Jin Seok Ahn

First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung

PURPOSE Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy. PATIENTS AND METHODS In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs. RESULTS Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died. CONCLUSION Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study

PURPOSE Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. PATIENTS AND METHODS Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). RESULTS Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. CONCLUSION Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Phase III Trial of Two Versus Four Additional Cycles in Patients Who Are Nonprogressive After Two Cycles of Platinum-Based Chemotherapy in Non–Small-Cell Lung Cancer

PURPOSE This trial was conducted to determine the optimal duration of chemotherapy in Korean patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with stages IIIB to IV NSCLC who had not progressed after two cycles of chemotherapy were randomly assigned to receive either four (arm A) or two (arm B) more cycles of third-generation, platinum-doublet treatment. RESULTS Of the 452 enrolled patients, 314 were randomly assigned to the groups. One-year survival rates were 59.0% in arm A and 62.4% in arm B, and the difference of 3.4% (95% CI, -8.0 to 4.8) met the predefined criteria for noninferiority. The median time to progression (TTP), however, was 6.2 months (95% CI, 5.7 to 6.7 months) in arm A and 4.6 months (95% CI, 4.4 to 4.8 months) in arm B, the difference of which is statistically significant (P = .001). The frequencies of hematologic and nonhematologic toxicities were similar in the two arms. CONCLUSION This study confirms the noninferiority of overall survival with four cycles compared with six cycles of chemotherapy for the first-line treatment of advanced NSCLC and supports the current American Society of Clinical Oncology guidelines. Notably, patients receiving six cycles of chemotherapy compared with four cycles showed a favorable TTP, suggesting that further investigation of the new strategies of maintenance therapy with less toxic agents after three to four cycles of induction chemotherapy might be warranted to improve survival, with consideration of both ethnicity and pharmacogenomic signatures.

Randomized Phase III Trial of Gefitinib versus Docetaxel in Non–Small Cell Lung Cancer Patients Who Have Previously Received Platinum-Based Chemotherapy

Purpose: The ISTANA (IRESSA as Second-line Therapy in Advanced NSCLC—KoreA) study compared gefitinib with docetaxel in patients with advanced or metastatic non–small cell lung carcinoma (NSCLC) pretreated with platinum-based chemotherapy. Experimental Design: We conducted a multicenter, randomized, open-label phase III trial of gefitinib (250 mg/d) versus docetaxel (75 mg/m2 day 1 every 3 weeks) in patients with advanced or metastatic NSCLC treated with one previous platinum-based chemotherapy. The primary endpoint was progression-free survival. Results: A total of 161 patients (male, 62%; never smoker, 41%; adenocarcinoma, 68%) were enrolled. Progression-free survival was longer for gefitinib compared with docetaxel (hazard ratio, 0.729; 90% confidence interval, 0.533-0.998; one-sided P = 0.0441). Gefitinib significantly improved objective response rate (28.1% versus 7.6%; two-sided P = 0.0007). In the final analysis of overall survival, the hazard ratio was 0.870 (95% confidence interval, 0.613-1.236; two-sided P = 0.4370). No significant differences were seen in the quality of life or symptom improvement rates between the two treatment groups. Gefitinib was well tolerated, was consistent with previous data and disease, and had fewer serious adverse events and fewer Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events than docetaxel. The incidence of interstitial lung disease–type events was 3.7% (n = 3) with gefitinib and 3.9% (n = 3) with docetaxel. Conclusions: The primary endpoint of progression-free survival was longer with gefitinib than docetaxel, and the secondary endpoints showed superior objective response rate, good tolerability, and similar quality of life improvement rates for gefitinib than docetaxel. Therefore, gefitinib is an important valid treatment option for second-line therapy for Korean NSCLC patients. Clin Cancer Res; 16(4); 1307–14

Discordance of Molecular Biomarkers Associated with Epidermal Growth Factor Receptor Pathway between Primary Tumors and Lymph Node Metastasis in Non-small Cell Lung Cancer

