Gefitinib Therapy Research Articles

A comparison of gefitinib for advanced non-small cell lung cancer patients with different EGFR mutation types.

e20544 Background: The aim of this study was to compare the efficacy and toxicity of gefitinib as first or second line therapy for advanced non-small cell lung cancer (NSCLC) patients with positive exon 21 (L858R) or exon 19 deletion mutation. Methods: We retrospectively analyzed the clinical data of 60 endothelial growth factor receptor ( EGFR) mutated advanced lung adenocarcinoma patients from July 2011 to November 2015, who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death. Results: At the time of last follow-up visit, 1 death had occurred. Among the 59 patients who remained survival, 17 patients progressed. Overall, the median progression-free survival (mPFS) was 10 months (95% confidence interval (CI): 7.53–12.46 months, p < 0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in first line therapy than that in second line therapy: in first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58–14.41 months, p < 0.05); in the second line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31–12.68 months, p < 0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted mPFS was significantly longer for patient with exon 19 deletion than that with positive exon 21in both first line therapy and second line therapy. The most common Grade 1 or 2 adverse events included rash (76.6%), abnormal liver function (60%), dry skin (48.3%), diarrhoea (46.6%), fatigue (40%) and paronychia (33.3%) etcetera in non-haematological toxicity, whereas anemia(33.3%), leukocytopenia (20%) etcetera were included in haematological toxicity. Conclusions: Patients with NSCLC who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in first line therapy than that in second line therapy when treated with gefitinib. And EGFR mutation types may influence the response to gefitinib therapy.

Impact of early progression on prognosis for non-small cell lung cancer patients with EGFR mutation.

e20570 Background: For epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine kinase inhibitors (TKIs) improve progression free survival compared with cytotoxic chemotherapy. However, some patients show early progression (EP) in first-line EGFR-TKI treatment, and their prognosis is still unclear. This study aimed to examine the implications of EP for prognosis of EGFR mutant NSCLC patients. Methods: Advanced EGFR mutant NSCLC patients treated with gefitinib (GEF) as first-line between 2005 and 2015 at Shizuoka Cancer Center were retrospectively reviewed. EP on GEF was defined as disease progression before 180 days according to the Jackman criteria. Results: Forty-five of 198 patients treated with GEF as first-line, showed EP. Patient characteristics was as follows (with EP/ without EP) : median age (range), 69 (32-88)/ 70 (35-92) years; male, 40/ 28%; ECOG performance status (PS) 0-1, 64/ 79%; deletion in exon 19 (del 19), 36/ 53%; L858R in exon 21, 53/ 43%; never smoker, 44/ 65%; liver metastasis, 27/ 12%; brain metastasis, 44/ 37%. The median overall survival was 395 days (95% CI: 267-547 days) for patients with EP and 979 days (95% CI: 808-1124 days) for those without EP. Post progression survival after treatment with GEF was significantly shorter in patients with EP (median: 254 days vs. 420 days, HR: 0.55 (95% CI: 0.39-0.79), P < 0.05). Among patients with EP, 56% received subsequent chemotherapy (patients without EP: 71%). In univariate analysis, EP was significantly associated with four factors; liver metastasis, smoking history, PS 2-4, absence of del 19. In multivariate analysis, smoking history (OR: 0.38, 95% CI: 0.18-0.80), PS 2-4 (OR: 0.43, 95% CI: 0.19-0.98), and del 19 (OR: 2.15, 95% CI: 1.04-4.45) were significantly correlated (P < 0.05) with EP. Conclusions: Patients with EP during first-line GEF therapy for advanced EGFR mutant NSCLC showed poor prognosis. Since smokers, patients with PS 2-4, or absence of del 19 tend to show EP, improving first-line treatment is necessary to improve their prognosis.

Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer

IntroductionIn this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non–small-cell lung cancer. MethodsRetrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. ResultsThe total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. ConclusionIf the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.

