Virtual Library

Start Your Search

Juergen Wolf

Moderator of

  • +

    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
    • +

      MA09.01 - A Phase I/II Trial of Dasatinib and Osimertinib in TKI Naïve Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2710)

      15:15 - 16:45  |  Presenting Author(s): Chul Kim  |  Author(s): Stephen V. Liu, Jeanette Crawford, Deepa S Subramaniam, Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard of care in patients with EGFR-mutant NSCLC. However, a fraction of patients do not respond to EGFR-TKI therapy or have short duration of response. In addition, virtually all patients develop resistance. In a preclinical study, we have shown that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of resistance to EGFR-TKI therapy through the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically.

      Method

      This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib, a Src inhibitor, in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with pleural or pericardial effusions were excluded. The primary endpoint of the phase I portion was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation includes 2 dose levels (DLs) (DL1: osimertinib 80 mg QD, dasatinib 50 mg BID, DL2: osimertinib 80 mg QD, dasatinib 70 mg BID). 2 DLs below the starting dose level (DL-1: osimertinib 80 mg QD, dasatinib 70 mg QD; DL-2: osimertinib 80 mg QD, dasatinib 50 mg QD) could be explored if necessary. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      10 patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. None of the patients enrolled at DL2 had dose limiting toxicities (DLTs) but given the frequent dose reductions required and toxicities beyond the DLT period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n=9), diarrhea (n=8), rash (n=7), AST elevation (n=6), ALT elevation (n=6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in first-line, the trial was closed to enrollment.

      Conclusion

      The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures.

      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.

    • +

      MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)

      15:15 - 16:45  |  Presenting Author(s): Jonathan Wesley Riess  |  Author(s): Nicolas Floch, Philip C. Mack, Matthew J. Martin, Daniel Vang, Paul D. Smith, Darren Cross, Mingshan Cheng, James Keck, Susan Groshen, Michael Rabin, Sukhmani Padda, Geoffrey R Oxnard, Jacob Sands, Kavitha Ramchandran, Mariana Koczywas, Jeffrey A. Moscow, Pasi A Jänne, Primo N. Lara, Edward Newman, David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.

      Method

      Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).

      Result

      The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.

      Conclusion

      In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.

      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.

    • +

      MA09.03 - Identification of Mechanisms of Acquired Resistance to Poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2904)

      15:15 - 16:45  |  Presenting Author(s): Jacqulyne Ponville Robichaux  |  Author(s): Yasir Elamin, Brett Carter, Mehmet Altan, Don Lynn Gibbons, Frank Fossella, George R Simon, Vincent Lam, George Blumenschein Jr, Anne Tsao, Jonathan Kurie, Frank E Mott, Marcelo Vailati Negrao, Limei Hu, Junqin He, Monique Nilsson, Brent Roeck, Zane Yang, Vassiliki A Papadimitrakopoulou, John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR occur in ~2% Insertions/mutations in exon 20 of EGFR occur in ~2% of all lung adenocarcinomas. These alterations are characterized by primary resistance to approved tyrosine kinase inhibitors (TKIs) with response rates of <12%. We have shown that exon 20 insertions restrict the size of the drug-binding pocket, limiting binding of large inhibitors. However, poziotinib can circumvent these steric changes and is a potent inhibitor of EGFR exon 20 mutants. In our investigator-initiated phase 2 trial of EGFR exon 20 mutant NSCLC, poziotinib was associated with a best objective response rate of 55% (Heymach et al, 19th WCLC). Herein, we use preclinical models and clinical samples from our phase 2 study to identify mechanisms of acquired poziotinib resistance (NCT03066206).

      Method

      EGFR exon 20 insertion (D770insNPG) genetically engineered mice (GEM) were treated with poziotinib until progression. Upon progression, tumor DNA and protein were analyzed using whole exome sequencing (WES) and reverse phase protein assay (RPPA). Mandatory and optional biopsies were obtained at baseline and progression, respectively, from patients treated in our phase 2 trial of poziotinib in EGFR exon 20 mutant NSCLC. Serial cfDNA was collected at baseline, 8 weeks of therapy, and on progression. Patient samples were analyzed using targeted next generation sequencing or WES.

      Result

      Poziotinib acquired-resistance GEM tumors acquired mutations in ErbB4, KRAS, and other genes which represent potential targetable bypass pathways. Resistant GEM tumors displayed increased activation of MAPK, AKT, ERK and MEK compared to sensitive tumors, suggesting that poziotinib acquired resistance is associated with reactivation of the MAPK/PI3K pathways. We enrolled 50 EGFR exon 20 mutant patients in our phase 2 trial. Analysis of matched pre-poziotinib and on-progression samples from 20 responding patients revealed acquired EGFR tyrosine kinase domain point mutations in 4 patients (T790M (2), V774A (1), D770A, (1)). Ba/F3 cells co-expressing EGFR exon 20 insertion (S768supSVD) and T790M were resistant to poziotinib, suggesting that T790M is a poziotinib resistance driver. Potential acquired EGFR-independent resistance mechanisms identified in patients to date include PIK3CA E545K (1), MAP2K2 S94L (1), MET amplification (1), EGFR amplification (2), and CDK6 amplification (2).

