Sung Jin Yoon

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.

Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first : result of a randomized pilot study.

This randomized pilot trial investigated whether primary chemotherapy was feasible in terms of efficacy, survival, toxicity profile, and quality of life compared with whole‐brain radiotherapy (WBRT) given first in chemotherapy‐naive patients nonsmall cell lung cancer (NSCLC) with synchronous brain metastasis when neurologic symptoms or signs are absent or controlled by supportive care.

Comparison of targeted next-generation sequencing with conventional sequencing for predicting the responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in never-smokers with lung adenocarcinoma.

PURPOSE To investigate the clinical utility of targeted next-generation sequencing (NGS) for predicting the responsiveness to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, we compared the efficacy with conventional sequencing in never-smokers with lung adenocarcinoma (NSLAs). PATIENTS AND METHODS We obtained DNA from 48 NSLAs who received gefitinib or erlotinib for their recurrent disease after surgery. Sanger sequencing and peptide nucleic acid clamp polymerase chain reaction (PCR) were used to analyze EGFR, KRAS, BRAF, and PIK3CA mutations. We analyzed ALK, RET, and ROS1 rearrangements by fluorescent in situ hybridization or reverse transcriptase-PCR and quantitative real-time PCR. After molecular screening, Ion Torrent NGS was performed in 31 cases harboring only EGFR exon 19 deletions (19DEL), an L858R mutation, or none of the above mutations. RESULTS The 31 samples were divided into four groups: (1) responders to EGFR-TKIs with only 19DEL or L858R (n=15); (2) primary resistance to EGFR-TKI with only 19DEL or L858R (n=4); (3) primary resistance to EGFR-TKI without any mutations (n=8); (4) responders to EGFR-TKI without any mutations (n=4). With NGS, all conventionally detected mutations were confirmed except for one L858R in group 2. Additional uncovered predictive mutations with NGS included one PIK3CA E542K in group 2, two KRAS (G12V and G12D), one PIK3CA E542K, one concomitant PIK3CA and EGFR L858R in group 3, and one EGFR 19DEL in group 4. CONCLUSIONS Targeted NGS provided a more accurate and clinically useful molecular classification of NSLAs. It may improve the efficacy of EGFR-TKI therapy in lung cancer.

DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma

The objective of this study was to investigate whether polymorphisms in DNA repair genes affect clinical outcome of never‐smokers with lung adenocarcinoma (NSLA).

Randomized phase II study of maintenance irinotecan therapy versus observation following induction chemotherapy with irinotecan and cisplatin in extensive disease small cell lung cancer.

Introduction: To determine whether irinotecan maintenance therapy in extensive disease-small cell lung cancer can improve survival of patients who responded to irinotecan plus cisplatin (IP) induction therapy. Methods: A total of 120 chemo-naive patients with adequate organ functions and Eastern Cooperative Oncology Group performance status of 0 to 2 were enrolled from March 2003 through April 2006. After IP induction therapy, with either schedule A (I: 60 mg/m2 intravenously (IV) on days 1, 8, and 15; P: 30 mg/m2 IV on days 1 and 8, every 4 weeks for six cycles) or schedule B (I: 60 mg/m2 and P: 30 mg/m2 IV on days 1, and 8, every 3 weeks for eight cycles), responding patients were randomized to either maintenance with irinotecan 100 mg/m2 IV on days 1, 8, and 15, every 4 weeks up to six cycles, or observation. Results: Overall, 100 (83%) of 120 patients achieved objective tumor responses (12 complete responses, 88 partial responses) after IP induction therapy. Of those patients who remained in remission upon completion of planned cycles of induction therapy, 45 were randomized to maintenance (n = 21) or observation (n = 24). Median progression-free survival (PFS) and overall survival (OS) for all patients were 7.2 and 14.0 months, respectively. For the maintenance arm, median PFS and OS were 12.0 and 17.6 months, respectively. For the observation arm, median PFS and OS were 9.9 and 20.5 months, respectively, which was not significantly different from the maintenance arm. Conclusions: IP chemotherapy is very useful for the treatment of small cell lung cancer. However, maintenance irinotecan therapy did not seem to further affect the clinical outcome of patients who had responded to IP induction therapy.

