Virtual Library

Start Your Search

J. Wolf

Moderator of

  • +

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

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • +

      MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (ID 5354)

      11:00 - 12:30  |  Author(s): S. Ignatius Ou, L. Gandhi, A. Shaw, R. Govindan, M.A. Socinski, D..R. Camidge, L. De Petris, D. Kim, A. Chiappori, D. Moro-Sibilot, M. Duruisseaux, L. Crinò, T. De Pas, E. Dansin, A. Tessmer, J.C. Yang, J. Han, W. Bordogna, S. Golding, A. Zeaiter, S.M. Gadgeel

      • 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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.02 - Updated Efficacy and Safety Data from the Phase 2 NP28761 Study of Alectinib in ALK-Positive Non-Small-Cell Lung Cancer (ID 4918)

      11:00 - 12:30  |  Author(s): D..R. Camidge, S.M. Gadgeel, S. Ou, L. Gandhi, G.J. Riely, J. Cetnar, H. West, M.A. Socinski, A. Chiappori, T.M. Mekhail, B.H. Chao, H. Borghaei, K.A. Gold, W. Bordogna, B. Balas, J. Noe, S. Golding, A. Zeaiter, A. Shaw

      • Abstract
      • Presentation
      • Slides

      Background:
      Alectinib, a CNS-active and highly selective ALK inhibitor, has efficacy in patients with ALK-positive NSCLC with and without previous crizotinib treatment. Updated efficacy and safety from the alectinib phase 2 North American NP28761 study (NCT01871805) of patients with ALK-positive NSCLC previously treated with crizotinib, with 15 months’ additional follow-up from the primary analysis and 9 months’ additional follow-up from the previous analysis are presented.

      Methods:
      Patients ≥18 years old with ALK-positive NSCLC (FDA-approved FISH test), disease progression following crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. Primary endpoint: overall response rate (ORR) by independent review committee (IRC; RECIST v1.1.) Secondary endpoints: investigator-assessed ORR; progression-free survival (PFS); overall survival (OS), CNS ORR (CORR); disease control rate (DCR); safety.

      Results:
      At the updated cut-off (22 January 2016) an additional 15 months' follow-up from the primary analysis, 87 patients were enrolled. Median follow-up: 17.0 months (range 1.1–28.6). ORR in the response evaluable population (REP; n=67) by IRC: 52.2% (95% CI 39.7–64.6), median duration of response: 14.9 months. Median PFS and OS: 8.0 and 22.7 months, respectively. Table 1 presents other efficacy endpoints. Grade ≥3 AEs were reported in 41% of the safety population (n=87); most common: elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%), aspartate aminotransferase (5%). Two patients withdrew due to AEs; 28% had AEs leading to dose modification/interruption. Mean dose intensity was 92.0%.

      IRC REP Responders, n CR, n (%) PR, n (%) SD, n (%) PD, n (%) Missing/NE, n (%) DCR, % (95% CI) n=67[*] 35 0 (0) 35 (52.2) 18 (26.9) 11 (16.4) 3 (4.5) 79.1 (67.4,88.1)
      Investigator REP Responders, n ORR, % (95% CI) n=87 [46[†]] 52.9 (41.9, 63.7)
      Measurable baseline CNS lesions (IRC)‖ Responders, n CORR, % (95% CI) Measurable/non-measurable baseline CNS lesions (IRC) Responders CORR,[‖] % (95% CI) n=16 12[‡] 75.0 (47.6, 92.7) n=52 21[§] 40.4 (27.0, 54.9)
      *n=20 did not have measurable disease per IRC and were not included in the IRC REP; [†]2 CR;[ ‡]4 CR;[ §]13 CR; [‖]non-measurable disease classified as CR, non-CR/non-PD or PD; NE=not evaluable/estimable

      Conclusion:
      Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.03 - Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) (ID 5597)

      11:00 - 12:30  |  Author(s): Y.H. Kim, T. Hida, H. Nokihara, M. Kondo, K. Azuma, T. Seto, Y. Takiguchi, M. Nishio, H. Yoshioka, F. Imamura, K. Hotta, S. Watanabe, K. Goto, K. Nakagawa, T. Mitsudomi, N. Yamamoto, H. Kuriki, R. Asabe, T. Tanaka, T. Tamura

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.

      Methods:
      ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.

      Results:
      207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.