      Conclusion

      Parallel to acquired resistance mechanisms seen in classical EGFR mutation, acquired resistance to poziotinib can be mediated through EGFR-dependent mechanisms, notably T790M and other EGFR tyrosine kinase domain point mutations. EGFR-independent resistance mechanisms include activation of bypass pathways. Preclinical validation of resistance mechanisms and additional analysis of patient samples 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.

    • +

      MA09.04 - Discussant - MA09.01, MA09.02, MA09.03 (Now Available) (ID 3747)

      15:15 - 16:45  |  Presenting Author(s): Juergen Wolf

      • 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.

    • +

      MA09.05 - Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors (Now Available) (ID 1169)

      15:15 - 16:45  |  Presenting Author(s): Natalie Vokes  |  Author(s): Tom Nguyen, Christine A Lydon, Emily Chambers, Lynette M Sholl, Mizuki Nishino, Eliezer M Van Allen, Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival, and the molecular determinants of this differential response have been incompletely characterized.

      Method

      We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Duration of therapy (DOT) on first-line EGFR TKI and overall survival (OS) were assessed. Mutations associated with differential benefit to therapy were identified by comparing mutation rates in outliers with DOT or OS ≥75th percentile vs ≤25th percentile. Fisher’s exact test was used to calculate statistical significance, and the Benjamini-Hochberg method was used to correct for false discovery rate (FDR). Time to event outcomes were assessed with the Kaplan-Meier method.

      Result

      We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). The median DOT on first-line TKI was 12 months (range 0-72 months) and median OS was 28 months (range 1-133 months). Pre-treatment sequencing was available for 188 patients, 65 of whom also had documented assessment of resistance mechanism (T790M 78%, other 22%). Pre-existing concurrent TP53 mutations were associated with shorter DOT (median 10 vs 16 mo, p=0.0017), but there was no significant difference in OS (median 25 vs 36 mo, p=0.2) and no association with resistance mechanism (p=0.674). In addition to TP53, BCOR and SMARCA4 mutations were enriched in patients with shorter DOT, whereas MTOR mutations were enriched in patients with DOT in the top quartile, though these analyses did not pass FDR correction. Pre-treatment SMARCA4 mutations were more frequent in patients with survival in the bottom quartile (Fisher’s p=0.01), and were associated with decreased OS (median 32 vs 12 mo, log-rank p<0.0001).

      Conclusion

      Genomic features may contribute to differential outcomes in patients with EGFR-mutated NSCLC. In addition to TP53 mutations, pre-treatment SMARCA4 mutations may associate with worse outcomes in these 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.

    • +

      MA09.06 - Adaptive Mechanisms of Resistance to Targeted Therapy in EGFR Mutant Brain Metastasis (Now Available) (ID 1329)

      15:15 - 16:45  |  Presenting Author(s): Don X. Nguyen  |  Author(s): Sally Adua, Minghui Zhao, Darren Cross, Paul Smith

      • Abstract
      • Presentation
      • Slides

      Background

      A subset of non-small cell lung cancers (NSCLCs) can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, a significant proportion of patients with brain metastasis progress after front-line treatment, underscoring the central nervous system (CNS) as a unique sanctuary site for persistent disease. Herein, we performed an integrated examination of the cellular, pharmacological, and molecular causes of resistance to targeted therapies in brain metastases.

      Method

      The efficacy of osimertinib, a brain penetrant third generation TKI, was studied in mice using EGFR mutant NSCLC models derived from cell lines or patient biopsies. Animals with multi-organ metastases were treated continuously until disease progression was detected in the brain parenchyma. We also developed an in situ transcriptomic approach, referred to as Brain Metastasis Xenograft-RNA Sequencing (BMX-seq), to distinguish the transcriptome of tumor versus stroma in vivo. Molecular and biological responses were integrated with pharmacological analysis of loco-regional distribution of osimertinib in and around brain lesions.

      Result

      In EGFR mutant models with multi-organ metastases, extra-cranial tumors could be effectively controlled, while brain metastases eventually progress despite strong osimertinib penetrance into the normal and tumor bearing CNS. Importantly, tumor cells isolated from progressing brain metastases did not exhibit resistance in vitro. However, these cells exhibited an enhanced resistant capacity when transplanted into the brain, demonstrating that this resistant phenotype is selected for and that exposure to the brain is a requirement for drug resistance in vivo.

      BMX-seq reveals that the stroma of drug resistant brain metastasis is characterized by activation of innate pro-inflammatory pathways. Reciprocally, we identified stromal induced activation of cytoskeletal and interferon response genes in drug resistant tumor cells. Interestingly, several of these genes are induced in situ independently of drug treatment, suggesting that the brain metastatic niche can precondition tumor cells for ensuing drug resistance. Finally, we demonstrate that inhibiting mediators of interferon and cystoskeletal signaling increases the sensitivity of brain metastasis to osimertinib in vivo.

