Current views on the role of Notch signaling and the pathogenesis of human leukemia

Background

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^nd EGFR-TKI administration.

Methods

We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.

Results

Three patients (27%) were treated with gefitinib as the 2^nd EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^nd EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^nd EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^nd EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.

Conclusions

Our results indicate that a 2^nd EGFR-TKI treatment can be an effective treatment option for gefitinib responders.     

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience

Purpose

Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients.

Methods

This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed.

Results

In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005).

Conclusion

In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.     

In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines

Purpose

In clinical trials, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) administered concomitantly with first-line cytotoxicity chemotherapy failed to confer a survival benefit to patients with non-small-cell lung cancer (NSCLC). The aim of this study was to test whether paclitaxel followed by gefitinib is superior to other treatment schedules of NSCLC cell lines and to clarify the underlying mechanisms.

Methods

Human lung cancer cell lines with wild-type and mutant-type EGFR genes were used as in vitro models to define the differential effects of various schedules of paclitaxel with gefitinib treatment on cell growth, signaling pathway, and cell cycle distribution.

Results

Sequence-dependent antiproliferative effects differed between EGFR-TKI-resistant and EGFR-TKI-sensitive lung cancer cell lines. Exposure to paclitaxel resulted in an increased pEGFR level. This increase in phosphorylation was inhibited by subsequent exposure to gefitinib, whereas during the reverse sequence, the inhibition effect was reduced. After paclitaxel exposure, a higher level of pEGFR was observed in mitotic than in interphase cells. The sequence of paclitaxel followed by gefitinib resulted in greater anti-VEGF activity than did the reverse sequence. We confirmed that gefitinib arrested cells in G1, and paclitaxel arrested them in S phase. The sequence of paclitaxel followed by gefitinib arrested cells in G1, whereas the reverse sequence arrested cells in S and G2 phases.

Conclusions

These findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to other sequences in treating NSCLC cell lines. Our results also provide molecular evidence to support clinical treatment strategies for patients with lung cancer.     

Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer

Purpose

Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them.

Methods

We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250?mg daily gefitinib or 150?mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry.

Results

The concentration and penetration rate of gefitinib (mean?±?standard deviation) in the CSF were 3.7?±?1.9?ng/mL (8.2?±?4.3?nM) and 1.13?±?0.36?%, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7?±?16.8?ng/mL (66.9?±?39.0?nM) and 2.77?±?0.45?%, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P?=?0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib.

Conclusions

This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.     

Serum levels of surfactant protein D predict the anti-tumor activity of gefitinib in patients with advanced non-small cell lung cancer

Purpose

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment.

Methods

We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250?mg gefitinib daily. Eligibility criteria included performance status ??3, age ??80?years, and stage IIIB?CIV disease. In addition, EGFR mutations were analyzed in 24 patients.

Results

Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS.

Conclusions

The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.     

Survival of patients with brain metastases from non-small cell lung cancer harboring EGFR mutations treated with epidermal growth factor receptor tyrosine kinase inhibitors

Brain metastases (BM) is one of the most crucial distant metastases in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. There is no consensus about which EGFR tyrosine kinase inhibitor (TKI) is most effective against BM in such patients. Here, we compared prognoses of patients with EGFR-TKI naïve EGFR-positive BM treated with erlotinib or gefitinib after BM diagnosis. Of 269 patients with NSCLC treated with EGFR-TKIs at a single institution, we reviewed medical records of 205 patients with documented EGFR mutations. Eleven patients were administered erlotinib, and 52 patients were administered gefitinib as the first-line EGFR-TKI treatment after diagnosis. We used propensity score matching to balance patient backgrounds between groups, and the log-rank test to compare survival curves. Patients with BM at the induction of chemotherapy had a poorer prognosis than those without BM [median overall survival (OS) 18.5 vs. 28.0 months]. Meanwhile, there was no significant difference in OS between those with or without BM at the initiation of EGFR-TKI treatment (20.3 vs. 23.8 months). Median OS of patients treated with erlotinib was not significantly longer than that of patients treated with gefitinib (25.0 vs. 18.1 months). The presence of BM at the initiation of EGFR-TKI treatment had no apparent effect on survival. Erlotinib was deemed more effective than gefitinib in preventing intracranial lesions and prolonging survival; however, prospective studies are needed to confirm these results.     

The administration of gefitinib in patients with advanced non-small-cell lung cancer after the failure of erlotinib

Purpose

Recent studies have demonstrated that erlotinib therapy may be considered an option for patients with advanced non-small-cell lung cancer who experienced disease progression after treatment with gefitinib, particularly in patients in whom the disease had been stabilized for a long time prior to gefitinib therapy. The aim of this study was to evaluate the disease control rate and toxicity of gefitinib in patients whose disease progressed after erlotinib therapy.