Introduction: For the identification of the patients who most likely benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), molecular assays are considered to be of paramount importance. Given the heterogeneity of NSCLC at the molecular level, this study was conducted to determine the discrepancy in EGFR mutations between primary tumors and the corresponding lymph node metastasis. Patients and Methods: Surgically resected 101 paired primary NSCLC and metastatic lymph nodes were evaluated for the EGFR mutations by direct DNA sequencing and heteroduplex analysis. Results: EGFR mutation was detected in 29.7% (30 of 101) of the primary tumors and in 27.7% of lymph node metastases (28 of 101) by either direct sequencing or heteroduplex analysis, respectively. By direct sequencing, 12 cases (11.9%) showed discordance in EGFR mutations between primary tumors and metastasis. In 11 cases, EGFR mutations were detected only in the primary tumor, whereas 1 case only in lymph node metastases. By heteroduplex analysis, 17 cases (16.8%) were discordant. Ten cases were primary tumor positive and lymph node negative, whereas seven cases were lymph node positive and primary tumor negative. Conclusions: A considerable proportion of NSCLC showed discrepancy in EGFR mutations between primary tumors and metastatic lymph nodes, suggesting tumor heterogeneity at the molecular level during the process of metastasis.

Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

PURPOSE Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. PATIENTS AND METHODS We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated. RESULTS This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC. CONCLUSION These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.

Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs. Mol Cancer Ther; 11(3); 784–91. ©2012 AACR.

Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy ☆

PURPOSE Gefitinib and erlotinib are potent EGFR TKIs, with antitumor activity. In this randomized, single-center, non-comparative phase II trial, the efficacy and safety of gefitinib and erlotinib was evaluated as the second-line therapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least two out of three clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker) were eligible. RESULTS A total of 96 (48 per arm) patients were randomly assigned to gefitinib- or erlotinib-arm, respectively. Baseline characteristics were well-balanced between the two arms. The response rates (RR) were 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9 months (95% CI, 1.3-8.5) in the gefitinib arm and 3.1 months (95% CI, 0.0-6.4) in the erlotinib arm. The most common grade 3/4 toxicity was skin rash. Exploratory analyses showed that there was no significant difference in RR and PFS in the gefitinib arm compared to the erlotinib arm (RR (%) 47.9 vs. 39.6, p=0.269; median survival (months) 4.9 vs. 3.1, p=0.336). There was no significant difference in QOL between the two arms. CONCLUSION Both gefitinib and erlotinib showed effective activity and tolerable toxicity profiles as second-line treatment for the selected population of NSCLC. We may consider conducting a phase III trial to directly compare the efficacy and toxicity between gefitinib and erlotinib in an enriched patient population.

Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Introduction: This study is to evaluate whether thymidylate synthase (TS) or thyroid transcription factor 1 (TTF1) protein expression can predict clinical outcomes for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC). Methods: Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy were immunohistochemically analyzed for the expressions of TS and TTF1. Results: TS and TTF1 expression were successfully analyzed in 193 and 284 cases, respectively. Tumors with TS-negativity or TTF1-positivity were more frequent in patients who were female, younger, had adenocarcinoma, or had never smoked. Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity (33.7% versus 14.1%, p = 0.002) and TTF1-positivity (28.1% versus 9.8%, p < 0.001). In univariate analysis, progression-free survival for pemetrexed-based chemotherapy was significantly longer in groups with adenocarcinoma (2.9 versus 1.4 months, p = 0.001), TS-negativity (4.1 versus 2.0 months, p = 0.001), and TTF1-positivity (3.8 versus 1.3 months, p < 0.001). In multivariate analysis, TS-negativity (hazard ratio [HR] = 0.70; 95% confidence interval [CI], 0.51–0.97) and TTF1-positivity (HR = 0.51; 95% CI, 0.35–0.73) were associated with longer progression-free survival. Patients with TTF1-positive tumors also had significantly longer overall survival times than patients with TTF1-negative tumors (25.4 versus 14.2 months, HR = 0.55; 95% CI, 0.39–0.77). Conclusions: Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression should be further validated in a prospective randomized study.