      Conclusion

      Although advances have been made in the brain penetrating abilities of targeted therapies, acquired resistance in this unique TME still develops. Our results suggest that adaptive molecular interactions within the brain TME preconditions metastatic cells for TKI resistance and that targeting such pathways in combination with osimertinib should be explored to treat NSCLC patients suffering from or at risk for brain relapse.

      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.

    • +

      MA09.07 - Activity of Larotrectinib in TRK Fusion Lung Cancer (Now Available) (ID 1600)

      15:15 - 16:45  |  Presenting Author(s): Anna F Farago  |  Author(s): Shivaani Kummar, Victor Moreno, Jyoti D Patel, Ulrik Lassen, Lee Rosen, Nora C. Ku, Michael C. Cox, Shivani Nanda, Barrett H. Childs, David M. Hyman, Alexander Drilon

      • Abstract
      • Presentation
      • Slides

      Background

      Tropomyosin receptor kinase (TRK) fusions involving NTRK1, NTRK2, and NTRK3 occur in a range of tumor types. Larotrectinib, the first FDA-approved highly selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% by independent central review across a broad spectrum of tumors that harbor NTRK gene fusions (Drilon et al., NEJM 2018;378:731–9). Here, we report updated data on the patients with lung cancer who have been treated with larotrectinib.

      Method

      Patients with non-small cell lung cancer (NSCLC) in two clinical trials (NCT02122913 and NCT02576431) with TRK fusion cancer were included in this analysis. Larotrectinib (100 mg BID) was administered on a continuous 28-day schedule until withdrawal, unacceptable toxicity, or disease progression. Response was assessed by investigator (INV) and independent review committee (IRC) per RECIST v1.1.

      Result

      As of July 30, 2018, 11 patients with metastatic lung adenocarcinoma were enrolled. Median age was 52 years (range 25–76 years). Eight patients had fusions involving NTRK1 and diverse fusion partners: EPS15 (n=2), TPM3 (n=2), IRF2BP2 (n=2), TPR (n=1), and SQSTM1 (n=1). Three patients had fusions involving NTRK3 (fusion partner: SQSTM1 [n=2] and ETV6 [n=1]). Ten patients had prior systemic therapy (five patients had three or more prior therapies) with best responses on last prior therapy being one partial response, four with stable disease, three progressive disease, and three unknown or unevaluable. Seven patients were evaluable for response to larotrectinib. INV and IRC assessment were in agreement, with one complete response, four partial responses (including one patient with central nervous system [CNS] metastases), and two with stable disease (ORR 71%). Results from four patients not evaluable at the July 30, 2018 data cut-off due to insufficient follow-up are expected in April 2019 and will be presented at the meeting. The median time to response was 1.8 months. One patient with brain metastases had an intracranial near complete response (–95% reduction) to larotrectinib, as well as an extracranial response. The duration of response by IRC ranged from 7.4+ months to 25.8+ months; the median duration of response was not reached. One patient continued receiving treatment post-progression. Two patients discontinued treatment due to disease progression and one withdrew without cause. Larotrectinib was well tolerated, with treatment-related adverse events being predominantly grade 1–2.

      Conclusion

      Larotrectinib is highly active in advanced lung cancer patients harboring NTRK gene fusions, including those with CNS metastases, with a favorable safety profile. These results support the use of larotrectinib in NTRK fusion NSCLC.

      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.

    • +

      MA09.08 - Discussant - MA09.05, MA09.06, MA09.07 (Now Available) (ID 3748)

      15:15 - 16:45  |  Presenting Author(s): Ana Vivancos

      • 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.

    • +

      MA09.09 - Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with <i>EGFR</i>-Mutant NSCLC and MET Dysregulation: 18‑Month Follow-Up (Now Available) (ID 1783)

      15:15 - 16:45  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Ying Cheng, Jianying Zhou, Shun Lu, Yiping Zhang, Jun Zhao, Dong-Wan Kim, Ross Soo, Sang-we Kim, Hongming Pan, Yuh-Min Chen, Chih-Feng Chian, Xiaoqing Liu, Daniel SW Tan, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, Keunchil Park, James Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Background

      In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up.

      Method

      Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955).

      Result

      Low recruitment halted full enrolment with 55 of 156 planned patients enrolled.

      As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles.

      Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]).

      Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients.

      Conclusion

      Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification, and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.