Methods

From May 2005 to August 2006, 15 patients received a 250?mg/day dosage of gefitinib after having disease progression while taking erlotinib at a dose of 150?mg/day.

Results

Among patients who received erlotinib, 1 (7%) achieved a partial response (PR), and 5 (33%) achieved stable disease (SD). Among patients who received gefitinib, none achieved a PR, and 6 achieved SD (40%). Five out of 6 patients who achieved PR/SD with erlotinib also achieved SD with gefitinib; 8 out of 9 patients who achieved a progressive disease (PD) with erlotinib also achieved a PD with gefitinib. The median time to progression (TTP) and overall survival (OS) were 2.3 and 3.5?months, respectively. The TTP and OS in SD patients were 3.7 and 7.4?months, respectively. The most common toxicities of gefitinib were dry skin (grade 1–2) in 27% of patients and acneiform rashes and rashes/desquamation in 20% of patients. Diarrhea (grade 1–2) occurred in 7% of patients.

Conclusions

Our data suggest that patients who achieved PR/SD with erlotinib also benefit from taking gefitinib. Conversely, gefitinib is not recommended in patients whose disease progressed after taking erlotinib.     

Continued erlotinib maintenance and salvage radiation for solitary areas of disease progression: a useful strategy in selected non-small cell lung cancers?

Purpose

Advanced non-small cell lung cancer (NSCLC) is a common and lethal malignancy that has rarely benefited from chemotherapy. Erlotinib is highly effective in NSCLC patients selected by clinical characteristics and/or the presence of epidermal growth factor receptor-sensitizing mutations. However, the way to delay or bypass erlotinib resistance is not systematically addressed. Different erlotinib-failure modes have been reported in NSCLC, and strategies to prolong erlotinib efficacy are perhaps adaptable to them. We report the feasibility and efficacy of continued erlotinib maintenance and local salvage radiation to overcome erlotinib resistances in selected NSCLC patients.

Patients and methods

Thirty of 52 consecutive erlotinib-treated advanced NSCLC from the NYU Langone Medical Center and the Arnau de Vilanova Hospital of Lleida responded initially to erlotinib. Twenty-six patients eventually showed a generalized-progression to erlotinib, and four progressed in solitary tumor sites. These four patients were treated with continued erlotinib maintenance and local salvage radiation.

Results

The progression-free survival (PFS) was statistically similar in patients with oligo or generalized-progression to erlotinib. However, all four cases with solitary-progression did benefit from continued erlotinib maintenance and salvage radiation with 41–140 % prolongation of PFS. It was reflected in an improved overall survival when they were compared with patients with generalized-progression (76.4 vs. 19.9 months; p = 0.018).

Conclusion

Continued erlotinib maintenance and local salvage radiation is feasible and could contribute to a better outcome in selected NSCLC patients with solitary-progression to erlotinib. Prospective randomized trials of this strategy are warranted.     

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

Purpose

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined.

Methods

We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR.

Results

Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4?%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n?=?6) or erlotinib (n?=?6). The most common mutation was exon 19 deletion (n?=?7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75?%, respectively. The median PFS was 3.67?months (95?% CI: 1.34?C5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53?months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83?months) who were treated with EGFR TKIs.

Conclusions

The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.     

Gefitinib and Erlotinib in Metastatic Non‐Small Cell Lung Cancer: A Meta‐Analysis of Toxicity and Efficacy of Randomized Clinical Trials

Background.

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC.

Methods.

We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies.

Results.

We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations.

Conclusion.

Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC.     

Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non–Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials

Background

Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non–small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations.

挽救性化疗治疗化疗及表皮生长因子受体酪氨酸激酶抑制剂治疗失败的晚期非小细胞肺癌的疗效和安全性

目的 探讨一线含铂方案及表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败后的晚期非小细胞肺癌(NSCLC)患者接受挽救性化疗的疗效和安全性.方法 对55例一线含铂方案及后续EGFR-TKI治疗失败的晚期NSCLC患者行挽救性化疗,其中培美曲塞单药化疗24例,多西他塞单药化疗21例,其他方案化疗10例.至疾病进展或患者拒绝继续治疗.评价挽救性化疗的客观缓解率(ORR)、疾病控制率(DCR)及患者的无进展生存时间(PFS).结果 55例患者均可评价疗效,其中部分缓解(PR)7例(12.7%),稳定(SD)21例(38.2%),进展(PD)27例(49.1%),无完全缓解(CR)患者.ORR为12.7%,DCR为50.9%.全组患者的中位随访时间为5.5个月,中位PFS为2.0个月.不同性别、PS评分及化疗方案患者的近期疗效及PFS差异均无统计学意义(均P＞0.05).EGFR-TKI治疗时间≥6个月患者的ORR(21.1%)和DCR(73.7%)均明显高于EGFR-TKI治疗时间＜6个月的患者(ORR为8.3%,DCR为38.9%;均P＜0.05);EGFR-TKI治疗时间≥6个月患者与＜6个月患者的中位PFS分别为4.5月和2.0个月,差异亦有统计学意义(P=0.008).55例患者均可评价不良反应,主要表现为骨髓抑制,患者均能耐受.全组未发生治疗相关性死亡.结论 一线含铂方案及EGFR-TKI治疗失败后的晚期NSCLC患者能从挽救性化疗中获益,尤其是对EGFR-TKI治疗时间≥6个月的患者.晚期NSCLC患者对于挽救性化疗的耐受性良好.     