      Conclusion:
      ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.04 - Discussant for MA07.01, MA07.02, MA07.03 (ID 6947)

      11:00 - 12:30  |  Author(s): B. Besse

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)

      11:00 - 12:30  |  Author(s): S. Michels, M. Gardizi, P. Schmalz, M. Thurat, E. Pereira, M. Sebastian, E. Carcereny, J. Corral, L. Paz-Arez, E. Felip, C. Grohé, D. Rodriguez Abreu, A. Insa Molla, H. Bischoff, N. Karachaliou, M. Reck, A.H. Scheel, V. Brandes, F. Rieke, L. Nogova, M. Scheffler, J. Franklin, M. Hellmich, B. Massuti, R. Buettner, R. Rosell, J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background:
      ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.

      Methods:
      Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.

      Results:
      In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).

      Conclusion:
      Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.06 - Crizotinib in ROS1 Rearranged or MET Deregulated Non-Small-Cell Lung Cancer (NSCLC): Preliminary Results of the METROS Trial (ID 6003)

      11:00 - 12:30  |  Author(s): L. Landi, A. Chella, R. Chiari, M. Tiseo, R. Buosi, C. Dazzi, C. Gridelli, F. Barbieri, A. Delmonte, G. Alì, G. Fontanini, L. Crinò, F. Cappuzzo

      • Abstract
      • Presentation
      • Slides

      Background:
      Crizotinib is an orally active inhibitor of receptor tyrosine kinases effective in NSCLC with ALK rearrangement. Recent data showed that this agent is dramatically effective in patients with ROS1 rearrangement and at least in some patients with MET deregulation, particularly individuals with exon 14 skipping mutations or with high levels of MET amplification.

      Methods:
      The METROS trial is a multicenter prospective phase II study designed to assess the efficacy and safety and tolerability of Crizotinib in pretreated metastatic NSCLC with MET amplification or MET exon 14 mutation or ROS1 rearrangement. The co-primary end-point was response rate to crizotinib in two cohorts of patients: cohort A) ROS1+: patients with ROS1 rearrangement; B) MET+: patients with MET amplification defined as ratio MET/CEP7 >2.2 on FISH testing or MET exon 14 skipping mutations. Eligible patients were treated with with crizotinib at the standard dose of 250 mg BID p.o.

      Results:
      At the time of the present analysis, preliminary data on the MET cohort are available. A total of 249 patients were screened and 18 resulted as MET+ (12 amplified and 6 mutated). Among them, 10 patients (9 amplified and 1 mutated) were included onto the study and received at least one dose of crizotinib, 6 patients were not eligibible beacause of not progressing to front line therapy, whereas 2 patients did not received crizotinib due to rapidly progressive disease. Characteristics of enrolled patients were: median age 68 years (range 39-77); male/female 8/2; ECOG PS 0/1/2: 6/3/1. In 8 cases crizotinib was offered as second-line therapy. All but one patients were current or past smokers. According to RECIST criteria, 2 partial responses and 4 stable disease were so far documented, with an overall disease control rate of 60%. Three patients are still on treatment. Therapy was generally well tolerated, with only 1 patient delaying therapy due to adverse events. Enrollment is still ongoing.

      Conclusion:
      Preliminary analysis of the METROS trial supports the potential efficacy of crizotinib in patients with MET deregulation, with a favorable toxicity profile. Updated results including median progression-free survival and survival were will be presented at the meeting.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.07 - Ceritinib in ROS1-Rearranged Non-Small-Cell Lung Cancer: An Update of Korean Nationwide Phase II Study (ID 5953)

      11:00 - 12:30  |  Author(s): B.C. Cho, S.M. Lim, H.R. Kim, J. Lee, K. Lee, Y. Lee, Y.J. Min, E.K. Cho, S. Lee, H.S. Shim, J. Chung, Y. Choi, M. Ahn

      • Abstract
      • Presentation
      • Slides

      Background:
      ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC.

      Methods:
      We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization (FISH). ROS1 immunohistochemistry (IHC) and next-generation sequencing (NGS) was performed in available tumor samples. Ceritinib 750mg was administered once daily and the primary endpoint was objective response rate (ORR) by central independent radiologic review. The secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), toxicity and concordance between FISH and IHC. ROS1 fusion partners were identified with the use of next-generation sequencing (NGS) in available tumor samples.