      Table: Summary of efficacy data

      Population

      Tepotinib + gefitinib

      Chemotherapy

      HR/OR
      (90% CI)

      Overall MET+*

      Patients, n

      31

      24

      mPFS, months (90% CI)

      4.9 (3.9, 6.9)

      4.4 (4.2, 6.8)

      0.67 (0.35, 1.28)

      mOS, months (90% CI)

      17.3 (12.1, 37.3)

      18.7 (15.9, 20.7)

      0.67 (0.33, 1.37)

      ORR, n (%) [90% CI]

      14 (45.2) [29.7, 61.3]

      8 (33.3) [17.8, 52.1]

      1.99 (0.56, 6.87)

      MET IHC3+

      Patients, n

      19

      15

      mPFS, months (90% CI)

      8.3 (4.1, 21.2)

      4.4 (4.1, 6.8)

      0.35 (0.17, 0.74)

      mOS, months (90% CI)

      37.3 (24.2, 37.3)

      17.9 (12.0, 20.7)

      0.32 (0.14, 0.78)

      ORR, n (%) [90% CI]

      13 (68.4) [47.0, 85.3]

      5 (33.3) [14.2, 57.7]

      4.33 (1.03, 18.33)

      MET amplification

      Patients, n

      12

      7

      mPFS, months (90% CI)

      21.2 (8.3, NE)

      4.2 (1.4, 7.0)

      0.13 (0.04, 0.43)

      mOS, months (90% CI)

      37.3 (NE, NE)

      13.1 (3.3, NE)

      0.08 (0.01, 0.51)

      ORR, n (%) [90% CI]

      8 (66.7) [39.1, 87.7]

      3 (42.9) [12.9, 77.5]

      2.67 (0.37, 19.56)

      CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

      All efficacy outcomes are investigator-assessed by RECIST v1.1.

      *IHC2+/IHC3+/gene amplification.

      MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+).

      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.

    • +

      MA09.10 - Comprehensive Analysis of Secondary Mutation as Resistance Mechanism to Seven MET-TKIs for MET Exon 14 Skipping in Vitro (Now Available) (ID 117)

      15:15 - 16:45  |  Presenting Author(s): Toshio Fujino  |  Author(s): Yoshihisa Kobayashi, Kenichi Suda, Takamasa Koga, Masaya Nishino, Shuta Ohara, Masato Chiba, Akira Hamada, Toshiki Takemoto, Junichi Soh, Tetsuya Misudomi

      • Abstract
      • Presentation
      • Slides

      Background

      MET exon 14 skipping mutation have been attracting attentions of thoracic oncologists as a new target of therapy for lung cancer. The efficacy of MET-TKI has been reported, while these tumors, almost always acquire resistance, as in the case of other oncogene-addicted lung cancers. However, its resistance mechanisms are not fully understood.

      Method

      MET exon14 skipping mutation was introduced to Ba/F3 cell retrovirally. Using N-ethyl-N-nitrosourea mutagenesis, we derived resistant clones to seven MET-TKIs and searched for secondary MET mutations. We evaluated their sensitivities to following different TKIs. Type Ia, crizotinib; Type Ib, capmatinib, tepotinib and savolitinib; Type II, cabozantinib, merestinib and glesatinib.

      Result

      We sequenced 201 resistant clones and could obtain 80 clones which had secondary mutations in the MET tyrosine kinase domain. A total of 26 different missense mutations occurring at 12 codons were identified. Of them, D1228 and Y1230 in the activation loop were common sites for type I TKIs that bind to active kinase form (DFG-in), while L1195 and F1200 were those for type II TKIs that bind to inactive form (DFG-out). In general, resistant mutations against type I were sensitive to type II, and vice versa.

      figure.png

      Conclusion

      We identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 skipping.

      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.

    • +

      MA09.11 - Mechanisms of Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14 Mutant Non-Small Cell Lung Cancer (Now Available) (ID 1421)

      15:15 - 16:45  |  Presenting Author(s): Gonzalo Recondo Jr.  |  Author(s): Magda Bahcall, Lynette M Sholl, Giulia Constanza Leonardi, Biagio Ricciuti, Tom Nguyen, Deepti Venkatraman, Giuseppe Lamberti, Renato Umeton, Pasi A Jänne, Mark Awad

      • Abstract
      • Presentation
      • Slides

      Background

      Type I and II MET tyrosine kinase inhibitors (TKIs) are under development for patients with MET exon 14 mutant non-small cell lung cancer (NSCLC). Understanding the mechanisms driving resistance to MET TKIs is critical to design novel treatment strategies for this molecular subtype of NSCLC.

      Method

      Among patients with MET exon 14 mutant NSCLC treated with MET TKIs, pre- and post-TKI tumor tissue specimens and plasma samples were analyzed using next-generation sequencing (NGS) to explore genomic mechanisms of resistance upon disease progression.