Clinical effect of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer

Purpose

To evaluate the efficacy and toxicities of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods

Untreated patients with advanced NSCLC were included in this study; erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity or for other reasons.

Results

A total of 35 patients were enrolled. Patient characteristics were as follows: mean age 75.6 years (ranged 70–81 years), 24 (68.6%) male, 16 (45.7%) former or current smokers, 13 (37.1%) adenocarcinoma, 18 (51.4%) squamous cell carcinoma and 4 (11.4%) bronchioloalveolar carcinoma. Out of 35 patients, 1 CR, 16 PR and 10 SD, resulting in an overall response rate (CR + PR) of 48.6% and disease control rate (DCR = CR + PR + SD) of 77.1%. The median TTP was 6.4 months, and the median OS was 12.7 months. The CBR was 80%, and the 1-year survival rate was 48.6%. The most common adverse event (AE) was mild skin rash and diarrhea (CTC AE 1/2). Among them, the female never smokers with a non-squamous cell carcinoma histology was superior to the male smokers with a squamous cell carcinoma in disease control rate, with significant differences (P < 0.05).

Conclusion

The results suggest that erlotinib monotherapy is an effective and well-tolerated treatment option for Asian elderly patients with advanced NSCLC.     

Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitors

Purpose

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is considered as one of the most important treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, not all patients benefit from this therapy because of primary or acquired resistance, both of which are usually caused by the activation of alternative signaling pathways. Thus, a combination of different signaling pathway inhibitors is a promising strategy. We used the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with gefitinib in NSCLC cell lines to analyze the efficacy of this combination regimen and the underlying molecular mechanism.

Methods

Acquired gefitinib-resistant cell lines, together with EGFR wild-type and mutant primary gefitinib-resistant NSCLC cell lines, were treated with everolimus alone, gefitinib alone, or the combination of the two drugs, and the effects were evaluated using cell proliferation assays. The effects of everolimus and gefitinib on the EGFR pathway in NSCLC cell lines were determined by Western blot analysis.

Results

Combined treatment resulted in synergistic antitumor effects in gefitinib-resistant cells A549 and H1975. The combination index (CI) of cells increased with increasing dose of everolimus. Everolimus demonstrated no apparent inhibition of phosphorylated Akt (p-Akt) and phosphorylated p44/42 MAPK (p-MAPK) in H1650 cells. Additionally, in gefitinib-resistant cell lines, the combination of gefitinib and everolimus not only showed stronger inhibition of phosphorylated mTOR and phosphorylated p70S6K expression than either drug alone but also reduced the levels of p-Akt and p-MAPK in both cell lines.

Conclusions

Our data showed that the combination of everolimus and gefitinib exhibits dose-dependent synergism in primary and acquired gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of everolimus to enhance the efficacy of gefitinib in EGFR-TKI-resistant patients with NSCLC.     

Epidermal Growth Factor Receptor (EGFR)‐Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR‐Mutated Elderly Pulmonary Adenocarcinoma Patients

Background.

Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown.

Materials and Methods.

We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected.

Results.

In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients.

Conclusion.

Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients.

Implications for Practice:

The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.     

First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer

Background

Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK) inhibitor of epidermal growth factor receptor (EGFR), displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC) in Chinese population are not sufficient.

Purpose

To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC), a study of single agent treatment with gefitinib in Chinese patients was conducted.

Methods

45 patients with advanced NSCLC were treated with gefitinib (250 mg daily) until the disease progression or intolerable toxicity.

Results

Among the 45 patients, 15 patients achieved partial response (PR), 17 patients experienced stable disease (SD), and 13 patients developed progression disease (PD). None of the patients achieved complete response (CR). The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively). The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively). In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively).

Conclusions

Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC.

