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J.H. Kang



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.04 - A Randomized Phase 3 Study Comparing First-line Pemetrexed plus Cisplatin Followed by Gefitinib as Maintenance with Gefitinib Monotherapy in East Asian Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (nSqNSCLC) (ID 1943)

      16:30 - 16:35  |  Author(s): J.H. Kang

      • Abstract
      • Presentation
      • Slides

      Background
      The IPASS study reported that in a clinically selected lung cancer patient population (East Asian, light ex-/nonsmokers with adenocarcinoma) gefitinib (G) provided superior progression-free survival (PFS) than chemotherapy with carboplatin/paclitaxel; however, the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumors whereas patients with wild-type (WT) tumors had inferior outcomes. Pemetrexed, in combination with cisplatin, (PC) has demonstrated improved efficacy in first-line treatment of nSqNSCLC and is a preferred chemotherapy choice. The primary objective was to compare PC induction therapy followed by G as maintenance therapy to G monotherapy, in terms of PFS, as first-line treatment in a similar “IPASS” patient population.

      Methods
      Patients with unknown EGFR mutation status (N=236) were randomized 1:1 to PCG treatment for 6 cycles or G. Patients on Arm A without progressive disease after 6 cycles received G maintenance therapy. Stage IIIB/IV nSQ NSCLC, light ex-smokers or never-smokers, and ECOG PS 0-1 patients with no prior systemic therapy were eligible. Primary endpoint analysis was conducted using a Wilcoxon test after 169 PFS events. This assessment provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples from consenting patients were analyzed for EGFR mutation status.

      Results
      Baseline characteristics were balanced across treatment arms. One-hundred-forty-one patients provided tissue for EGFR mutation analysis (59.7%). Mutation status was determined for 74 samples (52.5%);50/74 samples (67.6%) had mutations (mutation type: EX19_DEL, n=25; L858R, n=23; other, n=2). The primary analysis of PFS showed no significant difference between treatment arms (Wilcoxon p=0.217). The unadjusted HR was 0.85 (95% CI: 0.63, 1.13). During most of the study period, the KM curve for PC remained above the G curve. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (p=0.008), showing treatment effect significantly differed by EGFR mutation status. The HR for PFS favored PC in both EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients [EGFR-mutated patients HR=0.83 ([95% CI: 0.42, 1.62], p=0.585); EGFR-WT HR 0.18 ([95% CI: 0.06, 0.51], p=0.001)]. HRs for ITT and EGFR-mutated patients should be interpreted with caution as they were not constant. Arm A had more patients with ≥1 possibly drug-related CTCAE grade 3/4 TEAEs but similar rates of all-grade TEAEs during induction. Selected grade 3/4 or all-grade TEAEs which occurred significantly more included anemia, neutropenia, emesis, and neuropathy in Arm A and AST/ALT elevations, diarrhea, pruritus, and skin rash in Arm B. The toxicity profile was similar in both arms during the G maintenance period.

      Conclusion
      In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, results are consistent with the existing consensus that patients with WT EGFR do not benefit with front-line EGFR TKI treatment. Overall, the results show that identification of the EGFR mutational status is key in the management of advanced NSCLC. Even in the presence of clinically favorable predictors of EGFR mutation positivity (>60% in our population), “empirical” choice of EGFR TKIs as front-line therapy may be detrimental to NSCLC patients without EGFR mutations.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

      09:30 - 09:30  |  Author(s): J.H. Kang

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-024 - Metabolic activity on [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography and glucose transporter-1 expression may predict clinical outcomes in patients with limited disease of small cell lung cancer receiving concurrent chemoradiation (ID 1573)

      09:30 - 09:30  |  Author(s): J.H. Kang

      • Abstract

      Background
      Limited disease of small cell lung cancer (LD-SCLC) respond well to concurrent chemo-radiation (CCRT), but have high relapse rates and short relapse-free survival (RFS). We aimed to evaluate tumor metabolic activities measured by [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET) as a prognostic factor and analyze its relationships with markers of tumor biologic behavior.

      Methods
      Forty-one LD-SCLC patients receiving 4 cycles of EP (etoposide 120 mg/m[2], days 1–3; cisplatin 60 mg/m[2], day 1), 2 cycles of EP (etoposide 130 mg/m[2], days 1–3; cisplatin 30 mg/m[2], day 1) with concurrent mediastinal irradiation were enrolled. SUVmax of primary tumor was revised with the SUV of liver (SUVlivermax). Differences between pre- and post-treatment average SUV uptake of the primary tumor and intrathoracic lymph nodes were presented as ∆SUVliveravg. Thirty-one tumor biopsy specimens were immunostained for glucose transporter-1 (GLUT-1), Bcl-2, and hypoxia inducible factor-1α (HIF-1α).