Association of SUMO1 and UBC9 genotypes with tumor response in non-small-cell lung cancer treated with irinotecan-based chemotherapy

Irinotecan induces small ubiquitin-like modifier (SUMO)-1 conjugation to topoisomerase-I, leading to enhanced sensitivity to irinotecan. In this study, we genotyped SUMO1 and UBC9 polymorphisms in 147 non-small-cell lung cancer (NSCLC) treated with irinotecan chemotherapy to investigate the association between genotypes and tumor response rate. Immunohistochemistry for SUMO1 and UBC9 was performed in 42 tumor samples and correlated with genotypes. The UBC9 10920CG genotype was associated with significantly higher response rate than the C/C genotype (81 vs 37%, P=0.0002). This predictive effect on tumor response was also seen in multivariate analysis (odds ratio=8.5, P=0.003). Moreover, tumors arising from the UBC9 10920CG genotype were associated with higher prevalence of SUMO1 overexpression compared with those with CC genotype (78 vs 31%, P=0.021). This finding suggests that the UBC9 10920CG genotype enhances sensitivity to irinotecan chemotherapy in advanced NSCLC through upregulation of SUMO1 in tumor cells.

A pilot trial of gemcitabine and vinorelbine plus capecitabine in locally advanced or metastatic nonsmall cell lung cancer

Objectives:We conducted a pilot study of gemcitabine, vinorelbine and capecitabine combination to evaluate its toxicity and efficacy in chemo-naive patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) after a short phase IB trial. Methods:Eligible chemo-naive patients with stage IIIB or IV NSCLC received outpatient administration of gemcitabine 900 mg/m2 and vinorelbine 25 mg/m2 intravenously on days 1 and 8, every 3 weeks, concurrently with capecitabine 1000 mg/m2 given orally twice a day on days 1 to 5 and 8 to 12 (dose level I), or days 1 to 6 and 8 to 13 (dose level II). Results:Between November 2002 and December 2003, 19 patients participated in the study at either dose level I (7 patients) or dose level II (12 patients). The maximum tolerated dose, defined as the dose at which no more than 1 of 6 patients in a cohort experienced a dose-limiting toxicity (DLT) in the first cycle, was not established. However, 1 of 7 patients at dose level I, and 2 of 12 at dose level II experienced DLTs (ie, grade 3 hepatotoxicity in 2 patients, and grade 3 febrile neutropenia in 1 patient). In addition, 2 patients experienced treatment-related pneumonitis requiring mechanical ventilator support after the second course of therapy. Objective tumor response was observed in 5 (26.3%) of 19 patients. Further patient accrual was stopped according to the study design. Conclusions:This 3-drug combination showed disappointing antitumor activity against NSCLC with unexpected life-threatening pulmonary toxicity. No further investigation of this regimen is recommended for patients with NSCLC.

A randomized phase II study of irinotecan plus cisplatin versus irinotecan plus capecitabine with or without isosorbide-5-mononitrate in advanced non-small-cell lung cancer

BACKGROUND We investigated the efficacy of irinotecan/cisplatin (IP) versus irinotecan/capecitabine (IX) with or without isosorbide-5-mononitrate (ISMN) in chemo-naïve advanced non-small-cell lung cancer. PATIENTS AND METHODS Initially, 74 patients were randomly assigned to either IP or IX. Given the potential benefits of ISMN on chemotherapy, the protocol was amended during the study. Subsequently, 72 patients were randomly assigned to either IP + ISMN or IX + ISMN. Patients were treated with predefined second-line therapies (docetaxel/capecitabine for IP or IP + ISMN, docetaxel/cisplatin for IX or IX + ISMN) when disease progressed. RESULTS A total of 146 received treatment. Response rate (RR), median progression-free survival (PFS) and overall survival (OS) were 49%, 5.5 months, 14.5 months in IP; 33%, 3.3 months, 13.0 months in IP + ISMN; 30%, 4.3 months, 16.1 months in IX; and 25%, 3.4 months, 13.6 months in IX + ISMN, respectively. While IP arm showed a trend toward higher RR and longer PFS than IX arm, IX arm showed a trend toward longer OS than IP arm. No significant differences were observed between IP + ISMN and IX + ISMN. CONCLUSION IP showed better RR and PFS but no OS benefit when compared with IX. The addition of ISMN to IP or IX chemotherapy did not seem to improve the treatment outcome.BACKGROUND We investigated the efficacy of irinotecan/cisplatin (IP) versus irinotecan/capecitabine (IX) with or without isosorbide-5-mononitrate (ISMN) in chemo-naïve advanced non-small-cell lung cancer. PATIENTS AND METHODS Initially, 74 patients were randomly assigned to either IP or IX. Given the potential benefits of ISMN on chemotherapy, the protocol was amended during the study. Subsequently, 72 patients were randomly assigned to either IP + ISMN or IX + ISMN. Patients were treated with predefined second-line therapies (docetaxel/capecitabine for IP or IP + ISMN, docetaxel/cisplatin for IX or IX + ISMN) when disease progressed. RESULTS A total of 146 received treatment. Response rate (RR), median progression-free survival (PFS) and overall survival (OS) were 49%, 5.5 months, 14.5 months in IP; 33%, 3.3 months, 13.0 months in IP + ISMN; 30%, 4.3 months, 16.1 months in IX; and 25%, 3.4 months, 13.6 months in IX + ISMN, respectively. While IP arm showed a trend toward higher RR and longer PFS than IX arm, IX arm showed a trend toward longer OS than IP arm. No significant differences were observed between IP + ISMN and IX + ISMN. CONCLUSION IP showed better RR and PFS but no OS benefit when compared with IX. The addition of ISMN to IP or IX chemotherapy did not seem to improve the treatment outcome.

