly reduced tumor weight when compared with their respective controls. Tumor lysate analysis shows that Erlotinib plus GLE treated mice have significant lower expression of total ERK-1/2 and total AKT in their tumors when compared with Erlotinib treated mice. Our results suggest that the combination of Erlotinib with GLE may be affecting the downstream EGFR signaling pathway. We conclude that a combinatorial therapeutic approach might be the best way to increase prognosis in IBC patients. This project was sponsored by NIH/NCI #1F31CA174307 to ISA, Title V PPOHA US Department of Education #P031M105050 to UCC, NIH/RCMI #G12MD007583 to UCC/MMM, NIH/INBRE #5P20 GM103475 to UPR/UCC/MMM, NIH/SC3 #SC3GM111171 to UCC/MMM and NIH/NIGMS R25GM110513 to UCC/LAC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the supporting agencies. Citation Format: Tiffany J. Rios-Fuller, Ivette J. Suarez-Arroyo, Mercedes Lacourt-Ventura, Geronimo Maldonado, Luis A. Cubano, Michelle M. Martinez-Montemayor. Combination of Ganoderma lucidum extract and erlotinib decreases IBC progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B20.

An active treatment of lung adenocarcinoma cancer with brain metastases: icotinib.

Lung cancer has the highest mortality rate of all cancers worldwide. A total of 70%–75% of all lung cancers are non-small cell lung cancer (NSCLC) with two-thirds presenting with locally advanced or metastatic disease at diagnosis. Brain metastasis is one of the most common problems in the management of NSCLC, worsening the prognosis and quality of life of NSCLC patients. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib have been tested in patients with NSCLC and brain metastasis. Icotinib is a new type of oral EGFR-TKI. In this report, we describe a patient with lung adenocarcinoma cancer with brain metastases who received icotinib treatment and kept satisfactory health-related quality of life for 1 year.

Critical appraisal of the role of gefitinib in the management of locally advanced or metastatic non-small cell lung cancer.

Past studies have demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors can significantly improve clinical outcomes in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and sensitive EGFR gene mutations. Gefitinib (Iressa®), the first oral EGFR tyrosine kinase inhibitor, has been shown to be more effective and better tolerated than chemotherapy either in first-line or second-line treatment for patients with advanced NSCLC harboring sensitive EGFR mutations. Conversely, among patients with wild-type EGFR, gefitinib is inferior to standard chemotherapy in both the first-line and second-line settings. Further, gefitinib is effective in patients with brain metastases because of its low molecular weight and excellent penetration of the blood–brain barrier. In this review, we summarize the current data from clinical trials with gefitinib and appraise its role in the management of locally advanced or metastatic NSCLC.

Phase I study of the safety and pharmacokinetics of epitinib, an oral EGFR tyrosine kinase inhibitor, in patients with advanced solid tumors.

e19042 Background: Epitinib is an oral small molecule compound selectively inhibits epidermal growth factor receptor (EGFR). It has demonstrated potent inhibitory effects on multiple human tumor xenografts with a large safety window and broad tissue distribution including high drug contribution in brain. This first-in-human study is being conducted to assess the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib. Methods: This phase I study uses a 3+3 design for dose-escalation of Epitinib given once daily (QD) in 28-day treatment cycles in patients with solid tumors who failed or have no access to standard therapies. Safety and tumor response are assessed according to NCI CTCAE 4.0 and RECIST 1.1, respectively. Results: By Dec 31, 2012, 19 pts aged 40-66 yr old (ECOG PS 1) with NSCLC (n=16) or breast cancer (n=3) were enrolled in 5 dose cohorts of 20-160 mg. Six NSCLC pts had EGFR mutations (3 with T790M). All pts had ≥2 lines of prior systemic treatments (7 pts with gefitinib or elotinib). Most AEs were mild (Gr1). Treatment-related AEs included skin rash (36.8%), abnormal liver function tests (42.1%), diarrhea (10.5%), vomiting (5.3%), paronychia (5.3%), decreased neutrophil count (5.3%) and increased creatinine (5.3%). Three SAEs were reported as possibly unrelated to the study drug. No DLT was observed and MTD has not been reached yet. PK analysis showed that the mean elimination half-life of Epitinib was approximately 40 hours and Tmax was around 2 h. Both Cmaxand AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 15 evaluable pts, 1 EGFR mutation+ NSCLC pt achieved confirmed partial response (66.7% tumor reduction) for more than 6 months and the treatment is ongoing; 8 pts had stable disease, including 1 with T790M for 6 months and 1 with brain metastasis for 12 months who is still on treatment. Conclusions: Epitinib was well tolerated at doses up to 160mg QD to date with manageable adverse events and excellent pharmacokinetic properties. Encouraging clinical activity was observed, including durable SD in NSCLC patients with T790M or brain mets.

Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC

The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.