Evaluation of erlotinib for the treatment of patients with non-small cell lung cancer with epidermal growth factor receptor wild type

Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (NSCLC), regardless of the epidermal growth factor receptor (EGFR) mutation status. However, its efficacy for the treatment of patients with NSCLC with EGFR wild type or who are beyond the usage of gefitinib remains controversial. The present study therefore retrospectively assessed the efficacy of erlotinib in patients with wild type EGFR who had previously undergone gefitinib therapy. A total of 222 patients with NSCLC who received chemotherapeutic treatment with erlotinib between July 2007 and February 2013 were evaluated. The background variables, response rates, progression-free survival (PFS) and overall survival rates were retrospectively analyzed. The male/female ratio of patients was 103/119, and patients had a median age of 63 years (range, 33-95 years). A total of 10 of the 222 patients had clinical stages IIIB/IV, 191 had adenocarcinoma, 5 had large cell carcinoma, 10 had squamous cell carcinoma and 6 had NSCLC of a variety not otherwise specified. The EGFR mutation was positive, wild type or unknown in 95, 52 and 75 patients, respectively. In the 52 patients with EGFR wild type, there were 3 partial responders, 25 with stable disease and 24 with progressive disease, for a response rate of 6% [95% confidence interval (CI), 1.3-15%]. The median PFS of EGFR wild type and positive were 1.1 months (95% CI, 1.04-1.16 months) and 5.42 months (95% CI, 5.43-5.68 months), respectively. The results of the study demonstrated that erlotinib is not sufficiently effective for patients with NSCLC who possess the EGFR wild type status.

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa®) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

Dynamic monitoring of EGFR mutations in circulating cell-free DNA for EGFR-mutant metastatic patients with lung cancer: Early detection of drug resistance and prognostic significance.

Detecting genetic mutations in circulating cell-free DNA (cfDNA) is a promising approach of liquid biopsy. Between June 2014 and May 2015, 168 plasma samples were collected monthly from 20 patients with metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation receiving gefitinib therapy. Clinically relevant EGFR mutations, including exon 19 deletion, L858R and T790M, were quantified using droplet digital polymerase chain reaction. In baseline samples, 19 (95.0%) patients had the same mutation with the matched tumors, and pretreatment T790M mutations were also detected in 3 (15.0%) patients. The dynamics of EGFR mutations were generally associated with treatment response for patients with or without measurable disease. For patients with immeasurable tumor deposits, monitoring disease evolution using cfDNA-based mutation quantification appeared to be more reliable compared with measuring the diameters of target tumor lesions. In addition, molecular progressive disease, defined as a ≥20% increase of EGFR mutation concentration compared with the lowest concentration recorded during treatment, was tracked up to 8 months prior to objective progression. In survival analysis, sex (P=0.005), pretreatment T790M mutation status (P=0.006), T790M mutation status at the disease progression (P=0.043) and growth rate of EGFR mutations (P=0.023), had a significant impact on median progression-free survival. In conclusion, dynamic monitoring of EGFR mutations in cfDNA is feasible and appears to be useful in early prediction of drug resistance for patients with lung cancer receiving EGFR tyrosine kinase inhibitors.

ゲフィチニブ投与中に小細胞癌化を認めた肺腺癌の1例

背景．肺腺癌において，EGFRチロシンキナーゼ阻害薬（EGFR-TKI）に対する耐性化機序の半数以上は同遺伝子の二次変異によるものである．一方，低頻度ながら小細胞癌化による耐性獲得例も知られている．症例．73歳，男性．EGFR遺伝子変異陽性の肺腺癌（cT4N2M1a，stage IV）に対しゲフィチニブ投与を開始された．治療は奏効し，原発巣は良好にコントロールされた．しかし，経過中に肝腫瘍の出現および血清NSE高値を認め，肝生検でEGFR遺伝子変異陽性の小細胞癌が判明した．肺腺癌の小細胞癌化と考えられ，小細胞癌に対する化学療法を施行し，肝転移巣は縮小した．結論．EGFR-TKI治療への耐性化を認めた際，小細胞癌化の可能性を予測し，正確に診断することは治療方針の最適化に大きく寄与する．血清マーカーや病変の経過などから同病態が疑われる場合には，侵襲やリスクも考慮しつつ再生検を特に積極的に検討すべきと思われる．

Outcomes in lung cancer: An experience from routine tertiary care setting.

