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K. Park



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    ISS08 - A prIME Oncology Satellite Symposium Supported by Boehringer Ingelheim Pharma GmbH & Co. KG.: Reaching New Heights in the Management of Non-Small Cell Lung Cancer: Focus in EGFR-Targeted Therapy (ID 441)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
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      ISS08.04 - Tackling Acquired Resistance to EGFR– Targeted Therapy: Evaluating Current and Emerging Treatment Strategies (ID 7149)

      K. Park

      • Abstract

      Abstract not provided

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    MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA06.03 - Recurrence Dynamics after Trimodality Therapy (Neoadjuvant Chemoradiotherapy and Surgery) in Stage IIIa(N2) Lung Cancer (Now Available) (ID 4963)

      K. Park

      • Abstract
      • Presentation
      • Slides

      Background:
      In IIIa(N2) Non-small cell lung cancer (NSCLC), various strategies to cure have been tried but the major cause of mortality is still the recurrence. Therefore, understanding of the dynamics of recurrence is important to improve the treatment outcome. We investigated the timing and patterns of recurrence after treatment of IIIA(N2) NSCLC with trimodality treatment (neoadjuvant chemoradiotherapy and surgery).

      Methods:
      An institutional database of consecutive patients between 1997 and 2013 (N = 574) was reviewed retrospectively. Eligible patients had pathologically proven N2 disease of NSCLC and completion of a planned trimodality treatment. First events involving the development of loco-regional recurrence, distant metastases or both were considered. The hazard rate function was used to evaluate the dynamics of recurrence.

      Results:
      The 5-year overall survival rate was 47% and the 5-year recurrence free survival rate was 29%. Among the 299 patients (52.1% of total) who experienced recurrence, 26 (8.7%) had loco-regional recurrences, 248 (82.9%) had distant metastases, and 25 (8.4%) had both. The most frequent sites of distant metastases were lung (n=102, 41%), brain (n=63, 25%), and bone (n=63, 25%). The hazard rate function for the overall recurrence revealed the peak at approximately 8 months after surgery then the down-slope pattern before 38 months. A similar risk pattern was found in distant metastasis but low and steady risk pattern was detected in loco-regional recurrence. In distant metastases, similar patterns were found in individual organs, however, earlier peak at approximately 5 months presented in brain metastasis. A comparison of histology showed that adenocarcinoma exhibited higher recurrence hazard rate of distant metastasis than squamous cell carcinoma with similar pattern of recurrence (p=0.03). The status of nodal clearance after induction therapy exhibited that ypN2 patients (n= 229, 39.9%) had highest hazard rate (p=0.03). The recurrence hazard rate of ypN0 was the least, but the extent was not smaller, they showed approximately one of third of ypN2 at peak.

      Conclusion:
      The hazard rate of loco-regional failure after trimodality therapy was low. But the hazard rate of distant metastasis was considerably high yet and shifted to left with the peak within 12 moths after surgery. This study guides the intensive surveillance immediate after completion of trimodality therapy to identify risk groups of early recurrence and to develop therapeutic strategy.

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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (Now Available) (ID 5347)

      K. Park

      • Abstract
      • Presentation
      • Slides

      Background:
      The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.

      Methods:
      LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.

      Results:
      319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.

      Conclusion:
      Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
    • Now Available
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      P1.05-048 - Effect of Adjuvant Chemotherapy on the Patterns and Dynamics of Recurrences in Resected Stage II(N1) Lung Adenocarcinoma (Now Available) (ID 4990)

      K. Park

      • Abstract
      • Slides

      Background:
      Although the complete surgical resection in most cases of the non-small cell lung carcinoma with N1 involvement is feasible, a considerable number of patients develop recurrence and the disease course is highly variable. Timing and pattern of recurrence are essential to explain strong prognostic heterogeneity, however, research focusing on these subjects have rarely been reported. We investigated the patterns of recurrences and event rates over time in patients with completely resected N1-stageII lung adenocarcinoma.

      Methods:
      We retrospectively reviewed the medical records of 333 patients who underwent a complete surgical resection for N1-stage II lung adenocarcinoma. Survival curves were generated using the Kaplan-Meier method, and the event dynamics was estimated using the hazard function.