      Result

      Between April 2014 to March 2019, 38 patients were treated with MET TKIs. Among these, paired samples from 15 individuals were evaluable for this study. Patients were treated with MET TKIs in the first-line (N=7; 46.7%), second-line (N=5; 33.3%), third-line (N=1; 6.7%) and fourth-line (N=2: 13.3%) setting. Eight patients were treated with one type I MET TKI and 7 patients received ≥2 MET TKIs. On target mechanisms of resistance were identified in 5 patients (33.3%), through secondary mutations in the MET tyrosine kinase domain (N=4) and MET amplification (N=1). Single MET kinase domain mutations D1228H/N were detected in 2 patients progressing on treatment with a type I MET TKI. In two cases, tumor tissue revealed only one resistance mutation (case #1 with Y1230H; case #2 with H1094Y), whereas paired plasma analysis demonstrated ≥3 resistance mutations in ctDNA (case #1 with G1163R, D1228N, Y1230H/S; case #2 with H1094Y, L1195F/V), reflecting the emergence of polyclonal on-target resistance. Off-target mechanisms of acquired resistance were identified in 7 patients treated with Type I MET TKI (46.7%) and involved amplification of EGFR (N=2), EGFR/HER2 (N=1), EGFR/HER3 (N=1), KRAS (N=1), EGFR/KRAS/BRAF (N=1), CCND1 (N=1). In 2 cases with bypass activation, sequential treatment with type II MET TKIs did not confer benefit. A concurrent NF1 mutation was present at baseline in a patient with primary resistance to MET TKI (6.7%). In 2 patients (13.3%), no genomic mechanisms of resistance were identified.

      Conclusion

      The landscape of resistance mechanisms to MET TKIs in NSCLC includes single and polyclonal secondary kinase domain mutations and bypass track activation by amplification of key oncogenes involving the ErbB/HER family of tyrosine kinase receptors and the MAPK signaling pathway. Given the complexity of resistance, therapeutic efforts to prevent acquired resistance in MET exon 14 mutant NSCLC should be developed.

      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.

    • +

      MA09.12 - Discussant - MA09.09, MA09.010, MA09.11 (Now Available) (ID 3749)

      15:15 - 16:45  |  Presenting Author(s): Ravi Salgia

      • 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.

  • +

    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
    • +

      MA14.01 - Clinical and Genomic Features of Chinese Lung Cancer Patients with Germline Mutations (Now Available) (ID 682)

      15:45 - 17:15  |  Presenting Author(s): Wenying Peng  |  Author(s): Jin Li, Lian-peng Chang, Jing Bai, Yanyan Zhang, Yan-Fang Guan, Xingxiang Pu, Meilin Jiang, Jun Cao, Bolin Chen, Xuefeng Xia, Xin Yi, Jianjun Zhang, Lin Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Recent studies on next generation sequencing (NGS) data from cancer patients have demonstrated that germline mutations in genetic predisposition genes were more common than previous known in many cancer types including lung cancer. However, most previous studies have focused on western patient population and the germline mutation landscape in Asian lung cancer patients and the clinical and genomic features in these patients are largely unknown.

      Method

      NGS data from a targeted panel of 1,021 known cancer genes from paired cancer and germline DNA of 1,797 Chinese lung cancer patients was analyzed to identify pathogenic or likely pathogenic (P/LP) germline variants in predisposition genes based on American College of Medical Genetics and Genomics (ACMG) 2015 guideline.

      Result

      Totally, 5.95% of lung patients were found to harbor germline variants in 35 cancer predisposition genes. The prevalence of germline mutations was higher in patients under 40 compared to older counterparts (10.1% vs 5.74%, p=0.103, Chi-Square test ) although it did not reach statistical significance. However, germline BRCA1/2 mutations were associated with earlier age of onset (median 52.5 vs 60 years-old, p=0.0080 by Mann-Whitney test). Furthermore, patients with P/LP germline mutations had significantly more somatic mutations in KRAS (p=0.012, fisher’s exact test) and c-MET (p=0.018, fisher’s exact test) oncogenes, but less in tumor suppressor gene TP53 (p=0.019, fisher’s exact test). Compared to western lung cancer patients enrolled in TCGA, P/LP germline mutations in BRCA2, FANCA, ATM, MUTYH, BLM, TP53, BRCA1, CHEK2, PMS2, NBN and FANCC were identified in both current Chinese cohort and TCGA cohort with BRCA2 germline mutations significantly more common in Chinese cohort than TCGA cohort (p=0.015, Fisher’s exact test). In addition, RAD51D, FANCD2, BRIP1, MSH6, PMS1, PALB2, RAD51C, SDHA, TSC2, BAP1, CDH1, FLCN, NF1 and RUNX1) were exclusively identified in Chinese patients, while RET, ERCC3, FANCG and VHL were only detected in TCGA cohort.

      Conclusion

      These results implied that there might be both common and unique cancer predisposition germline mutations for lung cancer between Asian and Western patient populations.

      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.

    • +

      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): Rafal Dziadziuszko, Alexander Drilon, Tom John, Matthew G Krebs, George Demetri, Alice T. Shaw, Salvatore Siena, Juergen Wolf, Anna F Farago, Brian Simmons, Chenglin Ye, Xinhui Huang, Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

      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.

    • +

      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Presenting Author(s): D. Ross Camidge  |  Author(s): Fabrice Barlesi, Jonathan Goldman, Daniel Morgensztern, Rebecca S Heist, Everett E. Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S. Hong, John H. Strickler, Monica Motwani, Zhaowen Sun, Apurvasena Parikh, Philip Komarnitsky, Jun Wu, Karen Kelly

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

      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.