The aim of this study was to establish characteristics of lung cancer patients diagnosed at a tertiary care hospital in Bangalore. The retrospective study was undertaken comprising of 202 patients diagnosed of advanced lung cancer in a tertiary care setting. Data was analyzed to identify patients' characteristics, smoking history, tumor histology, stage of the disease, treatment received, and survival rates. Among the 202 patients diagnosed, 134 were males, and 68 were females. Tumor histology testing revealed that 168 patients had adenocarcinoma, 24 patients had squamous carcinoma, 5 patients had small cell carcinoma, and 5 patients were poorly differentiated carcinoma. Among the patients of adenocarcinoma, complete response, partial response (PR), stable disease, and progressive disease (PD) were seen in 0.6%, 52%, 17%, and 23.2% of the patients respectively. The median progression-free survival (PFS) for first-line treatment was 6.5 months; the highest PFS was seen with nab-paclitaxel/platinum combination. The mean overall survival was 11.7 months and the highest OS of 12.3 months with gefitinib therapy. In the squamous subset of patients, PR was observed in fourteen patients, of which five patients were treated with nab-paclitaxel/platinum. The mean overall survival of 10.5 months and mean PFS was 6.2 months with the highest PFS of 6.8 months were seen with weekly nab-paclitaxel. Among the small cell lung cancer patients, nine were treated with etoposide/platinum regimen with a compliance of 6 cycles. Three patients had a PR, and one had a PD on etoposide/platinum regimen. The mean overall survival in these patients was 4.6 months.

OA10.03 YAP-NOTCH and STAT3 Signaling Rebound as a Compensatory Response to Gefitinib or Osimertinib Treatment in EGFR Mutant Lung Cancer

Preclinical studies provide insights to therapy mechanisms of resistance that are not feasible with clinical studies. We investigated the signaling pathways that could be involved in adaptive resistance to gefitinib and/or osimertinib in EGFR mutant cells. We performed several laboratory methods to examine the signaling pathways involved in EGFR mutations. Signal transduction pathway analysis was designed using the Ingenuity Pathway Analysis (IPA) software (https://www.ingenuity.com/) Pathways mediating EGFR mutations are: i) ERK1/2 via Ras and MEK1/2 ii) AKT via PI3K and iii) STAT3 via JAK (Figure). By Western blot analysis, phosphorylation of Tyr705 on STAT3 was noted after 2 hours of gefitinib or osimertinib treatment in PC9 and H1975 EGFR mutant cells. Unexpectedly, YAP1 phosphorylation on Tyr357 and Notch activation was detected. Co-targeting STAT3 and Src with gefitinib or osimertinib ablates activation of STAT3 and YAP1-NOTCH3 signaling pathways (Figure). In vitro and in vivo, the combinatory therapy of gefitinib or osimertinib plus TPCA-1 (a dual inhibitor of IKKs and STAT3) plus saracatinib (a SFK inhibitor) leads to significant tumor shrinkage in PC9 and H1975 cells. In tumor samples of 64 EGFR mutant NSCLC patients treated with gefitinib, the median progression free survival (PFS) was significantly shorter in those with high levels of HES1, ALDH1A1, ALDH1A3, Bmi1, AXL, CDCP1, SHP2 and ILK (Figure). However, the mRNA levels of STAT3 and YAP1 stand out in the prediction of shorter PFS with a hazard ratio of 3.02 and 2.57, respectively (P<0.001). For the first time ever, we reported gefitinib induced activation of the YAP1-NOTCH signaling pathway, in addition to activation of STAT3, in EGFR mutant cells. Secondly, co-targeting STAT3 and Src, together with EGFR, causes significant tumor growth inhibition, in comparison with gefitinib or osimertinib single therapy.

OA23.07 Analysis of Outcomes in US IRESSA Clinical Access Program (ICAP) Patients on Gefitinib for More Than 10 Years

