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K. Park



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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): K. Park

      • 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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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-032 - Patient Report of Dacomitinib (PF-00299804)-Associated Symptom and HRQoL Benefit in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2293)

      09:30 - 09:30  |  Author(s): K. Park

      • Abstract

      Background
      Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

      Methods
      Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

      Results
      On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

      Conclusion
      Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-015 - The role of adjuvant treatment in N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiation followed by surgery: A retrospective single center experience. (ID 2673)

      09:30 - 09:30  |  Author(s): K. Park

      • Abstract

      Background
      The optimal management of locally advanced N2 positive non-small cell lung cancer (NSCLC) is still controversial. Some studies have shown promising results of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection in terms of survival benefit without increasing morbidity and mortality. However, the role of adjuvant treatment after completion of neoadjuvant CCRT followed by surgery in N2 positive NSCLC patients has not defined yet.

      Methods
      From March 2006 to December 2011, 249 N2 positive NSCLC patients received neoadjuvant CCRT (weekly docetaxel/cisplatin with 45Gy/25Fx of thoracic radiotherapy) followed by curative surgery. Patients who died with post-operative complications within a month after surgery (n=5) were excluded to minimize selection bias.

      Results
      Among 244 patients, 80 patients (32.8%) receieved adjuvant radiotherapy alone, 26 patients (10.7%) received adjuvant chemotherapy alone, 57 patients (23.4%) received both of adjuvant radiotherapy/chemotherapy, and 80 patients (32.8%) did not receive adjuvant treatment. Survival was compared according to adjuvant treatment (any kind of adjuvant treatment [n=164, 67.2%] vs. no adjuvant treatment [n=80, 32.8%]). There was no significant differences between two groups in age over 60 years, ECOG performance, initial T stage, initial multistation N2 disease, completion of neoadjuvant CCRT, R0 resection, and pathologic down staging of N2 disease. In the univariate analysis, median overall survival (OS) and progression-free survival (PFS) were 54.1 months vs. 37.9 months (P=0.016) and 23.4 months vs. 17.7 months (P=0.239) in adjuvant treatment group and no adjuvant treatment group, respectively. In subgroup analysis, adjuvant treatment group showed significantly better OS than no adjuvant treatment group in patients who achieved N2 down staging by neoadjuvant CCRT (n=146, 59.8%) (78.1 months vs. 44.7 months, P=0.027) but not in patients who did not achieve pathologic N2 down staging (n=98, 40.2%) (32.3 months vs. 21.6 months, P=0.125).

      Conclusion
      This results suggest that adjuvant treatment may contribute survival benefit even after completion of neoadjuvant CCRT following curative surgery in N2 positive NSCLC. The role of adjuvant treatment should be seeked further in carefully selected patients who benefit most, such as CCRT sensitive patients who achieved pathologic N2 down staging.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-011 - Serum albumin as a potential pharmacodynamic biomarker in patients treated with the anti-hepatocyte growth factor monoclonal antibody ficlatuzumab (ID 1067)

      09:30 - 09:30  |  Author(s): K. Park

      • Abstract

      Background
      Ficlatuzumab is an anti-hepatocyte growth factor (HGF) monoclonal antibody (mAb) being tested in clinical trials for cancer. Hypoalbuminemia has been observed in these trials, as well as in trials with other HGF/c-Met inhibitory mAbs. The relationship between serum albumin (SA) and ficlatuzumab treatment is examined.

      Methods
      Ficlatuzumab was studied in P05538, a first-in-human dose escalation trial; in P05670, a dose ranging trial investigating the pharmacodynamic (PD) effect of ficlatuzumab; and in P06162, a phase II study in combination with gefitinib (FG arm) versus gefitinib alone (G arm) in NSCLC patients. Patient data from these studies were evaluated longitudinally for peripheral edema, changes in SA, serum Ca[2+] (Ca), liver function tests (LFTs), prothrombin time (PT) and proteinuria.

