Kei Kunimasa

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR‐tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: Clinical benefit with optimal patient selection

BACKGROUND Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy. METHODS One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009. RESULTS The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months). CONCLUSIONS Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.

Complex Mutations in the Epidermal Growth Factor Receptor Gene in Non-small Cell Lung Cancer

Introduction: Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called “complex mutations” and the efficacy of gefitinib in treating patients with these mutations are unclear. Methods: We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations. Results: EGFR mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35–90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7–10.0 months) (p = 0.0459). Conclusions: Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.

How Sensitive Are Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Squamous Cell Carcinoma of the Lung Harboring EGFR Gene–Sensitive Mutations?

Introduction: Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations. Methods: Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry. Results: Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1. Conclusions: Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration.

Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial

BackgroundElderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status.MethodsWe screened 57 chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746–750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate.ResultsThe response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred.ConclusionsTreatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities.Trial registrationThis trial is registered at University hospital Medical Information Network-clinical trial registration (http://www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436.

Erlotinib for Pretreated Squamous Cell Carcinoma of the Lung in Japanese Patients

OBJECTIVE Erlotinib has demonstrated survival benefit in patients with not only adenocarcinoma but also squamous cell carcinoma. Epidermal growth factor receptor-tyrosine kinase inhibitors are more effective in Asian populations, including the Japanese than in western populations. However, a higher incidence of interstitial lung disease has been reported as a fatal adverse event in the Japanese population. There is little data on erlotinib for Japanese patients with pretreated squamous cell carcinoma. METHODS Between January 2004 and October 2010, we retrospectively evaluated the efficacy and toxicity of erlotinib administered as the first epidermal growth factor receptor-tyrosine kinase inhibitors for 41 Japanese patients with pretreated squamous cell carcinoma. Patients with pre-existing interstitial lung disease were carefully excluded by several examinations including high-resolution computed tomography. RESULTS The response rate and disease control rate were 9.7% [95% confidence interval: 2.7-23.1%) and 43.9% (95% confidence interval: 28.5-60.2%], respectively. Median time to treatment failure and overall survival were 2.2 months (95% confidence interval: 1.0-2.8 months) and 11.0 months (95% confidence interval: 5.7-15.7 months), respectively. Interstitial lung disease (Grade 5) was observed in one (2.4%) patient. Patients with Grade 0-1 skin rashes vs. patients with Grades 2-3 exhibited disease control rates of 28 vs. 83% (P = 0.0017), and median time to treatment failure of 1.2 months vs. 3.4 months (P = 0.0099). CONCLUSIONS Erlotinib has moderate efficacy for pretreated squamous cell carcinoma in Japanese patients. A higher grade of skin rash was associated with clinical benefit. Careful exclusion of pre-existing interstitial lung disease can minimize the occurrence of interstitial lung disease.

Pneumatosis Cystoides Intestinalis After Gefitinib Therapy for Pulmonary Adenocarcinoma

An 82-year-old female with right chest pain was referred to our hospital. She was diagnosed with adenocarcinoma of the lung with pleural dissemination and bone metastases. She was treated with oral gefitinib (250 mg once daily). At first, there was no apparent adverse event except for mild diarrhea. Two months after the first administration of gefitinib, she presented with mild abdominal pain, with the computed tomography revealing extensive intramural air within the intestinal wall, extending from the duodenum to the ascending colon, without portal venous air (Figure 1). A physical examination indicated no sign of toxicity, with the condition being presumed as pneumatosis cystoides intestinalis (PCI). Gefitinib was stopped and careful monitoring with dietary restriction was done. The symptoms gradually improved by conservative therapy and a follow-up computed tomography showed no sign of intramural air. Although gefitinib was readministered, the same episode repeated three times during gefitinib therapy. PCI is a rare condition that is characterized by intramural gas in the gastrointestinal tract, and its patho-

Glucose metabolism‐targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor‐induced drug‐tolerant persisters

In pathway‐targeted cancer drug therapies, the relatively rapid emergence of drug‐tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor–tyrosine kinase inhibitor‐induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR‐mutated lung adenocarcinoma cell lines, PC9 and II‐18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell‐related markers by quantitative RT‐PCR and the expression of the cellular senescence‐associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem‐like cell targeting drug, withaferin A. Drug‐tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem‐like cells (CSCs) and the other with the properties of therapy‐induced senescent (TIS) cells. The CD133high cell population had CSC properties and the CD133low cell population had TIS properties. The CD133low cell population containing TIS cells showed a senescence‐associated secretory phenotype that supported the emergence of the CD133high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133low cell population. Withaferin A effectively eliminated the CD133high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib‐resistant tumor growth.

Diagnostic utility of additional conventional techniques after endobronchial ultrasonography guidance during transbronchial biopsy

Endobronchial ultrasonography with a guide sheath transbronchial biopsy (EBUS‐GS TBB) has been used to diagnose peripheral pulmonary lesions (PPLs). In this study, we evaluated the diagnostic utility of conventional TBB after EBUS‐GS TBB.

Composite Physiologic Index, Percent Forced Vital Capacity and Percent Diffusing Capacity for Carbon Monoxide Could Be Predictors of Pirfenidone Tolerability in Patients with Idiopathic Pulmonary Fibrosis

OBJECTIVE The goals of this study were to assess the efficacy and tolerability of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) and to identify predictors of tolerability to pirfenidone. METHODS We conducted a retrospective observational study. When the patient showed deterioration in the percent forced vital capacity (%FVC) or experienced acute exacerbations or severe adverse events, treatment of the patient with pirfenidone was discontinued. We classified the patients who did not display progression following six months of pirfenidone treatment as the tolerant group and the patients who did display progression as the intolerant group. We retrospectively analyzed differences between the two groups in terms of baseline characteristics. The efficacy of pirfenidone was evaluated by the changes in vital capacity (VC) and %FVC before and after the start of treatment in the tolerant group. Patients A total of 20 patients who had been diagnosed with IPF were treated with pirfenidone. RESULTS In the tolerant group, the baseline %FVC (p=0.01) and the percentage diffusing capacity of the lungs for carbon monoxide (DLCO, p=0.02) were significantly higher, and the baseline composite physiologic index (CPI) was significantly lower (p=0.009) than in the intolerant group. In the tolerant group, pirfenidone significantly reduced the decline in VC and %FVC of the patients after treatment. In the intolerant group, five patients discontinued pirfenidone treatment because of anorexia. CONCLUSION We found that pirfenidone was better tolerated in patients with milder disease symptoms, as indicated by their baseline CPI, %FVC and %DLCO, and that patients in the tolerant group could benefit from the use of pirfenidone.