A Phase II Study of Weekly Paclitaxel Plus Gemcitabine as a Second-Line Therapy in Patients with Metastatic or Recurrent Small Cell Lung Cancer

Purpose Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen. Materials and Methods Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m2) and G (1,000 mg/m2) on days 1 and 8 of each cycle of 21 days until disease progression. Results Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide-platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia. Conclusion Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy.

Phase II study of induction chemotherapy (ICT) with gemcitabine (G) and vinorelbine (V) followed by concurrent chemoradiation therapy (CCRT) with oral etoposide (E) and cisplatin (P) for inoperable stage IIIA/B non-small cell lung cancer (NSCLC)

7255 Background: CCRT with EP was feasible and showed favorable survival outcome (Lee JS et al, Int J Radiat Oncol Biol Phys. 1998). We combined ICT with GV and CCRT with EP to reduce systemic failures. We used different regimens for ICT and CCRT, hoping to reduce toxicity and to kill resistant clones. METHODS Chemo-naïve pts with inoperable clinical stage III NSCLC without pleural effusion, KPS 70-100, and weight loss ≤ 5% were enrolled. Before CCRT, 3 cycles of ICT with G 1000 mg/m2 and V 30 mg/m2 on D1 and 8 were given every 3 weeks. Once-daily thoracic RT (1.8 Gy/day, 5 days/week, total 63 Gy over 7 weeks) was given concurrently with E 100mg on D1-5, 8-12, 29-33, 36-40 plus P 50 mg/m2 on D1, 8, 29, 36. RESULTS From 4/2002 to 11/2003, 42 pts were enrolled; median age: 59 (43-72) years; M/F: 37/5; histology: 26 squamous ca, 12 adenoca, 4 others; stage: 14 IIIA, 28 IIIB. 34 of 42 pts were evaluated for response and toxicity (5 too early to evaluate). After ICT with GV, there were 15 PR (44%), 11 SD (32%), 8 PD (24%; 4 locoregonal, 4 distant). CCRT was given to 28 of 30 pts who did not have distant failure (2 PR pts declined CCRT). 7 pts who had SD (5) and PD (2) after ICT achieved additional PR, but 6 pts (including 3 PR pts after ICT) progressed after CCRT. Overall response rate was 65% (22/34pts). After a median follow-up of 11.2 months, we observed 21 failures of 34 pts (16 distant, 3 local, 2 treatment related death) with median time to failure of 8.8 months. 1-year survival rate was 73% and median overall survival has not been reached yet. During ICT, toxicity was mild and manageable. But during CCRT, toxicity was significant; 80% G3/4 hematologic toxicity, 24% G3/4 esophagitis, and 30% G3/4 pneumonitis. CONCLUSIONS This regimen showed promising activity and survival data comparable to other studies. But considering toxicity of CCRT, newer agents or treatments to diminish toxicity are needed. Updated response and survival data will be presented. (Supported in part by NCC 0210240; Gemcitabine was provided by Eli Lilly and Co). No significant financial relationships to disclose.