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J. Von Pawel



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    MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI17.07 - Efficacy of Nintedanib/Docetaxel after Bevacizumab, Pemetrexed or Taxanes Therapy (ID 1521)

      16:45 - 18:15  |  Author(s): J. Von Pawel

      • Abstract
      • Presentation
      • Slides

      Background:
      Nintedanib is a triple angiokinase inhibitor of receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor and fibroblast growth factor. The randomized, placebo-controlled, Phase III LUME-Lung 1 study (NCT00805194; 1199.13) investigating nintedanib/docetaxel was the first trial of an antiangiogenic agent to demonstrate significant overall survival (OS) benefit in previously treated patients with non-small cell lung cancer (NSCLC) of adenocarcinoma histology; nintedanib/docetaxel is approved in the European Union for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1[st]-line chemotherapy. Here we report LUME-Lung 1 data from the adenocarcinoma population who received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes.

      Methods:
      In LUME-Lung 1, 1314 patients with Stage IIIB/IV recurrent NSCLC received either nintedanib/docetaxel or placebo/docetaxel. Primary endpoint was centrally assessed progression-free survival (PFS); OS was a key secondary endpoint. Prior treatment with anti-VEGF agent bevacizumab was a stratification factor. Analyses of the adenocarcinoma population (n=658) according to prior treatment with bevacizumab (n=45 in either arm), pemetrexed (1[st]-line [n=126] or maintenance [n=27]) or taxanes (n=142) were performed to determine if 1[st]-line regimens could influence subsequent outcomes for nintedanib/docetaxel.

      Results:
      Patient characteristics were generally well-balanced across prior-treatment subgroups. For the adenocarcinoma population, there was no interaction between 1[st]-line treatment with bevacizumab, pemetrexed or taxanes and treatment outcome with nintedanib/docetaxel. Independent of pretreatment, nintedanib/docetaxel-treated adenocarcinoma patients had an OS benefit (Table). In the overall patient population, efficacy outcomes for these subgroups were also similar regardless of prior treatment. Furthermore, there was no significant effect on nintedanib/docetaxel outcomes for the few adenocarcinoma patients who received maintenance pemetrexed. The adverse event (AE) profile for nintedanib/docetaxel in each subgroup was consistent with that reported for the adenocarcinoma population in LUME-Lung 1, with diarrhea and reversible liver enzyme elevations among the more frequently reported AEs. Among patients who received nintedanib/docetaxel, there was no difference between prior-treatment subgroups in the frequency of AEs commonly associated with the prior treatment, such as hypertension with bevacizumab, mucositis with pemetrexed and peripheral neuropathy with taxanes.

      Conclusion:
      In LUME-Lung 1, regardless of whether a patient with NSCLC of adenocarcinoma histology received 1[st]-line chemotherapy containing bevacizumab, pemetrexed or taxanes, subsequent treatment with nintedanib/docetaxel led to improved OS.

      Table: OS results in patients with NSCLC of adenocarcinoma tumor histology stratified by ± prior 1st-line bevacizumab, pemetrexed or taxanes treatment
      No BEV BEV No PEM PEM No TAX TAX
      N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D N/D Pl/D
      Patients, n 298 315 24 21 261 271 61 65 245 271 77 65
      Median OS, months 12.6 10.6 14.9 8.7 13.4 10.8 12.0 8.0 12.2 10.3 15.1 11.6
      HR (95% CI) 0.85 (0.71–1.01) 0.61 (0.31–1.20) 0.83 (0.68–1.00) 0.79 (0.53–1.18) 0.86 (0.71–1.05) 0.75 (0.51–1.11)
      Interaction p-value p=0.24 p=0.90 p=0.61
      BEV, bevacizumab; CI, confidence interval; HR, hazard ratio; N/D, nintedanib/docetaxel; NSCLC, non-small cell lung cancer; OS, overall survival; PEM, pemetrexed; Pl/D, placebo/docetaxel; TAX, taxanes.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-098 - Addition of Custirsen, a Clusterin Inhibitor, to Docetaxel in Stage IV Non-Small Cell Lung Cancer (NSCLC): The ENSPIRIT™ Phase 3 Trial (ID 2192)

      09:30 - 17:00  |  Author(s): J. Von Pawel

      • Abstract
      • Slides

      Background:
      Treatments that improve overall survival (OS) in advanced NSCLC are urgently needed. Docetaxel (DOC) is recommended as 2[nd]-line chemotherapy for advanced NSCLC, with a median OS of 7-8 months. The chaperone protein clusterin (CLU) is upregulated in NSCLC and other cancers in response to anticancer therapies. Custirsen (OGX-011) is a second-generation antisense oligonucleotide that inhibits CLU expression, enhances chemotherapeutic activity, and in vivo has reversed DOC resistance. In early phase studies in metastatic castration resistant prostate cancer (mCRPC), custirsen plus DOC was well tolerated and showed encouraging results. In a phase 3 mCRPC study (SYNERGY), 50% of patients defined as poor prognosis had survival benefit from custirsen when added to 1[st]-line DOC.

      Methods:
      ENSPIRIT was initiated September 2012. Eligible patients in this phase 3, multinational, open-label trial have failed 1 prior line of platinum (PT)-based therapy, have an ECOG of 0-1, and adequate bone marrow, renal, and liver function. Randomization is 1:1, with stratification by gender, NSCLC histology, best response to 1[st]-line PT therapy (response/stable disease vs progression), and ECOG score. Patients receive 21-day cycles of DOC (75 mg/m[2] IV day 1) or DOC plus custirsen (640 mg IV/wk, preceded by 3 doses during a 9-day loading period) until progressive disease, unacceptable toxicity, or withdrawal. The primary efficacy measure is OS. Two interim analyses are planned for stopping the trial based on inadequate evidence of clinical benefit or futility; the first futility analysis was completed in August 2014. A recent amendment changed the hypothesized hazard ratio for the primary analysis from 0.80 to 0.75 (power remains at 90%), resulting in a required sample size of 700 patients (instead of original 1100). In addition, the second futility has a more rigorous criterion for stopping due to survival futility and is to occur earlier than originally planned. The study will not be stopped early for efficacy. The aim of the ENSPIRIT amendment is to assess for a more clinically relevant survival benefit when adding custirsen to 2[nd]-line DOC or terminate the trial early for survival futility.

      Results:
      Not applicable.

      Conclusion:
      Not applicable.

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