Astrocyte elevated gene 1 (AEG-1) mRNA expression in non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

10541 Background: NSCLC p with EGFR mutations respond to the oral EGFR tyrosine kinase inhibitors erlotinib and gefitinib, although the duration of response in individual p is unpredictable. In our previous study, we found that erlotinib-treated p with low BRCA1 mRNA levels had a progression-free survival (PFS) of 27 months (m) vs 10 m for p with high levels (P=0.02). AEG-1 is a multifunctional oncogene that plays a role in several carcinogenic processes. Through PI3K/Akt, AEG-1 activates IKK, leading to phosphorylation and destabilization of the NF-kB inhibitor NFKBIA, which is a gatekeeper for EGFR signaling. Methods: Tumor mRNA expression levels of BRCA1 and AEG-1 were assessed by quantitative PCR in 77 erlotinib-treated p with EGFR mutations. Expression levels were dichotomized at the median. Results: PFS was longer in p with low AEG-1 expression (27 vs 12 m; P=0.003). Median survival (MS) was not reached for p with low AEG-1 levels and was 24 m for p with high levels (P=0.08). Based on these results, we generated an AEG-1/BRCA1 risk model: p with high levels of both genes were considered high-risk, p with low levels of both genes were low-risk, and p with high levels of one and low levels of the other gene were intermediate-risk. PFS was not reached in the low-risk group, while it was 18 m for the intermediate-risk group and 8 m for the high-risk group (P=0.00006) (HR for high- vs low-risk groups, 6.6; 95%CI, 2-4-18; P<0.00001). MS was not reached in the low-risk group, while it was 31 m for the intermediate-risk group and 18 m for the high-risk group (P=0.05). In the multivariate analysis for PFS, the only independent prognostic variables were bone metastases (HR, 2.7; 95%CI, 1.1-6.5; P=0.03) and the AEG-1/BRCA1 risk groups (HR for high-risk group, 7.7 (95%CI, 2.8-21.3; P<0.00001). Conclusions: The two-gene risk model based on AEG-1 and BRCA1 mRNA expression was strongly associated with clinical outcome, with significantly shorter PFS and MS in the high-risk group. This model can be useful for the proper individualized management of p with EGFR mutations.

A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have activity in solid tumors. The authors evaluated an oral EGFR TKI, erlotinib, in patients with previously treated esophageal cancer. Thirty patients with measurable, metastatic cancer of the esophageal and gastroesophageal junction received 150 mg erlotinib daily. EGFR-negative tumors (6 patients; 20%) and EGFR-over expressing tumors (24 patients; 80%) were treated. Most patients were men (70%) with adenocarcinoma (57%) and had received previous chemotherapy (97%). Two partial responses were observe d in the EGFR-positive cohort (2 of 24 patients; 8%), and no responses were observed in the EGFR-negative cohort (0 of 6 patients). Reponses were limited to patients who had squamous cell carcinoma (2 of 13 patients; 15%; response duration, 5.5-7 months). The time to tumor progression was longer in patients who had squamous cell carcinoma (3.3 months; range, 1-24 months) compared with patients who had adenocarcinoma (1.6 months; range, 1-6 months; P = .026). Therapy was tolerable with the expected toxicity of skin rash (grade 1-2, 67%; grade 3, 10%). Erlotinib had limited activity in patients with esophageal cancer, and responses and some protracted stable disease were observed in those with squamous cell carcinoma. Efficacy according to EGFR status could not be assessed given the rarity of EGFR-negative tumors. The current results indicated that further evaluation of this agent in squamous cell carcinoma is warranted. Cancer 2011. © 2010 American Cancer Society.

Cetuximab Monotherapy in Patients with Advanced Non-small Cell Lung Cancer After Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non-small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI). Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m on day 1 and then 250 mg/m weekly until disease progression or unacceptable toxicity. The primary end point was response rate. Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6-5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2-19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case. Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses.

Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report

BackgroundGallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene.Case presentationA 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found.ConclusionThis case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.

A review of erlotinib – an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor

Importance of the field: The epidermal growth factor receptor (EGFR) is a cell surface receptor for EGF and transforming growth factor-alpha which is overexpressed by a number of human tumors. Erlotinib, developed by OSI Pharmaceuticals, is an oral selective EGFR tyrosine kinase inhibitor, the only drug of its class approved for the treatment of locally advanced non-small cell lung cancer (NSCLC) after failure of at least one previous chemotherapy regimen and for first-line treatment of advanced pancreatic cancer with gemcitabine.Areas covered in this review: Findings from major Phase III studies that led to the approval of erlotinib are summarized in this review. Key aspects of erlotinib clinical pharmacology, dosing in special populations (e.g., smokers), and toxicity are also reviewed. The article also outlines the results of all correlative studies that have been done in clinical trials of patients receiving erlotinib to identify biomarkers that predict response, such as rash, EGFR status of the tumor by immunohistochemistry and activating EGFR mutations.What will the reader gain: The reader will have an outline of the landmark trials leading to the approval of this drug and know which ongoing Phase III trials are expected to enhance the knowledge of this drug's activity. The reader will also understand the pharmacologic bases for the recent change in dosing guidelines of erlotinib, and the current knowledge of clinical and laboratory correlates that can serve as surrogates of response.Take home message: This is a well-tolerated oral biologic agent with two approved clinical indications. More studies to individualize therapy and optimize dosing are needed.