In 2011, following gefitinib (IRESSA®) NDA voluntary withdrawal, US patients benefiting from gefitinib were eligible to continue gefitinib through the IRESSA Clinical Access Program (ICAP), an IRB-approved protocol. A subset of ICAP investigators subsequently collected additional retrospective data on their ICAP patients through another IRB-approved project (“chart-review subset”). For all enrolled ICAP patients, demographic and serious adverse event (SAE) reports were reviewed. All ICAP investigators were invited to participate in chart review; 47 accepted and collected data on patient/tumor characteristics and safety/tolerability of prolonged gefitinib therapy among their 79 ICAP patients. Across 137 US sites, 191 patients enrolled in ICAP. As of September 2016, 75 (39%) remain on gefitinib; discontinuations were due to progression (36%), death (34%), AEs (13%), or other (17%). Sixty-four (34%) patients reported 162 SAEs; 5 (2.6%) patients had 12 SAEs considered to be gefitinib-related by investigators. The chart-review subset included 79 (41%) patients with median age of 69 years at ICAP enrollment, who were predominantly female (70%) and white (84%); 95% had a confirmed NSCLC diagnosis. Due to the evolving understanding of genetic mutations in NSCLC at the time of gefitinib initiation, the majority of patients (79%) never had EGFR sequencing performed. Although tissue is not available for EGFR status confirmation, we assume these patients are nearly exclusively EGFR mutation-positive. Median total length of gefitinib was 11.1 years (6.5-15.1; Table). Long-term gefitinib was well-tolerated; 5% discontinued due to a gefitinib-related AE. Ten-year survival rate from first-ever initiation of gefitinib was 86% and 15-year was 59%.TableGefitinib treatment patterns and tolerability among ICAP chart-review patientsParameter n, %Observed Population (N=79)Total time on gefitinib, prior to and during ICAPMedian duration, y, range11.1 (6.5-15.1)Prior to ICAPMedian duration, y, range7.8 (5.4-10.9)Starting dose 250 mg/day67 (84.8)No dose changes due to AEs75 (94.9)During ICAPMedian duration, y, range3.5 (0.04-4.7)Dose: 250 mg/day76 (96.2)Treatment-related AEs Grade 1-2 Grade ≥3 Grade unknown13 (16.5) 1 (1.3) 2 (2.5)Dose reductions due to treatment-related AEs1 (1.3)Discontinuations due to treatment-related AEs4 (5.1)Discontinuations due to progressive disease11 (28.9) Open table in a new tab The majority of this subset of patients who participated in ICAP based on long-term clinical benefit from gefitinib continue to do well with gefitinib, demonstrating good tolerance of therapy and survival for a median duration of more than 10 years.

P2.03b-017 Differences of Central Nerve System Metastasis during Gefitinib or Erlotinib Therapy in Patients with EGFR-Mutated Lung Adenocarcinoma: Topic: Brain Meta

A few reports have suggested a difference in the incidences of new metastasis to the central nerve system (CNS) during gefitinib and erlotinib therapy. However, a direct comparison of these two therapies has not yet been reported. We planned a retrospective study to investigate the incidences of CNS metastasis progression (new CNS metastasis or progression of existing CNS metastasis) during gefitinib and erlotinib therapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation. We retrospectively analyzed the incidences of CNS metastasis progression and the outcomes of NSCLC patients harboring EGFR mutation who received gefitinib or erlotinib as a first-line EGFR-TKI treatment at the National Cancer Center Hospital between 2008 and 2014. A total of 175 patients were analyzed; 148 patients had received gefitinib, and 27 had received erlotinib. The median (range) ages were 64.5 (32-81) years and 62.0 (27-68) years, respectively; exon 19 deletion/L858R point mutations were present in 84/64 (56.7%/43.3%) and 17/10 (63.0%/37.0%) cases, respectively. The status of CNS metastasis before EGFR-TKI therapy was negative/positive in 105/43 (71.0%/29.0%) cases in the gefitinib group and 21/6 (77.8%/22.2%) cases in the erlotinib group, respectively. The incidence of CNS metastasis progression in the gefitinib group tended to be higher than that in the erlotinib group (29.0% vs. 11.1%; P = 0.051). In patients without CNS metastasis before EGFR-TKI therapy, the incidence of new CNS metastasis during EGFR-TKI treatment was significantly higher in the gefitinib group than in the erlotinib group (24.7% vs. 4.8%, P = 0.04). The progression-free survival (PFS) and overall survival (OS) periods of the patients who presented with CNS progression were shorter than those of the patients who presented without CNS progression (median PFS, 9.5 vs. 12.6 months, P = 0.034; median OS, 23.8 vs. 34.1 months, P = 0.002). Fifty-six patients underwent re-biopsy after the failure of EGFR-TKI therapy, but no difference in the incidences of EGFR T790M mutation was seen between patients with and those without CNS metastasis progression (40.0% for patients without CNS progression vs. 63.6% for patients with CNS metastasis progression, P = 0.19). The incidence of the progression of CNS metastasis during gefitinib therapy was higher than that during erlotinib therapy. In addition, the difference in this incidence was more remarkable among patients who had not developed CNS metastasis prior to the start of EGFR-TKI therapy.