      Results:
      The median recurrence-free survival was 36.8 months. The life table survival analysis showed that the 1-year, 3-year and 5-year recurrence free survival rates were 85.1%, 50.2% and 36.6%, respectively. Approximately 151(45.2%) patients experienced recurrence, and the patterns of recurrences included loco-regional in 41 patients (27.2%), distant in 68 (45.0%), and both in 42 (27.8%). Most commonly involved organs were the lung (n=77, 47.0%), followed by lymph nodes (n=41, 27.2%), bone (n=31, 20.5%), and brain (n=30, 19.9%). There were 228 patients received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy showed better recurrence free survival (chemotherapy group vs non-chemotherapy group; median survival 42.5 months vs 25.4 months), and post-recurrence survival(chemotherapy group vs non-chemotherapy group; median survival 39.8 months vs 22.6 months) compared to those of patients without adjuvant chemotherapy. The multivariate analysis revealed that adjuvant chemotherapy was significantly correlated with recurrence free survival (p=0.004) and post recurrence survival (p=0.001). Patients underwent adjuvant chemotherapy had less distant (p=0.014) and less lung (p=0.045) recurrence, while there is no difference in loco-regional (p=0.837) and brain (p=0.997) recurrence. The recurrence hazard curve demonstrated similarly shaped and sized initial and second peak at 16 and 24months, followed by a smaller peak at 40months. The temporal distribution of the recurrence risk varied depending on adjuvant chemotherapy. A visual inspection of the hazard curves suggested that the patients without adjuvant chemotherapy exhibited earlier and higher first peaks with higher hazard rate over time.

      Conclusion:
      In the patients who underwent completely resected N1-stageII lung adenocarcinoma, adjuvant chemotherapy not only reduced the recurrence hazard, but also delayed the recurrence, altered pattern of recurrence and improved post-recurrence survival.

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    P2.02 - Poster Session with Presenters Present (ID 462)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P2.02-044 - Impact of N2 Extent and Nodal Response on Survival after Trimodal Treatment for Stage IIIA-N2 Non-Small Cell Lung Cancer (Now Available) (ID 4662)

      K. Park

      • Abstract
      • Slides

      Background:
      Mediastinal nodal downstaging is an important prognostic factor of neoadjuvant concurrent chemoradiotherapy (CCRT) for stage IIIA-N2 non-small cell lung cancer (NSCLC) and the role of trimodal treatment remains controversial in patients with persistent N2 disease. We aimed to investigate survival outcomes based on the extent of pre-CCRT nodal involvement and mediastinal nodal response in patients who underwent neoadjuvant CCRT for stage IIIA-N2 NSCLC.

      Methods:
      A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed and survival outcomes were compared according to the extent of pre-CCRT mediastinal nodal involvement and mediastinal nodal response to CCRT. Extensive lymph node involvement was defined by short-axis diameter of lymph nodes > 2cm measured at computed tomography or involvement of 2 or more mediastinal lymph node stations.

      Results:
      From 2003 to 2013, 407 patients underwent curative-intent surgery after neoadjuvant CCRT for NSCLC with pathologically proven N2 disease. The mean age was 59 years (314 men, 77%) and histologic type included adenocarcinoma in 233 patients (57%), squamous cell carcinoma in 141 (35%), and large cell carcinoma in 11 (2.7%). Seventy-nine patients (19%) had extensive N2 disease on pre-CCRT imaging tests. The extent of surgery included lobectomy in 311 patients (76%), pneumonectomy in 43 (11%), and sleeve resection in 15 (3.7%). Post-CCRT pathologic nodal status was ypN0 in 155 patients (38%), ypN1 in 56 (14%), and ypN2 in 196 (48%). With a mean follow-up of 41 months, median overall survival (OS) and recurrence-free survival (RFS) were 73 months and 18 months, respectively. The 5-year OS and RFS rates were 61% and 42% in ypN0-1 and 40% and 13% in ypN2, respectively (OS, p=0.0032; RFS, p<0.0001). For patients with ypN0-1, the 5-year OS and RFS rates were 60% and 52% in extensive N2 disease and 61% and 40% in non-extensive N2 disease, respectively (OS, p=0.8106; RFS, p=0.1218). For patients with ypN2, the 5-year OS and RFS rates were 22% and 12% in extensive N2 disease and 47% and 12% in non-extensive N2 disease, respectively (OS, p=0.0403; RFS, p=0.4842).

      Conclusion:
      Pre-CCRT non-extensive N2 disease was associated with better OS, but was not with better RFS in patients with persistent N2 disease. Patients who achieved mediastinal downstaging showed acceptable OS and RFS regardless of N2 extensiveness. Considering heterogeneity of N2, the indication of neoadjuvant CCRT needs to be differentiated according to the extent of pre-CCRT nodal involvement and post-CCRT mediastinal nodal response.

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    P3.02a - Poster Session with Presenters Present (ID 470)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02a-036 - Phase 1 Study of Ceritinib 450 mg or 600 mg Taken with a Low-Fat Meal versus 750 mg in Fasted State in ALK+ Metastatic NSCLC (ID 7170)

      K. Park

      • Abstract

      Background:
      The anaplastic lymphoma kinase (ALK) inhibitor ceritinib is approved at 750 mg fasted for the treatment of patients with ALK-rearranged (ALK+) metastatic non-small cell lung cancer (NSCLC) pretreated with crizotinib. The pharmacokinetic (PK) part of this study (Part 1) compares PK exposure of ceritinib following food consumption versus a fasted state in advanced ALK+ NSCLC patients.

      Methods:
      Part 1 of this prospective, open-label, multicenter, randomized, 3-arm, phase 1 study (ASCEND-8; NCT02299505) is investigating PK and safety of ceritinib in advanced ALK+ NSCLC patients, treatment-naïve or pretreated with multiple lines of chemotherapy and/or crizotinib. Here, we compare steady-state PK of ceritinib 450 or 600 mg taken with a low‑fat meal versus ceritinib 750 mg fasted (primary endpoint) and report preliminary safety outcomes from Part 1. Part 2 continues to randomize treatment-naïve patients and will assess safety and efficacy.

      Results:
      As of June 16, 2016 (data cut-off), 137 patients were randomized in a 1:1:1 ratio to each treatment arm; 135 patients received one dose (safety set) and 97 patients had evaluable steady-state PK data. Disease characteristics were comparable between arms. Median follow-up duration was 4.14 months (range, 0.1–13.9). Relative to 750 mg fasted, the 450 mg fed arm demonstrated comparable steady-state PK, while the 600 mg fed arm showed ~25% higher steady-state PK (Table). Preliminary safety data suggests overall frequency of AEs and types of AEs were comparable between arms. However, incidences of gastrointestinal (GI)-related AEs (diarrhea, nausea or vomiting) were lowest, with no grade 3/4 GI AEs reported, in the 450 mg fed arm.Figure 1



      Conclusion:
      Steady-state PK was comparable in advanced ALK+ NSCLC patients taking ceritinib 450 mg with a low-fat meal versus 750 mg fasted. This study continues to enroll treatment-naïve patients into Part 2 to assess efficacy across the three treatment arms and assess longer safety follow-up.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      P3.02b-005 - Phase Ib Trial of Afatinib and BI 836845 in Advanced NSCLC: Dose Escalation and Safety Results (Now Available) (ID 4719)

      K. Park

      • Abstract
      • Slides

      Background:
      Insulin-like growth factor (IGF) signaling is implicated in acquired resistance to EGFR TKIs in NSCLC. BI 836845 is an IGF ligand-neutralizing antibody that binds to IGF-1 and IGF-2, and inhibits their growth-promoting activities. This Phase Ib trial evaluates BI 836845 in combination with afatinib in patients with NSCLC progressing following prior treatment with EGFR TKIs or platinum-based chemotherapy (NCT02191891).

      Methods:
      The trial consists of two sequential parts: a dose confirmation part (Part A, reported here) and an expansion part (Part B). In Part A, eligible patients were aged ≥18 years with advanced and/or metastatic NSCLC progressing on EGFR TKIs (patients with EGFR mutations) or platinum-based chemotherapy. Patients receiving prior afatinib therapy below the assigned dose level or <30mg/day, or with progression on an insufficient dose of EGFR TKI prior to the study, were excluded. Part A used a 3+3 dose-escalation design with a starting dose of BI 836845 1,000mg/week (1-hour intravenous infusion) plus oral afatinib 30mg/day, in 4-week cycles. Primary endpoints were the maximum tolerated dose (MTD) of BI 836845 in combination with afatinib, and the occurrence of dose-limiting toxicities (DLTs) during Cycle 1.

      Results:
      At data cut-off (18 April 2016), 16 patients were treated (BI 836845 1,000mg/afatinib 30mg [n=4]; BI 836845 1,000mg/afatinib 40mg [n=12]). Median age (range) was 60 (48–77) years. Fourteen (88%) patients had activating EGFR mutations. Nine (56%) patients discontinued treatment, mostly due to progressive disease (one patient discontinued BI 836845 for other reasons); seven patients remain on treatment. During Cycle 1, 0/3 patients (afatinib 30mg) and 0/12 patients (afatinib 40mg) had a DLT (one patient [afatinib 30mg] was replaced during Cycle 1 due to a non-DLT adverse event [AE]). Therefore, the MTD and recommended Phase II dose (RP2D) was determined to be BI 836845 1,000mg/week in combination with afatinib 40mg/day. All patients experienced at least one drug-related AE; the most common were diarrhea (n=12; 75%), paronychia (n=11; 69%) and rash (n=10; 63%). Drug-related AEs were mostly grade 1/2 (one patient [afatinib 30mg] had grade 3 stomatitis). No drug-related AEs led to discontinuation and no dose reductions were required for BI 836845 or afatinib.

      Conclusion:
      The MTD and RP2D of BI 836845 was determined as 1000mg/week in combination with afatinib 40mg/day in patients who have failed prior EGFR TKIs or chemotherapy. This combination demonstrated a clinically manageable safety profile, consisting of AEs commonly associated with afatinib. The expansion part (Part B) is ongoing.

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      P3.02b-044 - Afatinib versus Gefitinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients Aged ≥75 Years: Subgroup Analysis of LUX-Lung 7 (Now Available) (ID 5327)

      K. Park

      • Abstract
      • Slides

      Background:
      The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. In the Phase IIb LUX-Lung 7 trial, afatinib significantly improved median progression-free survival (PFS; HR=0.73 [95% CI, 0.57–0.95], p=0.017), objective response rate (70% vs 56%, p=0.008) and time to treatment failure (TTF; HR=0.73 [95% CI, 0.58–0.92], p=0.007) versus gefitinib in this setting (Park et al. Lancet Oncol 2016). Here we evaluated the efficacy and safety of afatinib versus gefitinib in patients aged ≥75 years in a subgroup analysis of LUX-Lung 7 (NCT01466660).

      Methods:
      Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC were randomized (1:1) to oral afatinib (40 mg/day) or gefitinib (250 mg/day), stratified by EGFR mutation type (Del19/L858R) and presence of brain metastases (Yes/No). Co-primary endpoints were PFS, TTF, and overall survival. Subgroup analyses of PFS and adverse events (AEs) by age (≥75/<75 years) were exploratory.

      Results:
      Of 319 patients randomised in LL7, 40 (13%) were aged ≥75 years (afatinib n=19, gefitinib n=21). Median PFS for both age groups was in line with the overall population and favoured afatinib versus gefitinib (patients ≥75 years: 14.7 vs 10.8 months, HR=0.69 [95% CI, 0.33–1.44]; patients <75 years: 11.0 vs 10.9 months, HR=0.76 [95% CI, 0.58–1.00]). The incidence of treatment-related AEs (grade 3/4) was slightly higher in the older subgroup (afatinib: 42%/0%; gefitinib: 24%/5%) than in the younger subgroup (afatinib: 28%/2%; gefitinib: 15%/<1%). There were no unexpected safety findings. The most common treatment-related AEs (all grade [grade 3]) with afatinib in the older patient subgroup were diarrhoea (89% [21%]), rash (63% [5%]), dry skin (37% [0%]), and decreased appetite (32% [0%]). Dose reduction/discontinuation of afatinib due to treatment-related AEs was required in 53%/16% and 40%/5% of the older and younger subgroup, respectively.

      Conclusion:
      A small subgroup of patients in the LUX-Lung 7 trial were ≥75 years old (13%). In exploratory subgroup analyses of patients aged ≥75 and <75 years old, advancing age did not adversely affect the PFS benefit and tolerability observed with afatinib versus gefitinib in treatment-naïve EGFRm+ NSCLC patients. These findings suggest that afatinib can provide an effective and tolerable treatment for older patients with EGFRm+ NSCLC.

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      P3.02b-053 - A Randomized, Open Label, Phase II Study Comparing Pemetrexed plus Cisplatin versus Pemetrexed Alone in EGFR Mutant NSCLC after EGFR-TKI: QOL Data (ID 5401)

      K. Park

      • Abstract

      Background:
      Various therapeutic strategies are available for NSCLC patients who develop disease progression on first-line EGFR-TKI. Platinum doublet is usually recommended, however, it has not been established which cytotoxic regimens are preferable for these patients. We conducted a prospective randomized phase II trial to compare the clinical outcomes between pemetrexed plus ciplatin combination therapy with pemetrexed monotherapy after failure of first-line EGFR-TKI.

      Methods:
      Patients with non-squamous NSCLC harboring activating EGFR mutation who have progressed on first-line EGFR-TKI were randomly assigned in a ratio of 1:1 to pemetrexed plus cisplatin or pemetrexed alone. Patients were treated with pemetrexed 500 mg/m[2] and cisplatin 70 mg/m[2] for four cycles, followed by maintenance pemetrexed as single agent every 3 weeks or treated with pemetrexed 500 mg/m[2] monotherapy every 3 weeks until progression. Primary objective wasPFS, and secondary objectives include overall response rate (ORR), OS, health-related quality of life (HRQOL), safety and toxicity profile. The HRQOL was assessed every 2 cycles by using EORTC QLQ-C30 and EORTC QLQ-LC13.

      Results:
      96 patients were randomized and 91 patients were treated at 14 centers in Korea. The characteristics of pemetrexed plus cisplatin (PC) arm (N=48) and pemetrexed alone (P) arm (N=48) were well balanced; the median age was 60 vs. 64 years old; 37 vs. 33 patients were females; 39 vs. 43 patients were ECOG PS 1. The ORR of PC arm (N=46) was 34.8% (16/46), while P arm (N=45) was 17.8% (8/45). With 20.4 (range 4.1-33.4) months of follow-up, the median PFS was 5.4 months (95% confidence interval [CI], 4.5-6.3) in PC arm and 6.4 months (95% CI, 3.6-9.2) in P arm (p=.313). One-year survival rate was 77% for PC arm, 68% for P arm, respectively. The most common adverse events include anorexia (N=34, 37.4%), nausea (N=24, 26.4%), neuropathy (N=10, 11.0%) and skin change (N=10, 11.0%). Adverse events ≥ Grade 3 were in 12 patients (26.1%) in PC arm and 8 patients (17.8%) in P arm. Dose reduction (5 vs. 2 patients) and dose delay (10 vs. 4 patients) were required more often in PC arm. With 385 pairs of questionnaire of EORTC QLQ-C30 and QLO-LC13 obtained from 94 patients, overall, the time trends of HRQOL were not significantly different between two arms. Further analysis of survival data will be updated.

      Conclusion:
      Pemetrexed plus cisplatin combination therapy showed higher response rate than pemetrexed monotherapy without significant difference in PFS. There was no significant difference in quality of life between two arms.

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      P3.02b-078 - Non-Small Cell Lung Cancer with De Novo EGFR T790M Mutation: Clinical Features of 22 Cases (ID 4981)

      K. Park

      • Abstract

      Background:
      This study aimed to evaluate the clinical features and outcomes in patients with non-small cell lung cancer (NSCLC) with de novo epidermal growth factor receptor (EGFR) T790M mutation.

      Methods:
      Specimens of 6,923 NSCLC patients, from March 2009 to May 2016, tested for EGFR mutation were analyzed. EGFR mutation was performed using DNA sequencing or PNA clamp method. The clinical characteristics and the clinical outcome to chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) were reviewed.

      Results:
      Of the 6,923 NSCLC patients, 1687 (24.4%) had activating EGFR mutations. Among them, 22 patients were found to have de novo EGFR T790M mutation, accounting for 1.3% of all the EGFR mutant cases. All but one had de novo T790M mutation without any activating EGFR mutation. Details of the 22 patients harboring the EGFR T790M mutation are listed in Table 1. The response rate to chemotherapy was 12.5% (best response; 1 PR, 4 SD and 3 PD) and the median time to progression (TTP) was 3.0 months. The response rate to EGFR TKIs treatment was 8.3% (best response; 1 PR, 3 SD and 8 PD), and the median TTP was 2.7 months. Three patients were treated with third generation EGFR TKIs (osimertinib or ASP 8237) and all achieved partial response (TTP; 33.3, 13.6 and 3.5 months, respectively).

      Conclusion:
      De novo EGFR T790M mutation is a rare event even in EGFR mutant NSCLC and associated with unfavorable clinical outcome to chemotherapy and EGFR TKIs.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-035 - Comparison of RECIST to Immune-Related Response Criteria (irRC) in Patients with NSCLC Treated with Immune-Check Point Inhibitor (ID 4962)

      K. Park

      • Abstract

      Background:
      Immune check point inhibitor has become essential therapeutic option for advanced non-small cell lung cancer (NSCLC). Immune-related response in NSCLC has not been well evaluated, thus we assessed the tumor response using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC) to identify atypical response in patients with advanced NSCLC treated with immunotherapeutic agents.

      Methods:
      Patients received immune check point inhibitors (pembrolizumab, atezolizumab, nivolumab, pembrolizumab plus tremelimumab) at Samsung Medical Center between July 2014 and October 2015. The tumor response was assessed according to both RECIST v1.1 and irRC. Pseudoprogression was defined as progressive disease at any time of assessment and not at next assessment per RECIST v1.1 or irRC.

      Results:
      Figure 1 Total 41 patients were analyzed, most of patients (80.5%) received anti-PD-1 agents (pembrolizumab or nivolumab) and 6 patients were treated with anti-PD-L1, atezolizumab, 2 patients received combination treatment with pembrolizumab and tremelimumab. Two patients showed pseudoprogression followed by regression per RECIST v1.1 not per irRC. 4 patients with progressive disease per RECIST v1.1 were partial response per irRC, objective response was 29.2% per RECIST v1.1 and 34.1% per irRC, respectively. There was no significant difference in response rate between two methods (p=0.923). The median duration of follow-up was 19.8 months, and the median progression-free survival of all patients was 4.5 months (95% CI 2.7-6.3)



      Conclusion:
      These results suggest that pseuoprogression is not frequently observed in NSCLC, and conventional RECIST v1.1 might underestimate the benefit of immune check point inhibitors. Given the small number of patients studied and short-term follow-up, further study will be warranted whether treatment with immune checkpoint inhibitor beyond RECIST progression can be benefit to patient with advanced NSCLC.

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    PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)

    • Event: WCLC 2016
    • Type: Plenary
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (Now Available) (ID 5822)

      K. Park

      • Abstract
      • Presentation
      • Slides

      Background:
      Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.

      Methods:
      OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.

      Results:
      For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.

      Conclusion:
      OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.

      OS
      Atezolizumab Docetaxel HR[a]95% CI
      n Median, mo n Median, mo
      Nonsquamous
      TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61)
      TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88)
      TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95)
      TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00)
      All 313 15.6 315 11.2 0.73(0.60-0.89)
      Squamous
      TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20)
      TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29)
      TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06)
      TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32)
      All 112 8.9 110 7.7 0.73(0.54-0.98)
      [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell


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    SC04 - EGFR Tyrosine Kinase Inhibitors: A Model for Successful Drug Development (ID 328)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
    • +

      SC04.03 - Sequencing of EGFR Tyrosine Kinase Inhibitors (Now Available) (ID 6615)

      K. Park

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Figure 1. Sequence of EGFR TKIsFigure 1 Sequencing of EGFR Tyrosine Kinase Inhibitors Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Treatment of EGFR-mutant(EGFRm) lung cancer with specific EGFR TKIs, such as gefitinib, erlotinib or afatinib, has opened the door to the precision medicine in the management of advanced non-small cell lung cancer with remarkable tumour shrinkage and improvement in progression-free survival (PFS) and quality of life compared to standard chemotherapy. Despite such a remarkable initial clinical response with EGFR TKIs in patients with EGFR+ NSCLC, however, the disease eventually comes back with the emergence of acquired resistance and median PFS is ~ 1 year. The most common mechanism of resistance is acquisition of the T790M gatekeeper mutation and the 3rd-generation EGFR TKIs irreversibly inhibit mutant EGFR, esp. T790M, with sparing wild-type(WT) EGFR. There are several EGFR mutant specific inhibitors(EMSIs) under development including AZD9291, CO-1686, BI1482694 /HM61713, ASP8273, etc. All these 3rd-generation EGFR TKIs have shown a promising early clinical efficacy in T790M(+) EGFRm NSCLC patients with ORR of ca. 60% and PFS of 9.6 – 10.3 months and appear to be well tolerated. Based upon these encouraging early results many confirmatory phase 3 trials(e.g., NCT02151981, NCT02322281) comparing to the standard chemotherapy in the 2nd-line setting are underway. It is very tempting that one might like to move the 3rd-generation EGFR TKI to 1st-line setting. The development of the 3rd-generation agents as the first-line therapy for patients with EGFRm disease has already started. Recently AZD9291 demonstrated an encouraging clinical activity and a manageable tolerability profile in 1st-line: confirmed objective response rate of 77% (95% CI 64, 87) and mPFS of 19.3 months (investigator-assessed). Currently it is being compared with the 1st/2nd-generation EGFR TKI in the 1st-line setting. The Phase III FLAURA study (NCT02296125), comparing AZD9291 80 mg once daily versus current standard of care EGFR-TKIs for treatment-naïve patients, is enrolling. Though the preliminary result in the 1L setting is quite provocative, extreme caution needs to be exerted since the currently available data are not mature enough to determine which agent is the best in its class and only from a small subset of patients. Though it is hoped that the T790M-mediated resistance can be delayed or prevented by using the EMSIs in the TKI-naïve setting, it is also possible that other less well known escape mechanisms might emerge. Given that EMSI works well after failing 1st/2nd-generation EGFR TKI I believe it seems to be a more reasonable approach to investigate if EMSI in the TKI-naïve setting is more effective than 1st/2nd-generation EGFR TKI followed by EMSI when failing 1st/2nd-generation EGFR TKI with acquired resistance. One of the biggest questions to emerge in the era of next-generation inhibitors that have activity against the basic driver oncogene is whether it makes sense to use this approach before the development of acquired resistance to prevent it from occurring in the first place. Can its use in the 1st-line(TKI-naïve) setting prevent the development of acquired resistance and lead to a longterm control of the disease? Considering the well-known genomic heterogeneity with its possible association with resistance to EGFR TKIs we need better understanding of the biology and resistance mechanisms to this class of new generation EGFR TKIs in order to develop better strategies for subsequent therapies to overcome the resistance including how to best sequence the available EGFR TKIs in the clinic as well as combination therapies. It is fair to say that during the past few years we’ve clearly made another progress in the management of NSCLC patients with EGFRm, including those who failed previous EGFR TKIs. However, the currently available data are not mature enough to determine which agent is the best in its class, with the notable differences primarily related to toxicity and we’re not there yet and still lots of unanswered questions remain and further researches are warranted. References 1. DR Camidge, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11: 473–481 2. SS Ramalingam, et al. The Next Generation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer. Cancer 2015;121:E1-E6 3. GR Oxnard et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nature Med 2015;21:560-564 4. LV Sequist et al. Heterogeneity Underlies the Emergence of EGFR T790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor . Cancer Discov 2015;5(7): 713–22 5. CM Lovly et al. Shades of T790M: Intratumor Heterogeneity in EGFR -Mutant Lung Cancer. Cancer Discov 2015;5(7): 694–6. 6. S Ramalingam, et al. ELCC 2016; Abstract LBA1_PR



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