      Results:
      Between June 7, 2013, and February 1, 2016, a total of 404 patients underwent ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. All patients except two (who did not respond to ceritinib) were crizotinib naïve. The median age of all patients was 62 years, and there were 24 females (75%). The majority of patients (84%) were never smokers, and all had adenocarcinoma histology. The median number of previous treatments before study enrollment was 3 (range, 2-7) and 17 (53%) patients had received three or more lines of chemotherapy. At the time of the data cut-off (April 18, 2016), the median follow-up was 7.5 months, and 15 (47%) patients had discontinued treatment. Of the 32 patients enrolled, 28 patients were evaluable for response by independent radiologic review. ORR was 63% (95% CI, 45.7-79.3), with 1 complete response and 19 partial responses. The median duration of response was 10.0 months (range, 0.4+-18.4+). Among 11 tumors that were tested by NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2, and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI, 7.2-not reached), with 17 (53%) patients still in follow-up for progression. The median overall survival was not reached at the time of the data cut-off. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%). Gastrointestinal adverse events (vomiting, nausea, diarrhea) mostly grade 1-2, were the most frequent adverse events (80%); these events were manageable.

      Conclusion:
      Ceritinib demonstrated potent clinical activity in patients with advanced, ROS1-rearranged NSCLC, who received at least one prior line of platinum-based chemotherapy. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which ceritinib is highly active (ClinicalTrials.gov number, NCT01964157).

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.08 - Discussant for MA07.05, MA07.06, MA07.07 (ID 7081)

      11:00 - 12:30  |  Author(s): E. Felip

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.09 - Mass Spectrometry Profiling and Imaging Platform for Novel Precision Drug Resistance Biomarkers Discovery in EML4-ALK Lung Adenocarcinoma (ID 6274)

      11:00 - 12:30  |  Author(s): P.C. Ma, P.S. Cantrell, C. Walsh, S. Wen, S. Komo, X. Wu, H. Yang, E.H. Seeley

      • Abstract
      • Presentation
      • Slides

      Background:
      Drug resistance emergence is a daunting obstacle that limits long-term outcome benefits in precision cancer therapy. Mechanism of the initial emergence of molecular tumor resistance is still not fully understood. Recently, we identified an early precision drug escape mechanism with adaptive tumor cellular reprogramming emerging within days after drug initiation. Here we present a mass spectrometry imaging (MSI) approach to profile the biomolecular changes emerging within residual drug resistant tumor cells under precision ALK inhibitor (ALK-i) treatment.

      Methods:
      EML4-ALK fusion (ALK+) H3122 lung adenocarcinoma xenograft as well as an ALK+ patient biopsy-derived cell line (Ma-ALK001.S) were adopted for the MSI studies. MSI was carried out on FFPE tissues to compare peptide profiles between control tumors and 7- and 14-day ALK-i treated tumors using a histology guided mass spectrometry approach. Additionally, frozen control and ALK-i treated tumors were subjected to full section MSI to determine the ALK-i drug distribution as well as the changing landscape of lipids and metabolites. In parallel, Ma-ALK001.S cell line was treated with alectinib (ALK-i) in culture with samples collected at 0 hr, 8 hr, 3 days, 7 days, and 14 days. Cells were subjected to both MALDI-MS profiling analysis and Laser Ablation Electrospray Ionization (LAESI)-MS analysis. Statistical analyses were performed using MarkerLynx and SCiLS.

      Results:
      ALK+ H3122 lung adenocarcinoma murine xenograft model in vivo under treatment with/without ALK-i TAE684 was used in MSI studies at treatment day 0, day 7 and day 14, during tumor response. Pairwise and 3-way Wilcoxon rank sum tests were carried out and a Bonferroni correction applied. The greatest number of significant peaks were observed between day 0 and day 14 (677). Pairwise linear discriminant analysis classification algorithm models were generated resulting in over 94% classification accuracy in all comparison. Direct MS/MS fragmentation revealed that ALK-i was detected within the frozen ALK-i dosed tumors in early drug-escape. Several lipids were identified to expression landscape changes emerging under ALK-i. Biomolecular (peptides, lipids, and metabolites) profiling of Ma-ALK001.S cell line using combined MALDI and LAESI MSI analysis was successful, which provided novel insights into the early mechanisms of molecular drug resistance emergence.