    • +

      MA14.04 - Discussant - MA14.01, MA14.02, MA14.03 (Now Available) (ID 3777)

      15:45 - 17:15  |  Presenting Author(s): Yuichiro Ohe

      • 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.

      • Abstract
      • Presentation
      • Slides

      Background

      Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).

      Method

      From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.

      Result

      Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).

      Conclusion

      The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.

      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.

    • +

      MA14.06 - Nintedanib-Docetaxel in 2nd Line Treatment in No Squamous Non-Small Cell Lung Cancer Patients, Refractory to First Line Treatment (GFPC02-15) (Now Available) (ID 558)

      15:45 - 17:15  |  Presenting Author(s): Alain Vergnenegre  |  Author(s): Jean Bernard Auliac, Isabelle Monnet, acya Bizieux, Laurent Greillier, Lionel Falchero, Gilles Robinet, Regien Lamy, Pierre-Alexandre Hauss, Florian Guisier, Hervé Lena, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Second line chemotherapy used in advanced Non Small Cell Lung Cancer (NSCLC) have demonstrated a slight survival benefit in patient refractory to a first line platinum based doublet chemotherapy. In exploratory analysis, Nintedanib in combination with docetaxel have shown interesting result in second line setting for refractory NSCLC patients.

      Objective: To assess the efficacy in terms of progression-free survival (PFS) of the nintedanib - docetaxel combination in second-line treatment in refractory no squamous NSCLC (NsqNSCL) patients

      Method

      This prospective, multicentric open-label phase II trial, included patients with advanced Nsq NSCLC (EGFR, ALK wild-type), PS 0-1, progressing during the first four cycles of cisplatin-based induction chemotherapy. Patients received Nintedanib (200 mg X2 /d d2-d20)- Docetaxel (75 mg/m2 d1-d21) combination until progressive disease or unacceptable toxicity.

      The primary endpoint was the PFS rate at 12 weeks. Secondary endpoints included median PFS, median overall survival (OS), overall response rate (ORR) and tolerability. Based on a A’Hern’s single-stage phase II design trial (sample size determination is based on exact binomial distribution), the Nintedanib-Docetaxel strategy will be rejected if the primary endpoint was below 22/53 patients at the end of study.

      Result

      The analysis included 53 evaluable patients managed in 21 centers; last patient included at the end of January 2019. Mean age 58.4 years, male 73 %, adenocarcinoma 97.5%, current/former smokers: 42/50 %, PS 0/1: 25%/75%; weight loss >5% : 19%, stage IV: 100% (38% with brain metastasis, median metastasis 2). All patients received for induction chemotherapy, a platin doublet (22% with bevacizumab), number of cycle 1-2/ 3-4: 57%/ 43%.

      Interim analysis reviewed by the independent committee conducted as planned, after the 27 first inclusions concluded that there was no sign of unexpected toxicity (adverse events grade 3-4 :22%, grade 5 :0%) or futility (9 patients meet primary end point on 25 evaluable). The results of the final analysis on the whole population (PFS at 12 weeks (primary end point), median PFS, median OS and toxicity) will be presented at the meeting

      Academic grant from Boehringer Ingelheim

      Conclusion

      Section not applicable

      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.

    • +

      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Presenting Author(s): Roy S. Herbst  |  Author(s): Hendrik Tobias Arkenau, Johanna Bendell, Edward Arrowsmith, Martin Wermke, Andres Soriano, Nicolas Penel, Rafael Santana-Davila, Helge Bischoff, Ian Chau, Bo Chao, David Ferry, Gu Mi, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

      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.

    • +

      MA14.08 - Discussant - MA14.05, MA14.06, MA14.07 (Now Available) (ID 3778)

      15:45 - 17:15  |  Presenting Author(s): Mirjana Rajer

      • 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.

    • +

      MA14.09 - Real-World Survival of Relapsed Compared to De-Novo Stage IV Diagnosis of Advanced Non-Small Cell Lung Cancer (Now Available) (ID 529)

      15:45 - 17:15  |  Presenting Author(s): Katie Kerrigan  |  Author(s): Benjamin Haaland, Blythe Adamson, Shiven Patel, Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      Differences in tumor biology and cancer therapy in early stage lung cancer may affect overall survival (OS) of patients with relapsed stage IV disease compared to others with de-novo stage IV disease. This study aimed to compare real-world survival of these patients.

      Method

      We selected patients with advanced NSCLC diagnosed between 2011 and 2017, who received at least one line of therapy, from the US Flatiron Health electronic health record-derived database. Patient data was collected through June 2018, providing at least 6 months of follow-up.

      OS was defined as time from advanced or metastatic diagnosis to the event of death, censored at last clinic visit or end of oral therapy. The unadjusted OS of patients was estimated using the Kaplan-Meier method. We fit multivariable Cox proportional hazards models to compare the hazard of death between groups.

