Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis

Considering whole-brain radiotherapy (WBRT) for asymptomatic brain metastases can reduce performance status and delay systemic treatment, primary chemotherapy can be a feasible alternative treatment. Good and rapid response to epidermal growth factor tyrosine kinase inhibitor (EGFR TKI) treatment makes this an attractive option for never-smokers with adenocarcinoma of the lung. Between January 2005 and August 2007, 23 Korean never-smoking patients with adenocarcinoma of the lung who had synchronous asymptomatic brain metastasis were consecutively treated with EGFR TKI therapy, either gefitinib 250 mg or erlotinib 150 mg once daily, as first-line treatment after giving informed consent, until disease progression, unacceptable toxicity or patient's refusal. They have not received either any prior chemotherapy or any radiotherapy including stereotactic radiosurgery. Objective tumor responses were assessed 1 month after treatment and then every 2 months or when clinically indicated. Out of the 23 patients treated, 16 achieved a PR and 3 experienced stable disease (SD) while 4 experienced progressive disease (PD), resulting in a response rate of 69.6% and a disease control rate of 82.6%. Intracranial tumor responses were observed in 17 patients (73.9%). After a median follow-up of 21.8 months, the median progression-free and overall survival (OS) time was 7.1 and 18.8 months, respectively. Eleven patients received WBRT with a median time-to-local-treatment for intracranial tumors of 19.3 months. In conclusion, EGFR TKI treatment showed promising antitumor activity against both intracranial and extracranial tumors in chemotherapy-naïve never-smokers with adenocarcinoma of the lung. Therefore, these agents should be considered as the treatment of choice in this clinical setting.     

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.     

Incidence of T790M in Patients With NSCLC Progressed to Gefitinib,Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA

BackgroundInsights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non–small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib.Patients and MethodsThe present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay.ResultsA total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001).ConclusionsAlthough gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.     

吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的临床观察

目的 探讨吉非替尼与厄洛替尼治疗非小细胞肺癌脑转移的疗效。方法 回顾性分析67例EGFR突变阳性的肺腺癌脑转移患者的病历资料,患者均口服吉非替尼250 mg/天（吉非替尼组,n=38）或厄洛替尼150 mg/天（厄洛替尼组,n=29）,直至发生颅内病变进展、死亡或不可耐受的不良反应。疗效分析采用RECIST 1.1版标准,生存分析采用Kaplan-Meier法并行Log-rank检验。结果 全组颅内病变的有效率（RR）和疾病控制率（DCR）分别为44.8％和92.5％,吉非替尼组和厄洛替尼组分别为42.1％、92.1％和48.3％、93.1％（P=0.881）。颅外病变的RR和DCR分别为53.7％和95.5％,吉非替尼组和厄洛替尼组分别为52.6％、94.7％和55.2％、96.6％（P=0.932）。全组患者的中位无进展生存期（PFS）和总生存期（OS）分别为10.8个月和15.3个月,吉非替尼组和厄洛替尼组分别为10.6个月、14.8个月和11.7个月、15.7个月（P=0.720,P=0.569）。结论 吉非替尼和厄洛替尼对EGFR突变阳性的非小细胞肺癌脑转移具有较好的疗效,可以作为脑转移患者的治疗选择,两种药物在脑转移瘤的疗效及患者的预后等方面无差异。     

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer

BackgroundOnly a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival.Patients and MethodsInformation about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals.ResultsA total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis.ConclusionDutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.     

Response to Pemetrexed Chemotherapy in Lung Adenocarcinoma-Bronchioloalveolar Carcinoma Insensitive to Erlotinib

Targeted therapy against epidermal growth factor receptor (EGFR) in non–small-cell lung cancer has heralded an era of mutationally targeted inhibition of this receptor and its oncogenic signal transduction using the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. EGFR TKIs have helped facilitate the concept of “personalized” cancer therapy into a reality. A majority of unselected patients remain as nonresponders with primary resistance to EGFR TKIs. Initial responders to EGFR TKIs all invariably relapse later with resistant disease. The optimal alternative therapeutic approach after a failed therapeutic trial of treatment with EGFR TKI remains to be better defined. Herein, we report a case of a patient with recurrent metastatic lung adenocarcinoma-bronchioloalveolar carcinoma that showed primary insensitivity to erlotinib therapy who later demonstrated substantial durable response to single-agent pemetrexed. We also present discussion on the evolving paradigm of the use of erlotinib in lung cancer and the current status of determinants of sensitivity in pemetrexed chemotherapy.     

Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature

Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer (NSCLC). They are both tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female (60.6%), non-smokers (64.5%), had adenocarcinoma histology (88.3%) and were of East Asian ethnicity (92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanisms especially those related to resistance to initial EGFR TKI therapy.     

EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia: present and future

Treatment with one of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has become an additional option for patients with non-small cell lung cancer (NSCLC). Further investigation clearly demonstrated that a subset of patients show a better response to these agents than the overall patient population: individuals with adenocarcinoma histology, females, never-smokers and those of East Asian origin. The ISEL and BR21 studies showed that East Asian patients had significantly longer survival compared with the total study population after EGFR-TKI treatment. The increased response to EGFR-TKIs observed in East Asian patients can likely be attributed to the higher prevalence of activating EGFR mutations found in these individuals. Data from several studies in Japan, Korea, Taiwan and China support this, showing a high occurrence of activating mutations. Furthermore, in prospective studies of gefitinib in these populations, sensitive activating mutations (deletions in exon 19 or L858R) are associated with high overall response and disease control rates. Within East Asian patients, predictors of response to gefitinib include female sex, adenocarcinoma histology, no smoking history and receiving gefitinib first-line, although there may be an interaction between these factors. All patients eventually develop acquired resistance to the currently available EGFR TKIs. In addition, the presence of EGFR mutations is a useful tool to determine NSCLC patients' prognosis; some studies suggested that this may apply if patients are receiving first-line chemotherapy, not only if they are receiving EGFR-TKIs.     

Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib,Erlotinib, and Afatinib in Advanced EGFR-Mutated Non–Small Cell Lung Cancer

IntroductionGefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment.MethodsWe performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI.ResultsSixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs.ConclusionsEGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.     

Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain

Key “driver” mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and gefitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining.     

Preclinical Rationale for PI3K/Akt/mTOR Pathway Inhibitors as Therapy for Epidermal Growth Factor Receptor Inhibitor-Resistant Non–Small-Cell Lung Cancer

Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non–small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months.Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials.     

Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)

BackgroundThis phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM).Patients and methodsForty-eight patients aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST.ResultsThe median PFS was 10.1 months [95% confidence interval (CI) 7.1–12.3] for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2.ConclusionsSingle-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.     

Select clinical trials of erlotinib (OSI-774) in non-small-cell lung cancer with emphasis on phase III outcomes

Lung cancer is primarily diagnosed during the advanced stage of disease, at which stage treatment options are severely limited. It is primarily for this reason that lung cancer carries a higher mortality rate than breast, prostate, and colon cancers combined. Traditional treatments for metastatic non-small-cell lung cancer (NSCLC) include chemotherapy; however, this approach, although the standard of care, is toxic and nonspecific, thereby rendering treatment inaccessible to those with a poor performance status. Alternatively, there are recent emerging treatment options that involve inhibiting specific molecular targets. This includes the epidermal growth factor receptor (EGFR), which is known to potentiate tumor cell proliferation and metastases, while also attenuating apoptosis. This target is especially important because approximately 85% of all lung cancers are categorized as NSCLC, which expresses EGFR at a rate of 40%-85%. In addition, newly developed EGFR-specific tyrosine kinase inhibitors (TKIs) have been used in clinical trials with encouraging results. To date, gefitinib and erlotinib (OSI-774; Tarceva) are the most studied of the EGFR TKIs for the treatment of NSCLC. In this article we have focused on 3 recently completed trials involving erlotinib as monotherapy (BR.21 study) or in combination with standard chemotherapeutic regimens (TALENT and TRIBUTE trials) for the treatment of NSCLC. When used in combination with carboplatin/paclitaxel (TALENT) or cisplatin/gemcitabine (TRIBUTE), erlotinib was found not to improve survival. These results contrast with what would be predicted from preclinical data outcomes, but they complement recent phase III reports involving similar combinations with gefitinib. Subset analysis of the TRIBUTE trial revealed that never-smokers had the greatest survival benefit. Conversely, erlotinib has exhibited overall survival benefits when used as monotherapy (BR.21 study). In addition, recent information involving mutations within the kinase domain of the EGFR may be implicated in the response seen with EGFR TKIs in recent trials.     

Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers

BackgroundPatients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control.MethodsWe evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib.ResultsWe enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1–2 and 50 mg days 3–7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60–84%). Median progression-free survival was 9.9 months (95% CI 5.8–15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0–13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54–91%).ConclusionThis is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.     

Thyroid carcinoma after treatment for malignancies in childhood and adolescence: from diagnosis through follow-up

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations derive greater benefits from first- and second-generation tyrosine kinase inhibitors (TKIs) than from chemotherapy, especially in the first-line setting. Thus, main treatment guidelines indicate to test all patients with lung adenocarcinoma for these genetic abnormalities and recommend the employment of TKIs in these patients. However, many unanswered questions about the optimal use of TKIs in lung cancer remain; in particular, an open question is which of the currently available TKIs (gefitinib, erlotinib and afatinib) might be the best choice in untreated NSCLC patients. In the current review, we will analyze the state of EGFR-TKIs therapy in untreated EGFR-mutated NSCLC patients with a focus on both efficacy and toxicity.     

Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first-line gefitinib,erlotinib and afatinib-treated non-small cell lung cancer patients with activating EGFR mutations

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians’ choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15–9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20–8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10–9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18–20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02–0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients’ clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.     