A Multicenter Double-blind Phase II Study of Metformin With Gefitinib as First-line Therapy of Locally Advanced Non–Small-cell Lung Cancer

We present the rationale and study design of the CGMT (combined gefitinib and metformin therapy) trial (www.ClinicalTrials.gov Identifier: NCT01864681), which is aimed at treating locally advanced non–small-cell lung cancer. The CGMT trial is a multicenter, phase II randomized, double-blinded, and placebo-controlled study, which is designed to evaluate the safety and efficacy of metformin in combination with gefitinib as first-line therapy in patients presenting with stage IIIb-IV non–small-cell lung cancer expressing the epidermal growth factor receptor mutant. Two therapies are proposed for this trial. The first regimen is comprised of gefitinib plus metformin. The second therapy is comprised of gefitinib plus placebo. The primary objective of this trail is to compare the progression-free survival rate at year 1 of the study. The secondary objective of this trial is to compare the 2-year overall survival, the 2-year progression-free survival, the objective response rate, and the disease-control rate, and to evaluate the relative safety of both therapies. Based on the statistical design, we plan to enroll approximately 200 patients.

EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients

IntroductionActivating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy. MethodsPatients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS. ResultsSignificant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10-15). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15–nucleotide deletion “non-ELREA” group having the shortest OS of 11.3 months (overall p = 0.025). ConclusionsEGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.

1247P - Monitoring of EGFRm level in cfDNA in patients with advanced NSCLC on the gefitinib therapy

1247P - Monitoring of EGFRm level in cfDNA in patients with advanced NSCLC on the gefitinib therapy

Combination Therapy of Gefitinib and Korean Herbal Medicines Could be a Beneficial Option for Patients with Non-Small-Cell Lung Cancer.

Lung cancer has a high mortality rate and is often diagnosed at the metastatic stage. Gefitinib is a targeted molecular therapeutic drug used to treat patients with non-small-cell lung cancer (NSCLC). Korean herbal medicines may also have therapeutic efficacy against lung cancer, reduce the side effects associated with chemotherapy, and improve patient quality of life (QOL). This case report describes the effects of a Korean herbal medicine regimen combined with gefitinib in a patient with NSCLC and bone metastasis. The Korean herbal medicine regimen included woohwanggeosa-dan, hwanggibujeong-dan and geonchilgyebok-jeong. The computed tomography (CT) findings showed that following combination treatment, the size of the tumor was markedly decreased without serious adverse events. Moreover, the Eastern Cooperative Oncology Group (ECOG) performance status was improved and cancer-related pain was decreased. These results suggest that a combination of Korean herbal medicines and gefitinib may be an effective therapeutic option for patients with advanced NSCLC and bone metastasis. Further studies are needed to examine the mechanism and the clinical efficacy of Korean herbal medicines against NSCLC.Lung cancer has a high mortality rate and is often diagnosed at the metastatic stage. Gefitinib is a targeted molecular therapeutic drug used to treat patients with non-small-cell lung cancer (NSCLC). Korean herbal medicines may also have therapeutic efficacy against lung cancer, reduce the side effects associated with chemotherapy, and improve patient quality of life (QOL). This case report describes the effects of a Korean herbal medicine regimen combined with gefitinib in a patient with NSCLC and bone metastasis. The Korean herbal medicine regimen included woohwanggeosa-dan, hwanggibujeong-dan and geonchilgyebok-jeong. The computed tomography (CT) findings showed that following combination treatment, the size of the tumor was markedly decreased without serious adverse events. Moreover, the Eastern Cooperative Oncology Group (ECOG) performance status was improved and cancer-related pain was decreased. These results suggest that a combination of Korean herbal medicines and gefitinib may be an effective therapeutic option for patients with advanced NSCLC and bone metastasis. Further studies are needed to examine the mechanism and the clinical efficacy of Korean herbal medicines against NSCLC.

Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience.

Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown. We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-naïve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI)≥25kg/m2 and assessed its potential relationship with≥grade 2 hepatic dysfunction. The patient demographics were as follows: 114 women; median age 72years (range 42-95years); BMI≥25kg/m2, n=32; performance status 0-1, n=136; stage IIIB/IV, n=141; and major EGFR mutations, n=171. Hepatic dysfunction≥grade 2 during the gefitinib therapy was observed in 44 (24.0%) patients, 22 (50.0%) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56days (range 6-1,352days). Overweight patients were more likely to develop hepatic dysfunction≥grade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95% confidence interval 1.01-4.95; p=0.046). These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.

Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1.

BackgroundRepetitive genotyping is useful to assess the genetic evolution of non-small-cell lung cancer (NSCLC) during treatment, but the need for sampling by biopsy is a major obstacle. Digital polymerase chain reaction (PCR) is a promising procedure for the detection of mutant alleles in plasma of cancer patients.MethodsThis prospective study enrolled patients with NSCLC and known epidermal growth factor receptor (EGFR) mutations and who had experienced disease progression during ongoing EGFR-tyrosine kinase inhibitor (TKI) therapy. Eligible patients received daily gefitinib and either pemetrexed or S-1 every 3 weeks until disease progression or the development of unacceptable toxicity. Peripheral blood was collected before and after the combination therapy for digital PCR and hepatocyte growth factor measurement.ResultsFrom May 2012 to January 2014, nine patients with a median age of 67 (range 52–80) years were enrolled. Patterns of disease progression during adjacent EGFR-TKI therapy were acquired resistance, observed in seven patients, and primary resistance, observed in two patients. Known EGFR mutations were detected in plasma samples of six (67%) patients at study enrollment. Of these, T790M mutation was concurrently detected in three (50%) patients. Four patients underwent gefitinib plus pemetrexed therapy, and five patients underwent gefitinib and S-1 therapy. The median number of cycles delivered was five, and the median progression-free survival was 5.7 months. Efficacy outcomes did not differ between treatments. After the combination therapy, plasma T790M status changed to positive in two patients. Hepatocyte growth factor level did not significantly change through the combination therapy.ConclusionThe usefulness of monitoring the genetic evolution of EGFR-driven tumors using noninvasive procedures was demonstrated. Since continuation of EGFR-TKI therapy with cytotoxic agents has an acceptable tolerability and a possibility of inducing T790M mutation, the combination therapy may be useful for EGFR-mutant NSCLC resistant to EGFR-TKI therapy without T790M mutation.

Abstract 250: Interleukin-6 as potential predictive marker for therapeutic effect of Gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations

Abstract Background: Although epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the key drug in patients with EGFR-mutant (mt) Non-small-cell Lung Cancer (NSCLC), some of them can not respond well to its therapy. An overexpression of Interleukin (IL)-6 in tumor cells is postulated as a potential mechanism for such resistance or low sensitivity to EGFR-TKI in the preclinical models (PNAS 2010). Here, we evaluated clinically if tumor IL-6 level can be predictive for the effect of EGFR-TKI therapy, and evaluated the expression of IL-6 in EGFR-mt NSCLC cell-lines, and the effect of EGFR-TKI. Methods: A total of 52 pts with advanced EGFR-mt NSCLC who had received gefitinib (G) were retrospectively assessed. The protein expression of IL-6 in the tumor cells was immunostained. Each specimen was assessed independently by 2 physicians (TT and YK) and 2 pathologists (KI and TT), and judged as positive if ≥ 50% of 100 tumor cells were stained positively (BJC 1999). Serum IL-6 level was measured by CLEIA in 11 (21%) of 52 pts. Next we checked 13 EGFR-mt NSCLC cell lines. Enzyme linked immunosorbent assay (ELISA) and real time PCR (RT-PCR) of cell culture supernate were peformed. Results: Patients demographics were as follows: 24 men; median age, 66 yrs; PS 0-1, 48; stage IV, 22; Ad, 49; exon19, 29. Of these, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse PFS (75% v 92% at 6m; p &amp;lt; 0.05), which was retained in the multivariate analysis (HR: 2.38; 95%CI: 1.00-5.68; p = 0.05). In contrast, PFS in the platinum-based chemotherapy did not differ in groups P and N (p = 0.47). The serum IL-6 level ranged from 0.75 to 23.80 pg/ml (median: 2.90 pg/ml), which correlated neither to that in the tumor cells (regression coefficient: 1.69, p = 0.29) nor PFS in gefitinib therapy (p = 0.44). The IL-6 level in cell culture supernatant was ranged from 1.46 to 1219.75 pg/ml (median: 85.84 pg/ml). 2 of 13 cell lines showed especially high IL-6 level; IL-6 level of 11-18 was 1090.91 pg/ml and H1650 was 1219.75 pg/ml. RT-PCR also showed the high expression level of IL-6 mRNA in 11-18 and H1650 compared with other cell lines. 11-18 and H1650 showed low sensitivity to G therapy. Conclusions: Pts in group P benefited less from G therapy. In vitro experiment suggested that secretion of IL-6 may confer the less sensitivity to EGFR-TKIs. These data suggest that the expression of IL-6 lead to early acquisition of resistance to EGFR-TKIs in EGFR-mt tumors. Citation Format: Tomoki Tamura, Katsuyuki Hotta, Yuka Kato, Takehiro Tanaka, Kouichi Ichimura, Kadoaki Oohashi, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Mitsune Tanimoto, Katsuyuki Kiura. Interleukin-6 as potential predictive marker for therapeutic effect of Gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 250.