Phase II trial of erlotinib in advanced pancreatic cancer (PC)

4609 Background: The epidermal growth factor receptor (EGFR) is a potentially important target in PC. Benefit from erlotinib (Tarceva), an oral EGFR tyrosine kinase inhibitor has been associated with the presence of a skin rash. The purpose of this study was to determine the efficacy of erlotinib, dosed to achieve a rash, in patients (pts) with PC. Methods: Erlotinib was given at an initial dose of 150 mg/day to eligible pts with locally advanced (LA) or metastatic PC who had progressed or were unable to tolerate gemcitabine-based chemotherapy. The dose of erlotinib was increased by 50mg every 2 weeks (maximum 300 mg/day) until &gt; grade 1 rash (CTCAE v 3.0) or other dose-limiting toxicities occurred. Erlotinib pharmacokinetic (PK) studies were performed. Baseline tumor tissue was collected for analysis of Kras mutations, EGFR by IHC and FISH. The primary endpoint of this two- stage phase II trial was prolonged disease control (PR + SD &gt; 8 wks) with a rate of &gt;20% assumed to be significant . Results: Fifty pts were accrued (median age 61, M:F = 25:25, ECOG 0:1:2 = 5:41:4, LA:Metastatic = 5:45, prior gemcitabine none:adjuvant:palliative = 2:16:35). 47 and 40 pts were evaluable for toxicity and response, respectively. Dose-escalation to 200–300 mg of erlotinib was possible in 9 pts. Most common treatment adverse events (TAEs) of any grade were: rash (35 pts, 74.5%), diarrhea (18 pts, 38.3 %), and fatigue (8 pts, 17%). Grade 3+ TAEs were rash in 2 pts and diarrhea in 2 pts. Best response was SD in 14 pts, 0.35 (95% CI: 0.2–0.5). Prolonged disease control (SD &gt; 8 wks) was observed in 10/40 evaluable pts, 0.25 (95% CI: 0.12–0.38), which met the primary study endpoint. Median TTP was 1.6 mo (95% CI:1.6–2.1), mOS 4.1 mo (95% CI:3.2–7.3), and 6 mo OS rate was 39% (95%CI: 24–61%). PK and correlative data are being analyzed and will be presented. Conclusions: Erlotinib is associated with prolonged stable disease in a subset of pts with advanced refractory PC. Dose escalation in the absence of toxicity is feasible and safe. [Table: see text]

Encouraging survival with erlotinib in advanced papillary renal cell carcinoma (pRCC): Final results from Southwest Oncology Group study 0317

5051 Background: Historically, patients (pts) with advanced or metastatic pRCC have a median survival time of 7 to 17 months following systemic therapy (Motzer, et al. JCO 2002; Patard et al. JCO 2005). Pre-clinical studies showed greater activity for epidermal growth factor receptor (EGFR) inhibition in clear cell RCC with wild type von Hippel-Lindau (vHL) gene. In this trial, we evaluated the efficacy of erlotinib, an oral EGFR tyrosine kinase inhibitor in pts with advanced pRCC (usually associated with wild-type vHL). Methods: Pts with histologically confirmed locally advanced or metastatic pRCC were treated with erlotinib 150 mg PO QD until disease progression, patient refusal, unacceptable toxicity, or a treatment delay > 3 wks. The primary endpoint was RECIST response rate (RR). A RR of ≥ 20% was to be considered a promising outcome. Secondary endpoints included overall survival & 6-month probability of treatment failure. EGFR expression by IHC and vHL mutation status by PCR were assessed in tumor specimens. Results: Of 52 pts registered, 7 were ineligible due to insufficient pathology material submission. Of 45 evaluable pts, there were 33M/12F with a median age of 63.4 y (range 27.9 to 82.8). Median follow-up was 17.1 months (range 1.5 to 41.6). Overall RR was 11% (5/45, 95% CI: 3 - 24%). The disease control rate (DCR) was 64% (5 PR + 24 Stable). Median overall survival time was 27 months (95% CI: 13 to 36). Probability of freedom from treatment failure at 6 months was 29% (95% CI: 17–42%). There was one Grade 5 adverse event (AE) of pneumonitis, one Grade 4 thrombotic AE, and eight other Grade 3 AEs. There were two vHL mutations detected. The correlative study between EGFR expression and treatment outcomes will be presented at the meeting. Conclusions: Although the RECIST RR of 11% did not exceed pre-specified estimates for further study, single agent erlotinib yielded encouraging DCR and OS results in pts with pRCC with an expected toxicity profile. Further evaluation of the EGFR axis in pRCC should be considered. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech