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D. Kim

Moderator of

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    SC11 - ALK, ROS1 and Rare Mutations in NSCLC (ID 335)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 5
    • Now Available
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      SC11.01 - Optimal Application & Sequence of ALK Inhibition Therapy (Now Available) (ID 6641)

      B. Solomon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC11.02 - Resistance to ALK Inhibitor Therapy (Now Available) (ID 6642)

      S. Ou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC11.03 - ROS1 as a Therapeutic Target in Advanced NSCLC (Now Available) (ID 6643)

      J. Wolf

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In non-small cell lung cancer (NSCLC) chromosomal rearrangements involving the gene encoding for the receptor tyrosine kinase ROS1 have been first described in 2007 (1). These aberrations have been shown to trigger constitutive kinase activity and activation of downstream pathways like the MAPK pathway. ROS1 rearrangements can be found in about 2% of lung adenocarcinoma and are associated with female gender and never-smoking status (2). Different fusion partners have been described. In routine diagnostics ROS1 fusion genes can be reliably detected by fluorescence in situ hybridization (FISH; e.g. dual color break apart FISH), RT-PCR or next-generation sequencing (NGS). ROS1 fusions occur mutually exclusive of aberrations in EGFR, ALK and KRAS. However, using NGS, co-occuring mutations, preferentially in TP53, but also in other genes involved in oncogenic pathways, can be found in about 50% of these patients (3). ROS1 fusions also seem to be of prognostic relevance, since remarkable long survival times have been described in patients treated with chemotherapy only (3). The ALK/MET/ROS1 inhibitor crizotinib has been evaluated in a US-American cohort of 50 ROS1 positive patients with advanced, mostly pretreated lung adenocarcinoma and showed impressive activity (4). The overall response rate (ORR) was 72% (95% CI 58 to 84) with 3 complete responses. Median progression free survival (PFS) was 19.2 months (95% CI 14.4 to not reached). Treatment was well tolerated and the side effect profile resembled that observed in the treatment of ALK positive lung cancer with crizotinib. A similiar ORR of 80% was reported in a retrospectively analyzed European cohort (5). However, PFS was only 9.1 months in these patients. The EUCROSS trial, a collaborative study of the German Lung Cancer Group Cologne and the Spanish Lung Cancer Group, is a prospective European phase II trial which recruited 34 ROS1 positive patients between June 2014 and September 2015. ROS1 fusion genes were diagnosed using dual color break apart FISH and the results were confirmed by next-generation sequencing. With an ORR of 69% (95% CI, 49.1 to 84.3) similar efficacy has been reported (6). Based on its high activity and favorable toxicity profile, crizotinib is now approved for the treatment of ROS1-positive NSCLC by the FDA since March 2016 and by the EMA since August 2016. Treatment of ROS1-positive NSCLC with crizotinib thus has become standard first-line treatment in the leading international guidelines. Current challenges for the further development and improvement of targeted treatment of ROS1-positive patients are (I) implementation of ROS1 diagnostics in routine molecular diagnostics and (II) development of next-generation ROS1 inhibitors overcoming crizotinib resistance. The increasing number of actionable mutations in NSCLC including ROS1 requires implementation of molecular multiplex testing, since sequentially conducted single gene assays are no more feasible given the usually limited biopsy tissue specimens. However, conventional NGS technology is restricted to point mutations and does not cover copy number variations (CNV) and gene fusions. Thus, new NGS technologies have to be integrated in routine diagnostics like hybrid capture-based NGS, which does not require DNA amplification by PCR and thus allows to detect reliably CNV and gene fusions. While increasing knowledge of the molecular mechanisms underlying TKI resistance has led to the development of a series of highly potent next-generation inhibitors in ALK-positive NSCLC now, resistance of ROS1-positive patients to crizotinib is incompletely understood. In preclinical studies as well as in biopsy tissue, somatic mutations in the ROS1 kinase domain associated with acquired crizotinib resistance have been described (7). In functional studies these mutations were associated with different degrees of resistance. Alternatively, bypass activation of oncogenic signal transduction pathways has been described as mechanism underlying resistance. For instance, a cKIT activating mutation and EGFR pathway activation have been reported in single cases (8). In vitro, the multikinase inhibitors cabozantinib, foretinib and lorlatinib have been shown to overcome crizotinib reistance triggered by secondary mutations in ROS1. Response to cabozantinib has also been described in a ROS1-positive patient with a mutation confering resistance to crizotinib (10) and was also observed in a phase I trial of lorlatinib in the same clinical setting. In summary, ROS1 positivity characterizes a subgroup of patients with a major benefit from treatment with crizotinib. Consequently, crizotinib has become the current standard of care for these patients. ROS1 status thus should be available before decision on first-line treatment. Acquired resitance to crizotinib may be caused by mutations in the ROS1 kinase domain or by activation of bypass pathways. The multikinase inhibitor cabozantinib and the next-generation ALK/ROS1 inhibitor lorlatinib have shown promising efficacy in early clinical evaluation. (1) Rikova K et al. Global survey of phosphotyrosine sgnaling identifies oncogenic kinases in lung cancer. Cell 2007, 14; 131(6):1190-203. (2) Bergethon K et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012, 30(8):863-70. (3) Scheffler M et al. ROS1 rearrangements in lung adenocarcinoma: prgnostic impact, therapeutic options and genetic variability. Oncotarget 2015, 6(12):10577-84. (4) Shaw A et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. NEJM 2014, 371(21): 1963-71. (5) Mazieres J et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015, 33(8):867-76. (6) Michels e al. EUCROSS: a prospective European phase II trial to evaluate efficacy and safety of crizotinib in advanced adenocarcinoma of the lung harboring ROS1 translocations. WCLC 2016 (oral presentation). (7) Awas MM et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. NEJM 2013, 368(25):2395-401. (8) Dzadziuszko R et al. Activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 2016, 11(8):1273-81. (9) Davies KD et al. Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 2013, 13 (8):e82236. (10) Drilon et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 2016, 22 (10):2351-8.

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      SC11.04 - Rare Mutations in Lung Cancer (Now Available) (ID 6644)

      O. Gautschi

      • Abstract
      • Presentation
      • Slides

      Abstract:
      "Lung adenocarcinoma" is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy [1]. Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al [2]. Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al [3]. Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials [4-6]. Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial [7]. These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY [8]). Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. References 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325)

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      SC11.05 - Q&A (Now Available) (ID 6878)

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (Now Available) (ID 5354)

      D. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.

      Methods:
      Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.

      Results:
      The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.

      Measurable CNS disease at baseline (n=50) Measurable and non-measurable CNS disease at baseline (n=136)
      CNS ORR, n (%) [95% CI] 32 (64.0) [49.2–77.1] 60* (44.1) [35.6–52.9]
      Complete response (CR), n (%) 11 (22.0) 39* (28.7)
      CNS DCR, n (%) [95% CI] 45 (90.0) [78.2–96.7] 117 (86.0) [79.1–91.4]
      Median CNS DoR, months [95% CI] Patients with event, n (%) 11.1 [7.6–NE] 18 (56.3) 13.8 [11.0–21.5] 32 (53.3)
      * N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD


      Conclusion:
      This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.

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    OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      OA03.07 - KEYNOTE-010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab  (Now Available) (ID 6769)

      D. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.

      Methods:
      1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.

      Results:
      In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.

      Conclusion:
      With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.

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    OA05 - Treatment Advances in SCLC (ID 373)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • Now Available
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      OA05.01 - Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer: Updated Survival Results from KEYNOTE-028 (Abstract under Embargo until December 5, 7:00 CET) (Now Available) (ID 6198)

      D. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present updated safety and efficacy data, including survival, for patients with ED SCLC enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.

      Methods:
      KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and overall survival (OS).

      Results:
      24 patients with ED SCLC and tumor PD-L1 positivity were enrolled and received ≥1 dose of pembrolizumab. At the data cutoff date (June 9, 2016), median follow-up duration was 9.8 months (range, 0.5-24.0 months); 3 patients (12.5%) remain on treatment. The ORR was 37.5% (95% CI, 18.8%-59.4%), including 1 complete and 8 partial responses in 24 evaluable patients. Median duration of response was 9.0 months (range, 1.9-19.9+ months). Median PFS was 1.9 months (95% CI, 1.7-5.9 months); the 6- and 12-month PFS rates were 29.8% and 24.8%, respectively. Median OS was 9.7 months (95% CI, 4.1 months-not reached); the 6- and 12-month OS rates were 66.0% and 35.7%, respectively. No new safety concerns were noted. Sixteen of 24 (66.7%) patients experienced treatment-related AEs. Two patients experienced grade 3-5 treatment-related AEs: 1 patient had blood bilirubin increased (grade 3) and 1 patient experienced grade 3 asthenia and grade 5 colitis.

      Conclusion:
      Pembrolizumab demonstrated promising antitumor activity in this pretreated, PD-L1–positive ED SCLC population. The responses were found to be durable and may have led to an OS benefit for the subset of patients who achieved objective responses with pembrolizumab.

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    OA08 - Targeted Therapies in Brain Metastases (ID 381)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA08.06 - Brigatinib Activity in Patients with ALK+ NSCLC and Intracranial CNS Metastases in Two Clinical Trials (Now Available) (ID 4374)

      D. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).

      Methods:
      In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.

      Results:
      In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).

      Conclusion:
      Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.

      IRC-Assessed Confirmed Intracranial Response Rates for Patients With Measurable Brain Metastases at Baseline
      Any No rad/active[a]
      Ph1/2[b] n=15 n=9
      iORR 8(53) 6(67)
      iDCR 13(87) 8(89)
      ALTA[c]
      Arm A n=26 n=19
      iORR 11(42) 8(42)
      iDCR 22(85) 16(84)
      Arm B n=18 n=15
      iORR 12(67) 11(73)
      iDCR 15(83) 14(93)
      Data are n(%) iDCR=intracranial disease control rate iORR=intracranial objective response rate IRC=independent review committee [a]No prior brain radiotherapy (Ph1/2); active (untreated or treated and progressed) brain lesions (ALTA) [b]NCT01449461; last scan date: October 8, 2015 [c]NCT02094573; last scan date: April 14, 2016


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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)

      D. Kim

      • 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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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03a-038 - Phase III Trial of Pemetrexed/Carboplatin vs Pemetrexed Only in Chemo-Naïve Elderly Non-SQCC NSCLC Patients Aged ≥ 70 (ID 5036)

      D. Kim

      • Abstract

      Background:
      We aimed to compare pemetrexed/carboplatin doublet (PC) versus pemetrexed singlet (P) as induction therapy in chemotherapy-naïve elderly patients aged 70 or more with advanced non-squamous non–small-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

      Methods:
      In this open-label multicenter phase III randomized trial, elderly patients aged 70 or more with advanced non-squamous NSCLC, ECOG PS of 0-1, no prior chemotherapy, adequate organ function and measurable disease were assigned to PC doublet (P, 500 mg/m2; C, area under the curve of 5) or P singlet (500 mg/m2) after stratified randomization according to center, gender and Charson Comorbidity Index (CCI). The treatment was given every 3 weeks till disease progression, unacceptable toxicity or withdrawal of consent. However, carboplatin was given for only the first four cycles during induction therapy period. The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, and safety.

      Results:
      A total of 267 eligible patients were enrolled from six centers between March 2012 and October 2015; median age was 74 years (70~86); 95% had PS of 1; 68% were men; and 61% had CCI of 1 or more. The median PFS was 5.4 months for PC doublet and 4.2 months for P singlet, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11; P= 0.2353). The median survival time was 12.5 months for PC and 9.0 months for P, respectively (HR, 0.86; 95% CI, 0.62 to 1.21; P =0.4108). The objective response rates for PC doublet and P singlet were 34.7% and 25.9%, respectively (p=0.1387). The most common adverse events in PC doublet arm were anemia (9.6%), fatigue (8%) and pneumonia (6.4%) while those in P singlet arm were pneumonia (4.2%), fatique (3.3%) and anemia (2.5%) in descending of frequency.

      Conclusion:
      The addition of carboplatin to pemetrexed during induction therapy period did not show the improvement of survival time in elderly patients aged 70 or more with advanced non-squamous NSCLC and ECOG PS of 0-1 even though it increased the response rate numerically. Updated data will be presented.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
    • Now Available
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      P2.06-017 - Amethyst NSCLC Trial: Phase 2 Study of MGCD265 in Patients with Advanced or Metastatic NSCLC with Activating Genetic Alterations in MET (Now Available) (ID 5384)

      D. Kim

      • Abstract
      • Slides

      Background:
      MGCD265 is a potent, orally available, small molecule RTK inhibitor of MET and Axl, both of which mediate signals for cell growth, survival, and migration. The Amethyst NSCLC trial is designed to evaluate the activity of MGCD265 in patients with NSCLC exhibiting genetic alterations involving MET. Alterations in MET, including gene amplification and/or genetic mutations, occur in approximately 7% of NSCLC cases converting MET to an oncogene capable of driving cancer development and progression. Amplification of MET has been associated with a poor prognosis in NSCLC. In addition, various genetic mutations result in the deletion of exon 14 in MET mRNA (METex14del) and the subsequent loss of the Y1003 regulatory binding site for CBL ubiquitin ligase, required for MET degradation and signal attenuation. Loss of the Y1003 binding site of MET results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. The importance of MET as a driver is demonstrated in xenograft models of NSCLC with METex14del and MET amplification, and where MGCD265 induces tumor regression. Additionally, confirmed partial responses have been observed in pts with NSCLC characterized by METex14del who were treated with MGCD265 in the Phase 1 setting.

      Methods:
      Pts with platinum pre-treated NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) are eligible for this multi-center, global, Phase 2 trial. Pts are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each cohort. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open globally, and recruitment is ongoing.

      Results:
      Section not applicable.

      Conclusion:
      Section not applicable.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      P3.02a-013 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial (Now Available) (ID 4046)

      D. Kim

      • Abstract
      • Slides

      Background:
      Brigatinib, an investigational next-generation ALK inhibitor, has yielded promising activity in crizotinib-treated ALK+ NSCLC patients in a phase 1/2 trial (NCT01449461). As responses and adverse events (AEs) varied with starting dose, two brigatinib regimens are under evaluation in ALTA (NCT02094573).

      Methods:
      Patients with crizotinib-refractory advanced ALK+ NSCLC were randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B) and stratified by presence of brain metastases at baseline and best response to prior crizotinib. Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1.

      Results:
      222 patients were enrolled (arm A, n=112/arm B, n=110). Median age (A/B) was 51/57 years, 55%/58% were female, 74%/74% previously received chemotherapy, and 71%/67% had brain metastases. As of February 29, 2016, 64/112 (57%) patients in arm A and 76/110 (69%) patients in arm B were receiving brigatinib; median follow-up was 7.8/8.3 months. The Table shows investigator-assessed endpoints by arm and subgroup for select baseline characteristics. Independent review committee–assessed endpoints (A/B, n=112/n=110; as of May 16, 2016): confirmed ORR 48%/53%, median PFS 9.2/15.6 months. Any-grade treatment-emergent AEs (≥25% overall frequency; A/B, n=109/n=110 treated): nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (18%/34%); grade ≥3 events (excluding neoplasm progression; ≥3% frequency): hypertension (6%/6%), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%). A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated patients (3%, grade ≥3); 7/14 patients were successfully retreated. No such events occurred after escalation to 180 mg in arm B.

      Conclusion:
      In each arm, brigatinib yielded substantial responses and prolonged PFS, with an acceptable safety profile. 180 mg with 90 mg lead-in was not associated with increased early pulmonary events and showed a consistent improvement in efficacy, compared with 90 mg, particularly with respect to PFS.

      Investigator-Assessed Endpoints by Arm and Subgroup
      Confirmed ORR, n/N(%) Median PFS, months
      Arm A B A+B A B A+B
      All patients 50/112(45) 59/110(54) 109/222(49) 9.2 12.9 11.1
      Prior chemotherapy
      Yes 35/83(42) 44/81(54) 79/164(48) 8.8 12.9 11.8
      No 15/29(52) 15/29(52) 30/58(52) 9.2 8.1 9.2
      Race
      Asian 18/39(46) 18/30(60) 36/69(52) 8.8 11.1 11.1
      Non-Asian 32/73(44) 41/80(51) 73/153(48) 9.2 12.9 11.8
      Brain metastases at baseline
      Yes 31/80(39) 43/74(58) 74/154(48) 9.2 11.8 11.1
      No 19/32(59) 16/36(44) 35/68(51) 7.4 15.6 15.6
      Best response to prior crizotinib
      Partial+complete 36/71(51) 47/73(64) 83/144(58) 11.1 15.6 15.6
      Other 14/41(34) 12/37(32) 26/78(33) 7.4 12.9 9.2
      ORR=objective response rate PFS=progression-free survival


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      P3.02a-016 - Pooled Efficacy and Safety Data from Two Phase II Studies (NP28673 and NP28761) of Alectinib in ALK+ Non-Small-Cell Lung Cancer (NSCLC) (Now Available) (ID 5044)

      D. Kim

      • Abstract
      • Slides

      Background:
      Alectinib is an FDA-approved ALK TKI, for treatment of patients with ALK+ metastatic NSCLC who have progressed on, or are intolerant to, crizotinib. Systemic and CNS efficacy was demonstrated in two single-arm, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]). We report the pooled systemic efficacy and safety analysis of alectinib from 2016 cut-offs 22 January, NP28761 and 1 February, NP28673.

      Methods:
      Patients were ≥18 years, had locally advanced or metastatic ALK+ NSCLC [FDA-approved FISH test] and had progressed on, or were intolerant to, crizotinib. Patients received oral alectinib 600mg twice daily until disease progression, death or withdrawal. The pooled analysis assessed objective response rate (ORR) by an independent review committee (IRC) using RECIST v1.1 (primary endpoint in both studies); disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety.

      Results:
      The pooled dataset included 225 patients, (n=138 NP28673; n=87 NP28761). Median age was 53 years, 60% of patients had baseline CNS metastases and 77% had received prior chemotherapy. The response-evaluable (RE) population by IRC included 189 patients (84%). Median follow-up was 18.8 months (0.6–29.7). In the RE population (n=189) ORR by IRC was 51.3% (95% CI 44.0–58.6; all partial responses), a DCR of 78.8% (95% CI 72.3–84.4), with a median DOR of 14.9 months (95% CI 11.1–20.4) after 58% of events. In patients with prior chemotherapy (n=148), IRC ORR was 49.3% (95% CI 41.0–57.7); DCR: 79.1% (95% CI 71.6–85.3); median DOR: 14.9 months (95% CI 11.0–21.9) after 59% of events. In patients who were chemotherapy-naïve (n=41), IRC ORR was 58.5% (95% CI 42.1–73.7); DCR: 78.0% (95% CI 62.4–89.4); median DOR: 11.2 months (95% CI 8.0–NE) after 54% of events. In the total pooled population (n=225) median PFS by IRC was 8.3 months (95% CI 7.0–11.3) after 69% of events and median OS was 26.0 months (95% CI 21.4–NE) after 43% of events. Grade ≥3 adverse events (AEs) occurred in 40% of patients and the most common were dyspnoea (4%), elevated levels of blood creatine phosphokinase (4%) and alanine aminotransferase (3%). The mean dose intensity was 94.6%. Fourteen patients withdrew due to AEs; 20.9% had AEs leading to dose interruptions/modification.

      Conclusion:
      This pooled analysis confirmed alectinib has robust systemic efficacy with a durable response in this population and in patients with or without prior chemotherapy. Alectinib had an acceptable safety profile.

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      P3.02a-018 - Efficacy of Pemetrexed Based Chemotherapy Compared with Non-Pemetrexed Based Chemotherapy in Advanced, ALK-Positive NSCLC (ID 5555)

      D. Kim

      • Abstract

      Background:
      Previous retrospective studies suggested that lung cancer patients with anaplastic lymphoma kinase (ALK) gene rearrangements are associated with sensitivity to pemetrexed chemotherapy. To determine the efficacy of pemetrexed based chemotherapy compared with non-pemetrexed based chemotherapy, we retrospectively evaluated clinical outcome in ALK positive non-small cell lung cancer (NSCLC) patients.

      Methods:
      We identified 126 patients with advanced, ALK-positive NSCLC who received 1st line cytotoxic chemotherapy from Seoul National University Hospital and Seoul National University Bundang Hospital. We compared response rate, progression-free survival, and overall survival according to chemotherapy regimens. We also analyzed the intra-cranial time to progression and proportion of ALK-positive cells as a predictive factor of pemetrexed efficacy.

      Results:
      Forty eight patients received pemetrexed based chemotherapy and Seventy eight patients received non-pemetrexed based chemotherapy as first line systemic treatment. One hundred eighteen patients received platinum double combination chemotherapy. The pemetrexed based chemotherapy group shows superior overall response rate (44.7% versus 14.3%, p<0.001) and disease control rate (85.1% versus 62.3%, p=0.008). Pemetrexed based chemotherapy group had longer progression free survival (6.6 months versus 3.8 months, p<0.001). Exposure to pemetrexed and exposure to second generation ALK inhibitor were independent prognostic factors of overall survival (p=0.016 and p=0.011, respectively). Intra-cranial time to progression (TTP) was similar among treatment group (32.7 months versus 35.7 months, p= 0.733). Proportion of ALK positive cells was not statistically significant predictive factor of survival in pemetrexed based chemotherapy.

      Conclusion:
      Pemetrexed based regimen may prolong progression free survival compared with other regimens in ALK positive NSCLC in the first line setting. Exposure to pemetrexed is associated with improved survival compared with that of premetrexed-naive controls in ALK positive NSCLC.

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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)

      D. Kim

      • 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: 1
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      P3.02b-001 - Phase 1 Dose Escalation of PF-06747775 (EGFR-T790M Inhibitor) in Patients with Advanced EGFRm (Del 19 or L858R+/-T790M) NSCLC (ID 4747)

      D. Kim

      • Abstract

      Background:
      PF-06747775 (PF-7775) is a highly potent, selective third generation irreversible EGFR-TKI, effective against EGFR-TKI sensitizing and resistance (T790M) mutations in NSCLC cell lines; IC50s between 3-12 nM and 26X greater selectivity toward mutant vs. wild-type (WT)EGFR. This is the first report from an ongoing phase I, first in human multicenter study (NCT02349633) of PF-7775 in patients with metastatic EGFRm+ NSCLC.

      Methods:
      EGFRm+ NSCLC pts, with acquired resistance to EGFR-TKIs enrolled into dose escalation cohorts of PF-7775, orally once daily, beginning at 25 mg. Stable brain metastases were allowed. All pts were assessed for pharmacokinetics (PK), response to therapy, and adverse events (AEs). Prospective central T790M testing was optional for dose escalation cohorts, but is required in subsequent expansion cohorts. Plasma samples were collected from all patients for ctDNA analysis of EGFR mutations.

      Results:
      Dose escalation is complete. 26 patients enrolled in 7 dose levels (25-600 mg): 58% female, mean age 63.5 years, Asian/Caucasian 61%/34%, 14/25 T790M+. Dosing reached 600 mg and then was expanded at a lower dose for better long term tolerability. RECIST responses were observed at all dose levels. BOR is PR 11(42.3%; 5 T790M+), stable disease 6(23.1%; 4 T790M+), PD 2(7.7%: 1 T790M+), symptomatic deterioration 1(3.8%; 1 T790M+), and indeterminate 6(23.1%; 3 T790M+). The AE profile is very favorable as predicted from the large WT margin. No DLTs were observed. Grade 3 AEs were noted at > 150 mg (diarrhea {n=4, 15.4%} and skin toxicities {n=8, 30.8%}). Figure 1. Best Change from Baseline in Tumor Size (%) Figure 1 PK were generally dose-proportional at doses of 25-600 mg, with a median apparent t~1/2~ of 6 h (range 4-30).



      Conclusion:
      PF-7775 has demonstrated early signals of clinical activity and is well tolerated in EGFRm+ NSCLC pts with acquired resistance to 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-061 - Neutrophil/Lymphocyte Ratio Predicts the Efficacy of Anti-PD-1 Antibody in Patients with Advanced Lung Cancer (ID 4974)

      D. Kim

      • Abstract

      Background:
      Therapeutic antibodies to programmed death receptor 1 (PD-1) have shown clinical activity in lung cancer. The aim of this study is to investigate the clinical factors, including inflammatory markers such as neutrophil/lymphocyte ratio (NLR), to predict response to anti-PD-1 antibody in advanced lung cancer patients.

      Methods:
      We retrospectively analyzed 51 patients who had advanced lung cancer and had been treated with anti-PD-1 antibodies between 2013 and 2015. The values of NLR were assessed at two time points: at baseline (pre-treatment) and at 6 week after the start of treatment (post-treatment). NLR of 5 was used as the cutoff value.

      Results:
      The median age of the patients was 68 years; 76.5% were male, and 27.5% were never smokers. Most patients had adenocarcinoma (n = 28); 17 had squamous cell carcinoma, and 6 had others. Eighteen of 51 patients (35.3%) had clinical objective response to anti-PD-1 antibody. Non-adenocarcinoma histology and low post-treatment NLR was significantly associated with clinical response, while gender, smoking history, line of treatment and pre-treatment NLR were not predictive of response. Liver metastasis, brain metastasis, and high post-treatment NLR were significantly associated with worse tumor response. Patients with a high post-treatment NLR had significantly shorter PFS (median 1.3 months vs. 6.1 months, p < 0.001). Multivariable analysis demonstrated that high post-treatment NLR (hazard ratio [HR] 20.1, 95% confidence interval [CI] 5.5 - 73.9, p < 0.001), presence of liver metastasis (HR 5.5, 95% CI 2.1 - 14.6, p = 0.001), and CNS metastasis (HR 2.9, 95% CI 1.1 - 7.4, p = 0.027) were independent predictive factors for short PFS. Figure 1



      Conclusion:
      Clinical factors including post-treatment NLR at 6 week might be predictive of clinical benefits from anti-PD-1 antibody therapy in lung cancer.

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    P3.04 - Poster Session with Presenters Present (ID 474)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P3.04-024 - Long-Term Outcome of Sublobar Resection versus Lobectomy for Stage I and II Non-Small Cell Lung Cancer (ID 6182)

      D. Kim

      • Abstract

      Background:
      Lobectomy is conventional lung resection surgery for lung cancer. However, the patients who have poor lung function or small size lung nodule underwent sublobar resection. We retrospective reviewed the oncologic outcome after sublobar resection lobectomy in stage I and II non-small cell lung cancer.

      Methods:
      1019 consecutive patients who underwent lung resection surgery due to non-small cell lung cancer between January 2000 and December 2009 were evaluated through retrospective chart review. We used the Kaplan-Meier method to exam survival and recurrence, Cox proportional hazard model to identify variables affection survival and recurrence.

      Results:
      We performed lobectomy in 928 patients, while sublobar resection in 90 patients. 5-year survival and 10-year survival were not shown statistically significant between sublobar resection and lobectomy (77.0% vs. 80.7%, 58.5% vs. 62.1%, p=0.566). 5-year and 10-year disease free survival were not also shown the difference between sublobar resection and lobectomy (68.9% vs. 63.8%, 67.8% vs. 58.7%, p=0.246). Univariate analysis using the Cox proportional hazards regression model identified sublobar resection is not predicting factor for recurrence (p=0.246).

      Conclusion:
      Our results suggest that the oncologic outcome of sublobar resection versus lobecotomy is not significant difference in stage I and II non-small cell lung cancer patients. These results will be validated by prospective randomized trial.