      Conclusion:
      MSI allowed for direct in situ determination of the evolving expression landscape of biomolecules in ALK+ lung cancer under ALK-i precision therapy. These results provide a rationale to advance our MSI profiling studies for biomarkers discovery to gain deeper insights into molecular mechanisms of adaptive precision drug resistance emergence.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.10 - HDAC Inhibition Overcomes Crizotinib-Resistance by Mesenchymal-Epithelial Transition (MET) in EML4-ALK Lung Cancer Cells (ID 4367)

      11:00 - 12:30  |  Author(s): K. Fukuda, S. Takeuchi, R. Katayama, S. Nanjo, T. Yamada, T. Suzuki, K. Takeuchi, M. Nishio, S. Yano

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK rearrangement, most commonly EML4-ALK, is detected in approximately 3–7% of non-small cell lung cancer (NSCLC). Crizotinib, an ALK tyrosine kinase inhibitor (TKI), shows dramatic clinical efficacy in ALK-rearranged NSCLC patients. However, almost all patients acquire resistance after only 1 to 2 years. A variety of mechanisms, including ALK-secondary mutations, ALK amplification, and activation of alternative pathway, have been reported to mediate acquired resistance to crizotinib. While epithelial–mesenchymal transition (EMT) was recently reported to be associated with resistance to crizotinib in EML4-ALK lung cancer cells in vitro, the underlying mechanism has not been defined and no optimal therapy to overcome EMT-associated resistance has been identified.

      Methods:
      We continuously gave crizotinib treatment to SCID mice inoculated with EML4-ALK lung cancer cell line A925L into thoracic cavity and established crizotinib resistant A925LCR cells. After the limiting dilution of A925LCR cells, we obtained several single cell clones. The effects of the HDAC inhibitor quisinostat on the EMT state and the growth of the cells were examined in vitro and in vivo.

      Results:
      We found that some clones acquired EMT phenotypes, such as spindle shape morphology, expression of EMT-related proteins, and increased cell motility. Interestingly, Histone deacetylase (HDAC) inhibitor, quisinostat, induced mesenchymal-epithelial transition (MET) of A925LCR clones in vitro. Quisinostat reduced ZEB1 expression, induced MET, and thus restored sensitivity to crizotinib. Knockdown of ZEB1 expression in the A925LCR clones by si-RNA also induced MET and restored sensitivity to crizotinib, suggesting that quisinostat-induced MET depends on ZEB-1 suppression. MicroRNA profile analysis revealed that the A925LCR clones expressed significantly lower levels of miR-200 family including miR-200c which targets ZEB1, compared with parental A925L cells. Furthermore, quisinostat recovered miR-200c expression and antago-miR-200c abrogated quisinostat-induced MET in the A925LCR clone cells. These results indicate that quisinostat induced MET by up-regulating miR-200c expression which target ZEB1 and thereby re-sensitizing to crizotinib. In a pleural carcinomatosis model with A925LCR clone cells, quisinostat induced MET and caused remarkable tumor regression during the subsequent crizotinib re-challenge. Furthermore, we analyzed tumor tissue obtained at autopsy from an ALK-rearranged NSCLC patient who acquired resistance to crizotinib. We found that EMT was induced in both primary and metastasis lesions after crizotinib treatment, indicating that EMT is associated with crizotinib resistance in clinical therapy.

      Conclusion:
      Our findings suggest that EMT is possibly occurred in acquired resistance to crizotinib and intermittent use of HDAC inhibitor could be a novel therapeutic strategy for overcoming EMT-associated crizotinib-resistance in EML4-ALK lung cancer.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.11 - Safety and Efficacy of Lorlatinib (PF-06463922) in Patients with Advanced ALK+ or ROS1+ Non-Small-Cell Lung Cancer (NSCLC) (ID 5053)

      11:00 - 12:30  |  Author(s): E. Felip, T.M. Bauer, B. Solomon, B. Besse, L.P. James, J.S. Clancy, K. Klamerus, J. Martini, A. Abbattista, A. Shaw

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC often become resistant to tyrosine kinase inhibitor (TKI) therapy; central nervous system (CNS) relapse is common. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI, active against most known resistance mutations.