Pneumatosis intestinalis after gefitinib therapy for pulmonary adenocarcinoma: a case report

BackgroundPneumatosis intestinalis (PI) is defined as the presence of gas in the bowel wall and is a relatively rare finding. PI has been associated with various pathological conditions and medications. Although several chemotherapeutic agents and molecular targeted therapy agents are reported to be associated with PI, there have been few reports describing the association between the anti-epidermal growth factor receptor agent gefitinib, a tyrosine kinase inhibitor (TKI), and PI. The present report describes a case of PI secondary to gefitinib therapy.Case presentationAn 80-year-old woman who had been diagnosed with recurrent lung adenocarcinoma presented with remarkable appetite loss, abdominal distension, and constipation after starting gefitinib therapy. A computed tomography (CT) scan of the abdomen revealed PI extending from the small intestine to the rectum. The patient was managed conservatively, and gefitinib therapy was discontinued. Subsequently, the symptoms improved and a follow-up abdominal X-ray showed a reduction in intramural air. After gefitinib was restarted, PI occurred three more times.ConclusionsAlthough PI is extremely rare, physicians should be aware of the risk of PI in patients undergoing gefitinib therapy.

A novel pharmacodynamic approach to assess and predict tumor response to the epidermal growth factor receptor inhibitor gefitinib in patients with esophageal cancer.

This study aimed to describe a short-term ex vivo assay to predict response to epidermal growth factor receptor (EGFR) targeted therapy (gefitinib) in adenocarcinoma patients. Four patients with locally advanced esophageal adenocarcinoma were treated with gefitinib (250 mg/day) for 14 days and pharmacokinetic (PK) studies were conducted to monitor plasma drug concentrations. Tumor cells were sampled by endoscopic biopsy prior to (baseline, day 0) and at the completion of (day 14) treatment. Cells obtained at baseline were exposed to gefitinib in short-term cell culture conditions (ex vivo assay). Western blot analyses with phospho-specific antibodies were performed to evaluate activation and biochemical response to therapy of EGFR and its downstream signaling components ERK and AKT ex vivo and in vivo. The in vivo profiles were correlated with the gefitinib-mediated alteration in proliferating cell nuclear antigen (PCNA) expression, a marker of cell proliferation. The correlation between EGFR expression and ERK activity was also investigated by immunohistochemical analysis in pretreatment biopsies. Mutational status of the genes encoding EGFR, K-RAS, and PI3KCA (the phosphoinositide 3-kinase catalytic subunit p110) as well as expression levels of PTEN protein were tested in order to investigate potential confounders of the gefitinib effect. All patients completed the gefitinib therapy. PK studies demonstrated constant gefitinib concentrations during the treatment, confirming persistent exposure of target tissue to the drug at sufficient levels to achieve EGFR blockade. Ex vivo culture with gefitinib resulted in distinct response patterns representing various states of activity of the ERK and AKT pathways. The results of the ex vivo studies correctly predicted the pharmacodynamic (PD) effects of the agents in tumor tissue in vivo. PCNA expression correlated with ERK pathway inhibition, but not with gefitinib-mediated inhibition of EGFR activity alone. Immunohistochemical analysis performed on pretreatment biopsies correlated with Western blot analysis of EGFR and phospho-ERK expression. No mutations were identified in exons 18-21 of EGFR, exons 2 and 3 of K-RAS or exons 9 and 22 of PI3KCA. Levels of PTEN were comparable across tumors. The novel pharmacodynamic approach described in this proof of principle study may be useful to refine the patient selection to maximize the potential benefits of drugs and design individualized rational therapies for cancer patients.