      Results
      In P05538, all 23 evaluable patients had SA decrease with median change to nadir of -29% (-46 to -11%) and median nadir SA level of 25 g/L (15 to 33 g/L). In P05670, all 19 evaluable patients had decreased SA, with median change to nadir of -20% (-49 to -7%) and median nadir SA level of 31 g/L (14 to 40 g/L). In P06162, 88 of 90 (98%) evaluable patients in FG arm experienced SA decrease, with a median nadir change of -27% (range -62 to 8%). No significant SA changes were observed in the G arm. LFTs and PT were not significantly changed in any of the trials. Peripheral edema was observed in 52%, 32%, 38%, and 4% of the patients in P05538, P05670, FG, and G arms of P06162, respectively. In P06162, low Ca laboratory findings (not corrected for albumin) were reported in 72% of patients, with median change to nadir of -11% (-24% to 5%). Changes in uncorrected Ca were secondary to changes in albumin (% changes Pearson correlation=0.68, P<0.0001). No difference in the rate of proteinuria was observed across FG and G arms of the 6162 trial.

      Conclusion
      Decrease in SA during ficlatuzumab treatment was seen in almost all patients and appears to be unrelated to hepatotoxicity. Decrease in SA resulting from ficlatuzumab treatment may be the cause of peripheral edema. Both hypoalbuminemia and peripheral edema were frequently observed with other HGF/c-Met inhibitors, suggesting they may be class adverse events. Decrease in SA could be explored as a PD marker for HGF/c-Met inhibition.

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      P3.11-036 - Comparison of Clinical Outcome between Gefitinib and Erlotinib treatment in patients with non-small cell lung cancer harboring an epidermal growth factor receptor exon 19 or exon 21 mutations (ID 2599)

      09:30 - 09:30  |  Author(s): K. Park

      • Abstract

      Background
      Gefitinib and Erlotinib are oral small-molecule kinase inhibitors that inhibit signaling via EGFR and both agents showed dramatic response rate and prolonged PFS in patients harboring activating EGFR mutation. We investigated the clinical outcomes between gefitinib- and erlotinib-treated patients with recurrent or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations.

      Methods
      A total 375 patients with recurrent or metastatic stage IIIB/IV NSCLC who had either an exon 19 deletion or L858R mutation on exon 21 and received gefitinib(n=228) or erlotinib(n=147) therapy between August 2007 and December 2011 were retrospectively reviewed. By using a matched-pair case-control study design, 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, ECOG performance status, and types of EGFR mutation.

      Results
      The median age of all patients was 58 years(range, 30-84) and more than half of patients were never smokers(63.6%). Most patients had adenocarcinoma (98.3%) and good ECOG performance status (0, 1) (90.9%). The median number of cycles in TKI treatment was 12.7 in gefitinib group and 10.8 in erlotinib group. Of 242 patients, 64(26.4%) received an EGFR TKI as first line therapy. The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 85.5% versus 79.8 % (p=.375) and 94.0% versus 89.1%, respectively (p=.242). There was no statistically significant difference noted with regard to OS (median, 22.1 vs 25.2; p=.546) and PFS (median, 12.5 vs 9.9; p=.114) between the gefitinib-treated and erlotinib-treated groups. For a subgroup which patients were treated with TKI as first line therapy, the overall response rates were higher than those of patients who had progressed on prior chemotherapy (90.3% vs 79.9%; p=.063). However, there was no significant differences in PFS (median, 13.1 vs 10.1; p=.082) between subjects with first line TKI therapy and more than second line treatment. Regarding safety and dose adjustment of EGFR TKIs, patients with erlotinib more frequently had G3/4 toxicity than ones with gefitinib and required dose reduction(18.1% vs 1.65%).

      Conclusion
      Both gefitinib and erlotinib showed similar effective activity in selected population of NSCLC that harbored an EGFR mutation and further studies are needed to evaluate the efficacy of EGFR TKI as first line treatment.