      Result

      de-novo vs relapsed image final.jpg

      The study included 30,310 patients with median age of 68.8 years, 46.7% female, and 76.8% non-Hispanic white. We observed 22.8% had relapsed and 77.2% were de-novo stage IV. Relapsed patients had median OS of 15.5 months (95% CI: 14.9-16.2). Patients with de-novo stage IV had median overall survival of 12.0 months (95% CI: 11.7-12.2). The force of mortality among relapsed stage IV patients was 24% lower than the rate of death among de-novo stage IV patients (Hazard Ratio [HR]: 0.76; 95% CI 0.73-0.79; p <0.001), adjusting for age, gender, state, histology, smoking, race/ethnicity, and stratifying by year of diagnosis. Sensitivity analyses of an unadjusted model (HR 0.79, p <0.001) and a sub-group analysis of patients with advanced diagnoses in 2016-2017 (HR 0.74, p <0.001) suggested the results were robust.

      Conclusion

      Among patients with stage IV NSCLC that received at least one treatment, those who relapsed had better OS than those who presented with de-novo stage IV disease. These findings have implications for future clinical trial design.

      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.

    • +

      MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)

      15:45 - 17:15  |  Presenting Author(s): Whitney Elizabeth Lewis  |  Author(s): George R Simon, Frank E Mott, Vassiliki A Papadimitrakopoulou, Waree Rinsurongkawong, Jeff Lewis, Jack Lee, Jack Roth, Stephen Swisher, John Victor Heymach, Jianjun Zhang, Vincent Lam

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.

      Method

      We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.

      Result

      Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).

      Conclusion

      Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous 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.

    • +

      MA14.11 - CareTrack: An Application-Based Method of Documentation for Improving Patient Communication in Cancer Care (Now Available) (ID 1933)

      15:45 - 17:15  |  Presenting Author(s): Jawaid Younus  |  Author(s): Jacques Raphael, Phillip Blanchette, Fahad Khan, Vineet Sharma, Morgan Black, Mark Vincent, Sara Kuruvilla, Michael Sanatani

      • Abstract
      • Presentation
      • Slides

      Background

      Patients being able to accurately understand and recall medical information correctly has been shown to improve outcomes, however, most studies suggest that patient information understanding in oncology tends to be poor with as much as 40-80% of information being relayed by healthcare professionals being forgotten (Kessels, 2003).

      Method

      Our study aimed to implement the use of ‘CareTrack’, an easy-to-use iPad application, as a simple yet complete app-based information package that provides an appointment summary sheet with no identifying information for patients to take home. An iPad pre-loaded with the CareTrack application was provided to oncologists and they filled in the form for their patients at the end of the initial consultation for lung cancer. A hard printout copy was provided to the patient to take home and the option of an email copy was sent as well. Approximately one-week later a patient satisfaction questionnaire was administered over the phone to patients who participated in the study.

      Result

      Six oncologists were recruited to the study with 35 patients consented to the study and 25 of these patients completing the follow-up surveys. Our primary objective was to assess feasibility of the CareTrack application. The average physician time to complete the CareTrack form for each patient was 1 minute and 29 seconds thus demonstrating that this is a quick and easy tool for physician use. Our secondary objective was to assess patient satisfaction with a brief survey. Ninety-six percent (24/25) of patients found the CareTrack information provided useful and 100% (25/25) of patients found the information easy to understand. Most patients did not require frequent review of the CareTrack form (28%, 7/25) nor needed the form to remember the information (56%, 14/25) or when discussing diagnosis/stage/treatment at home (44%, 11/25). Importantly, 96% (24/25) of patients were comfortable seeing their cancer information and treatment plan displayed on the CareTrack tool and 84% (21/25) of patients would like to receive additional CareTrack information in the future if their staging and/or treatment planned is changed/updated.

      Conclusion

      To conclude, the CareTrack application was found to be easy to use and was able to effectively provide new lung cancer patients with a comprehensive yet easy-to-understand summary of their initial consult. In the future, we envision this project expanding province- and nation-wide as well as expanding to other disease sites (e.g. breast, colorectal etc.).

      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.

    • +

      MA14.12 - Discussant - MA14.09, MA14.10, MA14.11 (Now Available) (ID 3779)

      15:45 - 17:15  |  Presenting Author(s): Virginie Westeel

      • 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

  • +

    ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      ES06.04 - The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt (Now Available) (ID 3184)

      13:30 - 15:00  |  Presenting Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Best Treatment Sequence for Advanced NSCLC EGFR/ALK/ROS/BRAF wt

      Jürgen Wolf

      Most current guidelines recommend molecular testing of activating alterations in EGFR, ALK, ROS1 and BRAF before first line treatment decision in advanced NSCLC. These recommendations mostly are based on the approval status of the respective targeted therapies. For the remaining patients combinations of immunecheckpoint inhibitor (ICI) therapy and platinum-based chemotherapy (CT) has become standard for patients with a PD-L1 tumor proportion score (TPS) of below 50% and may also be used for patients with a higher score in case of aggressive tumor growth and good performance score (PS). Patients with a TPS of 50% and more may be treated with ICI alone. Tumor mutational burden (TMB) is currently evaluated as new predictive marker for either ICI mono- or combination therapy, the definitive value of this approach in first or second line so far, however, is still unclear.