      Methods:
      In Ph I of the ongoing Ph I/II study NCT01970865, patients had ALK+ or ROS1+ NSCLC ± brain metastases and were treatment naïve or had disease progression after ≥1 TKIs. Patients received lorlatinib on day –7 and then once or twice daily from day 1. Primary objective was identification of MTD and recommended Ph II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1 including intracranial activity.

      Results:
      Of 54 patients treated in Ph I (cutoff Jan 15, 2016), 41 were ALK+, 12 ROS1+, and 1 had mutation status unconfirmed for ALK+ or ROS1+. Patients were heavily pretreated: 27 had received ≥2 prior TKIs and 20 had 1 prior TKI; 39 patients had CNS metastases at baseline. Patients were treated across 10 dose levels (total daily dose of 10–200 mg). Response rates were:

      N CR PR uCR uPR Overall RR (CR + PR)
      n (%)
      ORR in ALK+ and ROS1+ 53 3(6) 22(42) - 1(2) 25(47)
      ORR in ALK+ with 1 prior TKI 14 1(7) 7(50) - - 8(57)
      ORR in ALK+ with ≥2 prior TKI 26 2(8) 9(34) - 1(4) 11(42)
      IC ORR (target + non-target lesions) in ALK+ and ROS+ 39 10(26) 4(10) 1(3) 2(5) 14(36)
      IC ORR (target lesions) in ALK+ and ROS+ 23 7(30 4(17) - 2(9) 11(47)
      ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed
      Median duration of response was 10.5 months (95% CI 2.9– not reached [NR]) and 12.4 months (95% CI 6.5–NR) for ALK+ and ALK+/ROS1+ pts, respectively. 26 patients remain on treatment. The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade ≥3 TRAE. No patient discontinued due to a TRAE. Analyses of ALK resistance mutations in archival tumor tissue and plasma circulating free DNA collected before lorlatinib treatment are ongoing.

      Conclusion:
      Lorlatinib was well tolerated and demonstrated durable responses, including intracranial responses, in ALK+ and ROS1+ NSCLC, most of whom had CNS metastases and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph II is ongoing.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA07.12 - Discussant for MA07.09, MA07.10, MA07.11 (ID 7046)

      11:00 - 12:30  |  Author(s): R.C. Doebele

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.



Author of

  • +

    ISS07 - Industry Supported Symposium: Immuno-Oncology and Lung Cancer: Emerging Data and Recent Developments - Bristol-Myers Squibb (ID 440)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
    • +

      ISS07.04 - Clinical Lessons Learned for the Use of I-O Therapies (ID 7143)

      12:45 - 14:15  |  Author(s): J. Wolf

      • Abstract

      Abstract not provided

  • +

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

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)

      11:00 - 12:30  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background:
      ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.

      Methods:
      Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.

      Results:
      In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).

      Conclusion:
      Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • +

      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)

      14:20 - 15:50  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 4
    • +

      P2.03b-028 - Improved Overall Survival Following Implementation of NGS in Routine Diagnostics of Advanced Lung Cancer in Germany: Results of the NGM (ID 5304)

      14:30 - 15:45  |  Author(s): J. Wolf

      • Abstract

      Background:
      Broad implementation of molecular diagnostics and personalized cancer care is hampered by insufficient molecular screening, missing reimbursement for comprehensive molecular testing and lack of access to appropriate drugs. The Network Genomic Medicine (NGM) Lung Cancer is a health care provider network offering comprehensive next generation sequencing (NGS)-based multiplex genotyping on a central diagnostics platform in Cologne for all inoperable lung cancer patients (pts) in Germany.

      Methods:
      The NGS panel used in NGM consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, while FISH analyses were performed separately. In 2015, we have started the second outcome evaluation for all NGM pts who had received NGS-based molecular diagnostics. In particular, we have focused on molecular subgroups of EGFR, ALK, BRAF-V600E, HER2 and ROS1 positive pts and especially on NGM pts treated in clinical trials.

      Results:
      From 2013-2015 6210 lung cancer pts (n=4244 non-squamous NSCLC) were genotyped. Preliminary data show the overall survival (OS) of 934 NSCLC pts including of 110 NSCLC pts treated in clinical trials. For 108 EGFR+ pts, the OS of clinical trials pts treated with so called 3[rd] generation EGFR-TKIs was 55 months (n=25) vs 22 months in control group (n=83) (p=0,002; mean OS: 29 months; 95%CI: 36-83 months). For 85 ALK+ pts, the OS of pts treated in clinical trials was 35 months (n=19) compared to OS of 23 months for 45 pts treated with one ALK inhibitor and 8 months for 19 pts treated with no ALK inhibitors (P<0,0001; mean OS: 22 months; 95%CI: 22-33 months).