     

Neue Entwicklungen in der Behandlung von soliden Tumoren mit zielgerichteten Medikamenten

Context

The current clinical development of very different solid tumor entities, such as non-small-cell lung cancer (NSCLC), predominantly adenocarcinomas, renal cell cancer (RCC) and malignant melanoma (MM) has increasingly led to a subdivision into specific patient subgroups that can be specifically identified by molecular biomarkers, at least for NSCLC and RCC. Based on the background that highly specific genetic driver alterations with oncogenic driver potential have already been identified for some of these subgroups, a straightforward pharmacological and clinical development of molecular targeted and personalized treatment options for these patients has thus become reality.

Material und methods

Research of literature and clinical trials.

Results

Consequently, several highly specific kinase inhibitors have become available and clinically approved for the treatment of adeno-NSCLC with epidermal growth factor receptor (EGFR) mutation (e.g. gefitinib, erlotinib), adeno-NSCLC with Eml4-Alk-translocation (e.g. crizotinib) and MM with Braf-V600E-mutation (e.g. dabrafenib, vemurafenib). For RCC a pharmacological intervention in the VEGF-PDGF-HIF1-alpha-pathway has been revealed to be highly effective although biomarkers for a specific, individualized selection of patients for such therapeutic approaches are still lacking. In accordance with the paradigms for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) rationally designed pharmacological interventions with next generation drugs or multi-drug combinations for primary or secondary/acquired resistance are already being developed following molecular targeted first-line treatment.     

EGFR-TKI治疗非小细胞肺癌研究进展

吉非替尼和厄洛替尼均为小分子量表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),已在化疗失败的晚期非小细胞肺癌(NSCLC)解救治疗中取得疗效,但仅对特定人群发挥作用。EGFR- TKI联合化疗一线治疗NSCLC并未能提高疗效;正在进行的临床研究聚焦于优势人群EGFR-TKI一线治疗或联合化疗的研究。     

Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors

Purpose

H1650 non-small cell lung cancer (NSCLC) cells display primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) although they have a deletion mutation on exon 19 of the EGFR gene. We investigated the effect of inhibition of both insulin-like growth factor receptor (IGFR) and EGFR signaling considering that IGFR signaling pathway has been implicated in the development and progression with therapeutic resistance of various cancers including lung cancer.

Methods

Three human NSCLC cell lines with an EGFR mutation of PC-9, HCC827 and H1650 were used for experiment. Cell viability and proliferative activity were assessed by MTT and three-dimensional culture assay. Combination index was obtained by CalcuSyn software. The change of EGFR- and IGFR-related signals was evaluated by western blots.

Results

H1650 cells were 1,000 times more resistant to gefitinib and erlotinib than HCC827 and PC-9 cells possessing the same EGFR mutation. Phosphatase and tensin homolog loss and sustained phosphorylation of Akt in spite of treatment with gefitinib were evident only in H1650 cells. Interestingly, IGFR phosphorylation was decreased by gefitinib in HCC827 and PC-9 cells while being maintained in H1650 cells. Combined treatment with the IGFR inhibitors α-IR3 and AG1024 enhanced gefitinib-induced growth inhibition and apoptosis, and down-regulated phosphorylation of Akt, EGFR and IGFR.

Conclusion

Combined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.     

Prognostic significance of NSE mRNA in advanced NSCLC treated with gefitinib

Purpose

Current knowledge of the prognostic biomarkers of advanced non-small cell lung cancer (NSCLC) treated with gefitinib is poor. NSE mRNA as a potential prognostic biomarker of the effectiveness of gefitinib treatment in NSCLC, especially in the Chinese population, needs to be further validated.

Patients and Methods

We retrospectively reviewed 168 advanced NSCLC patients treated with gefitinib between May 2006 and July 2010. NSE mRNA was measured using quantitative RT-PCR analysis for correlation with the clinical outcomes.

Results

We found that NSE mRNA expression was inversely correlated with sensitivity to gefitinib in NSCLC patients. Patients without elevated NSE mRNA had a more RR (CR + RR) 45.1 % than elevated 18.9 % (P = 0.0005). Moreover, the time to progression was 6.0 versus 4.2 months, respectively. Log-rank test was marginally significant (χ² = 12.11, P = 0.0007) and Cox multivariate analysis revealed that NSE mRNA (HR = 3.076; 95 % CI 1.943–4.870; P < 0.0001) was an independent prognostic factor of NSCLC patients in the Chinese population.

Conclusion

For NSCLC patients treated with gefitinib, patients without elevated NSE mRNA had a better prognosis than those with elevated NSE mRNA. Pretreatment NSE mRNA holds great potential as a prognostic biomarker in advanced NSCLC. Therefore, it is proposed that NSE mRNA should be routinely detected to screen patients who are more likely to benefit from gefitinib-based treatment.