      If these (EGFR-, ALK-, ROS1-, BRAF wildtype) patients relapse after ICI monotherapy, platinum-based CT, eventually with the addition of bevacizumab, widely is considered standard treatment. By comparison, for patients with relapse after ICI/CT combination systemic treatment options are quite unsatisfying. Docetaxel monotherapy has only marginal efficacy which may be modestly increased by the addition of antiangiogenic agents. Numerous immunotherapeutic approaches are evaluated In this situation (next generation ICIs and other immunomodulatory drugs), preferably in combinations. However, so far, no convincing results have been reported from these clinical trials.

      It is therefore particularly important to identify from these patients the subgroup with a possible benefit from driver-mutation directed treatments – either within a clinical trial or a compassionate use program or as off-label treatment. Numerous such approaches are in clinical evaluation. Examples are kinase inhibitors against RET-fusions, TRK-fusions, MET exon 14 skipping mutations, MET amplification, HER2 mutations, EGFR-/HER2 exon 20 mutations, NRG-1 fusions. High response rates and clinical significant duration of responses have already been reported for many of these personalized treatment options, some of them are already in accelerated approval procedures. Many of them will forge ahead towards first line treatment in particulary, since ICI therapy partly seems not to work well here.

      Until the approval of these new treatment options it is of particular importance to test patients at the latest upon failure of ICI with or without chemotherapy on the presence of driver mutations in their tumors and to try hard to bring them into a clinical trial or to enable off-label treatment.

      Given the dynamics in the field, this treatment algorithm will change in the near future not only by the approval of several of these new driver-mutation directed treatments, but also by the development of more effective and more tailored immunotherapies as well as by the availability of potent KRAS inhibitors.

      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.

  • +

    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • +

      MA09.04 - Discussant - MA09.01, MA09.02, MA09.03 (Now Available) (ID 3747)

      15:15 - 16:45  |  Presenting Author(s): Juergen Wolf

      • 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.

  • +

    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

      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.

  • +

    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

      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.

  • +

    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • +

      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Presenting Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

      table.jpg

      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.

  • +

    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • +

      OA15.05 - BIOLUMA: A Phase II Trial of Nivolumab and Ipilimumab in Lung Cancer – Prospective Evaluation of TMB in SCLC Patients (Now Available) (ID 592)

      14:30 - 16:00  |  Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      As requested by the author, the abstract for this presentation will not be published

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

  • +

    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.16-46 - Genetic Testing Patterns, Treatment Characteristics, and Overall Survival in ALK-Positive Metastatic NSCLC Patients Treated with Ceritinib (ID 1345)

      09:45 - 18:00  |  Author(s): Juergen Wolf

      • Abstract
      • Slides

      Background

      In patients with ALK-positive metastatic non-small cell lung cancer (mNSCLC), the majority of data on ALK inhibitor (ALKi) use and related survival outcomes are from clinical trials; information from community practice is sparse. This study therefore sought to assess ALK testing patterns, treatment characteristics, and overall survival (OS) in patients with mNSCLC treated with ceritinib in routine practice.

      Method

      In this retrospective cohort study, medical records for patients with ALK-positive mNSCLC (diagnosed during 2008-2016; aged ≥18 years) were selected from sites in Canada and Europe. Patients were treated with ceritinib in any line for mNSCLC and had at least 8 months of follow-up after ceritinib initiation, except for patients who died sooner than 8 months. Baseline patient characteristics, treatment patterns, and timing of ALK testing relative to start of therapy lines were descriptively assessed. OS was assessed using Kaplan-Meier methods.

      Result

      87 patients were selected (median age: 53 years). Nearly 56% of patients had been tested for ALK mutation before initiating the first-line therapy (1L); 72% were tested before 2L and 77% before 3L. The most common regimens were cisplatin/pemetrexed (25%) in 1L, crizotinib (28%) in 2L, and ceritinib (35%) in 3L. Over two-thirds (68%) received treatment with at least 2 ALKis. The most commonly observed ALKi sequences were crizotinib followed by ceritinib (52%), ceritinib only (23%), and crizotinib followed by ceritinib followed by alectinib (12%). Median OS (95% CI) from mNSCLC diagnosis was 39 (33.1-50.1) months. Median OS (95% CI) from treatment initiation was 36 (28.2-48.9) months for 1L, 29 (22.1-42.8) months for 2L, and 23 (14.0-40.5) months for 3L.

      Conclusion

      Only slightly more than half of patients with ALK-positive mNSCLC were tested for ALK mutation before initiating the first-line therapy during the study period. ALKis were the preferred therapies in the second and third lines. Median OS following the first-line therapy initiation was nearly 3 years among the selected study 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.