The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung adenocarcinoma, and a theoretical basis exists for utilising whole brain radiotherapy (WBRT) combined with erlotinib for the treatment for brain metastases in patients with lung adenocarcinoma. This therapeutic regimen has the potential to be a revolutionary treatment for which the most appropriate indication is lung adenocarcinoma. Currently, there is no difference in the treatment of brain metastasis, especially multiple brain metastases, in patients with lung adenocarcinoma of patients with other lung carcinomas. Furthermore, limited clinical trials that combine a TKI with WBRT to treat multiple lung adenocarcinoma metastases have been conducted, and many clinical questions remain unanswered. Lung adenocarcinoma has a high propensity to metastasize to the brain, and targeted therapy has been widely used; however, clinical trials are necessary to provide data to support the combination of erlotinib and WBRT.     

A Phase II Study of Erlotinib as a First-Line Therapy for Patients with Non—Small-Cell Lung Cancer with Favorable Clinical Predictors

BackgroundMany studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors suggest positive and negative predictors for response and survival. We conducted the study to evaluate the efficacy of erlotinib as a first-line therapy for patients with non—small-cell lung cancer who have favorable clinical predictors, such as never having smoked, adenocarcinoma, or female sex.Patients and MethodsThe eligible patients should have ≥ 2 of 3 favorable clinical predictors, including female sex, adenocarcinoma, and never-smoker status. Additional inclusion criteria were as follows: stage IIIB or IV disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, adequate organ function, and measurable lesions. Neither previous chemotherapy nor targeted therapy nor radiation therapy for measurable disease was allowed. Treatment consisted of erlotinib 100–150 mg orally given once daily till disease progression, unacceptable toxicity, or patient's refusal. Objective tumor responses were assessed 1 month after the commencement of erlotinib and then every 2 months.ResultsBetween October 2006 and June 2007, all 38 patients enrolled (median age, 54 years; male/female, 1/37; ECOG PS 0/1/2, 2/29/7; stage IIIB/IV disease, 3/35; never/current smoker 36/2) were evaluable for response. Among them, 26 reached a partial response (PR), 6 had stable disease (SD), and 6 had progressive disease (PD), giving an overall response rate of 68.4% (95% CI, 52.5%–81%) and a disease control rate of 84.2% (95%CI, 69.2%–92.9%). Out of 6 patients identified to have an EGFR gene mutation before initiating treatment, 5 reached a PR, and 1 had PD, while out of 6 patients with wild-type of EGFR, there were 2 PRs, 1 SD, and 3 PDs. After a median follow-up of 7.9 months, the expected median progression-free survival is 10.7 months, with an expected 1-year survival rate of 91.2%. The most common toxicity was skin rash, which was manageable.ConclusionErlotinib showed promising response rates as a first-line therapy for patients who have favorable predictors and could be a treatment of choice in this clinical setting.     

Emerging approaches to advanced bronchioloalveolar carcinoma

Opinion statement Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung adenocarcinoma that has distinct epidemiologic, histologic, radiographic, and clinical features. The strict pathologic definition requires an absence of any invasion through the basement membrane into pulmonary parenchyma, but there is a growing consensus based on recent clinical studies that this diagnosis should be considered to be based on the clinical features of diffuse ground-glass opacities with minimal or no extra-thoracic spread and histology demonstrating adenocarcinoma with a lepidic growth pattern characteristic of BAC, even if there is a component of invasive adenocarcinoma. Although unifocal or even potentially oligometastatic disease is appropriately treated with resection, advanced BAC is generally treated with systemic therapy. However, multifocal BAC may be indolent enough to follow asymptomatic patients without any systemic therapy if patients are comfortable with this approach, because the rate of disease progression may be slow enough to warrant no therapy for many months or even years. For patients who have symptoms and/or clear evidence of progression over a short interval, standard chemotherapy is appropriate, but I would consider treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to be the most appropriate initial therapy. This is based on the well-documented activity of the EGFR TKIs erlotinib and gefitinib, the latter no longer commercially available in advanced BAC. Advanced BAC is now emerging as an area of significant research, and clinical trials are particularly appealing considerations for such patients.     

Prolonged control of bone metastases in non-small-cell lung cancer patients treated with gefitinib

We describe two non-small-cell lung cancer (NSCLC) patients in which treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) gefitinib produced a prolonged control of bone disease. In the first patient, a 48-year-old male with adenocarcinoma (ADC) of the lung and multiple bone metastases, the bone scan became completely negative following treatment with gefitinib for 9 months. The patient remained alive and with no evidence of bone metastases for 20 months, despite two local recurrences that were surgically removed. Similarly, the bone scan of the second patient, a 49-year-old male with ADC of the lung and bone metastases, became negative after 6 months on gefitinib. The molecular mechanisms potentially involved in this phenomenon are discussed.