      Conclusion:
      While the first NGM evaluation in 2013 already showed a survival benefit of 2 years in EGFR-TKI treated EGFR+ pts compared to chemotherapy, our current evaluation in pts treated with 3[rd] generation EGFR-TKIs after acquired resistance to 1[st] gen. EGFR-TKIs shows the significant increasing of the OS. Similarly, we show a significant longer OS for ALK+ pts treated with 2 ALK inhibitors compared to treatment with one or no ALK inhibitor. Further results of this ongoing NGM evaluation will be provided.

    • +

      P2.03b-031 - Impact of PD-L1 Status on Clinical Response in SELECT-1: Selumetinib + Docetaxel in KRASm Advanced NSCLC (ID 5040)

      14:30 - 15:45  |  Author(s): J. Wolf

      • Abstract
      • Slides

      Background:
      Anti-PD-1/PD-L1 immunotherapy has delivered clinical benefit for patients with NSCLC, and PD-L1 has emerged as a predictive biomarker. In the Phase III SELECT-1 trial (NCT01933932), selumetinib (AZD6244, ARRY-142886), an oral, potent and selective, allosteric MEK1/2 inhibitor with a short half-life, plus second-line docetaxel did not provide clinical benefit for patients with KRAS-mutant (KRASm) NSCLC compared with placebo plus docetaxel (PBO+DOC). Although no incremental benefit was observed, it is important to evaluate biomarkers, such as PD-L1, to understand more about the biology of patients with KRASm NSCLC.

      Methods:
      In total, 510 patients with a prospectively, centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to selumetinib 75 mg BID, plus docetaxel 75 mg/m[2] q21d (SEL+DOC), or PBO+DOC. Evaluations included progression-free survival (PFS) by investigator assessment (RECIST 1.1; primary endpoint), and overall survival (OS). Association of tumour PD-L1 status with clinical responses was assessed as an exploratory objective. PD-L1 status was centrally determined using the PD-L1 IHC 28-8 pharmDx test (Dako) for all patients with sufficient tumour sample. Samples with a pre-specified cut-off of ≥5% tumour cell staining were considered PD-L1 positive.

      Results:
      SEL+DOC did not improve PFS or OS compared with PBO+DOC. PD-L1 status was determined for 385 (75%) patients: 224 (58%) samples were PD-L1 <5%, and 161 (42%) samples were PD-L1 ≥5%; the remaining 125 patients had unknown PD-L1 status due to insufficient tumour sample. Subgroups were balanced across treatments. PD-L1 subgroup analysis of PFS and OS is presented below.

      Subgroup Events (%) in SEL+DOC group Events (%) in PBO+DOC group HR (95% CI)
      PFS
      PD-L1 <5% 94/112 (84%) 101/112 (90%) 0.89 (0.67, 1.18)
      PD-L1 ≥5% 65/79 (82%) 71/82 (87%) 0.70 (0.50, 0.99)
      PD-L1 unknown 59/63 (94%) 57/62 (92%) 1.24 (0.86, 1.79)
      OS
      PD-L1 <5% 73/112 (65%) 74/112 (66%) 0.94 (0.68, 1.30)
      PD-L1 ≥5% 55/79 (70%) 58/82 (71%) 0.89 (0.61, 1.28)
      PD-L1 unknown 48/63 (76%) 38/62 (61%) 1.57 (1.02, 2.41)


      Conclusion:
      Prevalence of PD-L1 positive status in this KRASm cohort was similar to that reported for a pan-NSCLC cohort (Borghaei, NEJM 2015). No significant PFS or OS differences were observed between treatments in either PD-L1 positive or negative tumours. Additional biomarker analyses are planned for different KRAS codon mutations, and LKB1 and TP53 status.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P2.03b-036 - Analysis of Potentially Targetable Mutations in 821 Patients with Squamouscell Lung Cancer Undergoing Routine NGS-Based Molecular Diagnostics (ID 5939)

      14:30 - 15:45  |  Author(s): J. Wolf

      • Abstract
      • Slides

      Background:
      Molecular multiplex diagnostics is increasingly integrated now in routine diagnostics of lung adenocarcinoma (LAD). Although targetable aberrations are predominantly found in LAD, they have also been reported in squamouscell lung carcinoma (SQLC). We here present results of routine molecular multiplex diagnostics of advanced stage SQLC obtained within the German Network Genomic Medicine (NGM) and compare them with results reported previously in early stage SQLC in The Cancer Genome Atlas (TCGA) LUSC cohort.

      Methods:
      Tumor biopsies of 821 patients consecutively diagnosed within NGM were analyzed with next-generation parallel sequencing (NGS). The panel consisted of 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR, ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In subsets of patients, fluorescence in-situ hybridization (FISH) was performed for amplification detection of FGFR1 and MET. We queried the TCGA dataset with respect to the panel used and compared the findings. For NGM patients, therapy and outcome are also reported..

      Results:
      In addition to the expected frequencies of TP53, DDR2, PTEN and PIK3CA mutations, we detected EGFR mutations in 3.2% and BRAF mutations in 1.8%. Unlike the TCGA dataset, where the frequencies were 2.8% and 3.9%, respectively, the detected mutations in the NGM cohort included also activating targetable mutations (i. e., EGFR del19 and L858R, and BRAF V600E). FISH data revealed presence of MET amplification in 14.2% and of FGFR1 amplification in 20.0%. The association and correlation of these aberrations with clinical findings and prognosis as well as with PD-L1 expression status and mutational load will be presented.

      Conclusion:
      Our data give an overview on the presence and clinical characteristics of targetable mutations in advanced SQLC and show, that such mutations occur in a substantial amount of patients. Thus, molecular multiplex diagnostics might be indicated also in SQLC in order to use all therapeutic options available in these patients.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      P2.03b-076 - MAP2K1 Mutations in NSCLC: Clinical Presentation and Co-Occurrence of Additional Genetic Aberrations (ID 5885)

      14:30 - 15:45  |  Author(s): J. Wolf

      • Abstract
      • Slides

      Background:
      The clinical impact of somatic MAP2K1 mutations remain uncertain in non-small cell lung cancer (NSCLC). Activation of the MEK1-cascade might play a central role in resistance to targeted BRAF V600E, EML4-ALK and EGFR T790M inhibition, but so far, only MAP2K1 K57N could be identified and linked functionally for this target. Clinical trials combining specific inhibitors for predefined NSCLC subgroups with MEK inhibitors are continuous. We performed this study to characterize MAP2K1-mutated NSCLC clinically and molecularly.

      Methods:
      Tumor tissue collected consecutively from 4590 NSCLC patients within a molecular screening network between 07/2014 and 07/2015 was analyzed for MAP2K1 mutations using next-generation sequencing (NGS) with a set of 102 amplicons in 14 genes. Clinical and molecular characteristics of these patients are described and compared with an internal control group of NSCLC patients and an independent control Group of The Cancer Genome Atlas (TCGA).

      Results:
      We classified 20 (0,4%) patients with MAP2K1 mutations. They were frequently found in adenocarcinoma (n=19) and were expressively associated with smoking. The most common MAP2K1 mutation was K57N. The majority of patients (n=15) had additional oncogenic driver aberrations, including mutations in ALK, EGFR or BRAF, and MET amplification. TP53 mutations are found in 11 patients. In 5 patients (25.0%) MAP2K1 occured exclusively. TCGA analysis reveals additional 14 patients with MAP2K1 mutations, whereof 11 have additional TP53 mutations and two have KRAS mutations. The majority of patients in our cohort has stage IV NSCLC, all patients in TCGA receive surgery for localized stages.

      Conclusion:
      This analysis displays that MAP2K1 mutations might occur at any stage of NSCLC and can be associated with targetable aberrations in smoking stage IV patients. Combination of targeted therapy against the known driver aberrations with MEK inhibitors might be an hopeful therapeutic outlook in the near future.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      P3.02a-025 - PROs With Ceritinib Versus Chemotherapy in Patients With Previously Untreated ALK-rearranged Nonsquamous NSCLC (ASCEND-4) (ID 5128)

      14:30 - 15:45  |  Author(s): J. Wolf

      • Abstract

      Background:
      Here, we present the patient-reported outcomes (PROs) of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

      Methods:
      Untreated, ALK+, advanced, nonsquamous NSCLC patients (N=376) were randomized (1:1) to ceritinib 750 mg/day (n=189) or chemotherapy (n=187; [pemetrexed 500 mg/m[2 ]plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed). PROs were assessed using EORTC quality-of-life questionnaire (QLQ-C30), the lung cancer module (QLQ-LC13), Lung Cancer Symptom Scale (LCSS), and EQ-5D.