      Results
      Objective response rates (ORRs) after CCRT were 92.7% and 87.8% on chest CT and FDG-PET, respectively. Median overall survival (OS) and RFS were 13.7 (range 4.4–54.1) months and 10.4 (range 0.97–54.1) months, respectively. In multivariate analysis, pretreatment lactate dehydrogenase (LDH) and ∆SUVliveravg correlated significantly with RFS (hazard ratio [HR] 2.8, P = 0.043 and HR 0.3, P = 0.004, respectively). Gender, pretreatment LDH, objective tumor metabolic response, and SUVlivermax correlated significantly with OS (HR 12.1, P = 0.006; HR 3.7, P = 0.037; HR 10.1, P = 0.008 and HR 0.2, P = 0.014, respectively). High GLUT-1-positivity (>75%) and pretreatment LDH levels (>400 U/L) correlated significantly with better ORR (P = 0.012) and HIF-1α immunoreactivity score (IRS, P = 0.029), respectively.

      Conclusion
      ∆SUVliveravg and GLUT-1, with respect to tumor glucose metabolism, might predict RFS and ORR, respectively, in definitive CCRT-treated LD-SCLC patients.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-025 - Taxane-Platinum Induction Chemotherapy in Locoregionally Advanced Non-Small-Cell Lung Cancer: Outcomes and Prognostic Factors (ID 1546)

      09:30 - 09:30  |  Author(s): J.H. Kang

      • Abstract

      Background
      Induction chemotherapy (IC) in locoregionally advanced non-small-cell lung cancer (LA-NSCLC) has shown survival benefit. This retrospective study aimed to assess clinical outcomes and to identify prognostic factors in the LA-NSCLC patients who received taxane-platinum IC (TP-IC).

      Methods
      We reviewed medical charts, imaging studies, and pathologic reports in 51 LA-NSCLC pts who were treated with TP-IC between January 2003 and June 2012 at Seoul St. Mary’s Hospital and St. Vincent’s Hospital.

      Results
      Mean age at diagnosis was 63.1 years (range, 43-77). Forty-two pts (82.4%) were male. ECOG performance status was 0 in 17 pts (33.3%) and 1 in 34 (66.7%). Histology was squamous cell in 30 pts (58.8%), adenocarcinoma in 20 (39.2%), and large cell in 1. Thirty-four pts (66.7%) had stage IIIA disease, 13 (25.5%) IIIB and 4 (7.8%) IIB. All pts were treated with docetaxel 75 mg/m[2] or paclitaxel 175 mg/m[2], and cisplatin 75 mg/m[2] or carboplatin AUC 5 on day 1 every 3 weeks. Forty-four pts (86.3%) received docetaxel-cisplatin IC, 4 (7.8%) docetaxel-carboplatin, and 3 (15.7%) paclitaxel-cisplatin. The median number of IC cycles was 3 (range, 2-4). Mean relative dose intensity was 90.4% (±10.8) and RDI ≥90% was achieved in 31 pts (60.8%). During TP-IC, asthenia (88.1%), anorexia (89.1%), neutropenia (84.4%), alopecia (80.4%), nausea (71.7%) and myalgia (57.1%) were frequent. Most common grade 3/4 toxicity was neutropenia (80%) and febrile neutropenia occurred in 3 pts (5.9%). All toxicities were manageable with supportive care with no treatment-related death. Tumor response was assessed according to the RECIST and PERCIST criteria. According to RECIST, 3 pts (5.9%) achieved complete responses (CR), 32 (62.7%) partial responses (PR), 14 (27.5%) stable diseases (SD), and 2 (3.9%) progressive disease (PD). In addition, response evaluation by PERCIST was available in 38 pts, 5 pts (13.2%) achieved CR, 26 (68.4%) PR, 5 (13.2%) SD, and 2 (5.3%) PD. Thirty-one pts (60.8%) underwent surgery, 12 (23.5%) concurrent chemo-radiation (CCRT), 2 (4.3%) radiotherapy alone, 5 (9.8%) 2[nd] line chemotherapy or best supportive care and 1 lost follow-up. In 31 pts undergone surgical resection, 27 (87.1%) achieved R0 resection while 30-day postoperative death was reported in 2 pts. Median relapse-free survival (RFS) and overall survival (OS) were 10.7 months (95% CI, 8.1-13.2 months) and 25.5 months (95% CI, 20.4-30.6 months), respectively. The pts. with MD histology and objective metabolic response (CR+PR) by PERCIST showed significant longer RFS with HR of 6.27 (P=.002) and 3.23 (P=.04), respectively.

      Conclusion
      The TP-IC in LA-NSCLC showed remarkable tumor regression activity, leading to high R0 resection rate. MD histology and tumor response (CR+PR) by PET (PERCIST) were significant prognostic factors for RFS. Further study is ongoing to identify molecular markers affecting clinical outcomes.