      Results:
      Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. PRO compliance was high, ≥80% at most timepoints. Ceritinib significantly prolonged time to deterioration of lung cancer-specific symptoms (pain, dyspnea, and cough) versus chemotherapy in both LCSS and QLQ-LC13 instruments (composite endpoints for LCSS, HR=0.61 [0.41, 0.90]; and QLQ-LC13, HR=0.48 [0.34, 0.69]). Time to deterioration in LC13 questionnaire was significantly longer with ceritinib versus chemotherapy (23.6 [20.7, NE] vs 12.6 [8.9, 14.9] months) (Table). In the QLQ-C30 instrument, 4 of 5 functional domains and 6 of 9 symptom scales improved with ceritinib (P< 0.05); 2 scales related to gastrointestinal symptoms indicated deterioration for ceritinib. In agreement with most other scales showing symptom improvement, ceritinib demonstrated significant improvements in Global Health Status/QoL in the same instrument (QLQ-C30, P<0.001) as well as for EQ-5D-5L index (P<0.001) and EQ-5D-5L VAS (P<0.05 from cycle 13 until 49). Figure 1



      Conclusion:
      Untreated ALK+ NSCLC patients experienced significantly greater improvements in lung cancer-specific symptoms on treatment with ceritinib. General health status was significantly improved with ceritinib versus chemotherapy. Overall, PRO results from all 4 instruments independently showed improvements highlighting the consistency and robustness of these findings.

  • +

    PL03 - Presidential Symposium (ID 428)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
    • +

      PL03.07 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (Abstract under Embargo until December 6, 7:00 CET) (ID 4987)

      08:35 - 10:25  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background:
      Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

      Methods:
      Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).

      Results:
      Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1



      Conclusion:
      First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

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

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

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

      16:00 - 17:30  |  Author(s): 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.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    YI01b - Scientific Mentoring (ID 415)

    • Event: WCLC 2016
    • Type: Young Investigator Session
    • Track:
    • Presentations: 1
    • +

      YI01b.02 - Expectations from a Young Investigator (ID 6740)

      09:45 - 11:45  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Expectations from a Young Investigator Over the last two decades, research has pushed lung cancer investigations from the shallows of cancer treatment to one of the most innovative positions in oncology. The improvements in molecular diagnostics, in targeted therapy and immunotherapy with the linked creeping decline of traditional chemotherapy act as a model for many other tumor entities. Joined by this paradigm shift is a demographic change to young investigators who start their career in the innovative fields of lung cancer research instead of thinking in the traditional chemotherapy-based fashion. Nevertheless, in order to detect the needs and expectations from young investigators, even the definition of "young" is hard to handle, and subjective expectations might be biased by the socioeconomic background of the investigator. We therefore set out to find a way to present more robust and reliable data on the topic. We created an online questionnaire covering age, experiences, interests, and of course needs and expectations of young investigators. The expectations focus on research topics, treatment options, mentorships and social networking. The questionnaire will be forwarded to 20 investigators in the EU, Asia, South America and the US with link to the emerging fields of lung cancer research, in order to forward it to participants who they consider young in both clinical and preclinical investigations. For subgroup analyses, we will include students with interest in this field, too. Results will be analyzed by the presenters. The poll will be open until one week of the WCLCs Young Investigator's Scientific Mentoring Session, and results of this interim analysis will be presented by this talk. Nevertheless, all participants of the WCLC 2016 are invited to answer the questionnaire during the Conference, and a final data cut will be made at December 10th, 2016. We are aware of the potential biases in online polls. A valid e-mail address and the source of the online link (i. e., who was the "supervisor") are necessary. As an incentive to participate properly, we offer all participants to be part of the "WCLC young Investigator Expectations Network (WIEN)" which will coauthor the final manuscript. As we question the expectations of how lung cancer research will work in five years, it is intended to repeat the poll in a regular manner, maybe yearly. We expect a view on the expectations from young investigators worldwide and a feeling of their needs for the future.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.