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H. West



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    MINI 08 - Prognostic/Predictive Biomarkers (ID 106)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)

      H. West

      • Abstract
      • Presentation
      • Slides

      Background:
      VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.

      Methods:
      Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).

      Results:
      Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).

      Conclusion:
      VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.

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    MTE 03 - Squamous Cell Lung Cancer (Ticketed Session) (ID 55)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 AM - 08:00 AM, 107
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      MTE03.01 - Squamous Cell Lung Cancer (ID 1982)

      H. West

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In recent years, we have seen a new practical distinction made in terms of management recommendations for the histologic subtypes of non-small cell lung cancer (NSCLC). There is now a growing recognition of the biological relevance of the differences between major histologic subtypes, as clinical trials and distinct management algorithms emerge for the advanced squamous (SQ) NSCLC population. Though differences in the clinical behavior of SQ vs. non-squamous (NSQ) NSCLC have been recognized for decades (1), the first functional distinction emerged with the recognition of different results for SQ and NSQ populations in multiple trials of pemetrexed that together demonstrated that the efficacy of this agent was limited to patients with NSQ histology (2), ultimately leading to a change in the label of pemetrexed, previously approved for all NSCLC patients as second line therapy, to being indicated for NSQ patients only (3). Development of the anti-angiogenic agent bevacizumab was also limited to patients with NSQ histology after a post-hoc analysis of results in a phase II trial of carboplatin/paclitaxel with either of two dose levels of bevacizumab or placebo demonstrated a high risk of life-threatening or fatal pulmonary hemorrhage among patients with SQ histology (4). Subsequent development and clinical use of bevaicizumab in advanced NSCLC has been limited to NSQ histology. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are another class of anticancer therapy that are more effective in NSQ than SQ NSCLC (5). Though patients with SQ NSCLC were included in early, pivotal trials in molecularly unselected populations that revealed a modest overall survival (OS) benefit with erlotinib, molecular selection of patients with an activating EGFR mutation has shown that high response rates (RR) and prolonged benefit with EGFR TKIs is overwhelmingly in patients with an activating EGFR mutation, so rare in SQ NSCLC that routine testing for it is not recommended. ALK and ROS-1 rearrangements are similarly rare in SQ NSCLC, with routine for these markers in SQ NSCLC not recommended. Patients with SQ NSCLC remain candidates for erlotinib in the maintenance or salvage setting, in which its value is so modest as to be debatable. SQ NSCLC patients are presumed to be ALK and ROS-1 wild type and rarely candidates for therapies against these targets. Until very recently, therefore, SQ NSCLC has been characterized by the NSCLC treatments that are considered ineffective, prohibitively toxic, or of relatively marginal benefit. Several new management options, however, have emerged that are more directed to the SQ NSCLC population. Though the randomized phase III trial that let to approval of nab-paclitaxel in advanced NSCLC (6) was not specifically directed to patients with SQ NSCLC, the trial of carboplatin with either paclitaxel or nab-paclitaxel demonstrated a higher response rate in the nab-paclitaxel arm of 41% vs. 24% in favor of nab-paclitaxel. In the absence of other therapies that have shown enhanced efficacy in SQ NSCLC, nab-paclitaxel has an arguable role as first line therapy for SQ NSCLC, though there are no confirmatory trials or biomarker correlates to corroborate a special utility for nab-paclitaxel here. Another chemotherapy-based approach directed to SQ NSCLC is nedaplatin, a second generation platinum compound tested in a Japanese trial of 350 patients with chemotherapy-naïve advanced SQ NSCLC in which subjects were randomized to cisplatin/docetaxel or nedaplatin/docetaxel (docetaxel on each arm administered at the standard Japanese dose of 60 mg/m2 d1 every 21 days) (7). Median OS was >2 months longer with nedaplatin (13.6 vs. 11.4 months, HR 0.81, p = 0.037), and toxicity was relatively comparable between the two arms. Nedaplatin/docetaxel combination may now be considered a new standard treatment for advanced SQ NSCLC in Japan, but the non-standard dosing of docetaxel for global populations and the recognition of potential differences in efficacy of regimens among different racial populations will likely limit broader use of nedaplatin until studies outside of Japan confirm superior efficacy. The SQUIRE trial of the monoclonal antibody against EGFR necitumumab trial in 1093 first line SQ NSCLC patients showed a modest OS benefit when this agent was added to cisplatin/gemcitabine, compared with chemotherapy alone (8). In absolute terms, however, the median OS benefit of only 1.6 months (11.5 vs. 9.9 months), counterbalanced by greater toxicities and costs with the addition of necitumumab, has led to little enthusiasm for favoring the broader incorporation of this agent. Afatinib has been studied in the LUX-Lung-8 trial as an alternative to erlotinib in previously treated patients with SQ NSCLC (9). While the 1.1 month OS benefit and HR 0.81 with afatanib reflect only marginal superiority to erlotinib, afatanib is now arguably the EGFR TKI of choice in this setting, pending FDA approval. However, with the value of erlotinib for SQ NSCLC considered so debatable in this setting, this may be interpreted as damning with faint praise. By far the greatest excitement for patients with advanced SQ NSCLC stemps from immune checkpoint inhibitor therapy, starting with the programmed cell death protein 1 (PD-1) inhibitor nivolumab, which was compared in the randomized Checkmate 017 trial to docetaxel as second line therapy in 272 chemotherapy-pretreated patients with advanced SQ NSCLC (10). Demonstrating a far superior median OS of 9.2 vs. 6.0 months, HR 0.59 (p = 000025), a median duration of response not yet reached, and a far more favorable tolerability than docetaxel, nivolumab is now the clear, FDA-approved second line standard of care for SQ NSCLC. This trial also demonstrated no correlation of efficacy with nivolumab as a function of tumor expression of programmed death protein ligand-1 (PD-L1), supporting its use in an unselected SQ NSCLC population. As genomic testing becomes more readily available and incorporated into clinical practice, molecular markers relevant for patients with SQ NSCLC are likely to provide new targeted therapy opportunities to accompany those of immunotherapies and conventional chemotherapy for this large population still greatly needing new advances. References 1) Hirsch, JTO 2008 2) Scagliotti, JTO 2011 3) Cohen, Oncologist 2010 4) Johnson, JCO 2004 5) Shepherd, NEJM 2005 6) Socinski, JCO 2012 7) Shukuya, Proc ASCO 2015, A#8004 8) Thatcher, Lancet Oncol 2015 9) Soria, Proc ASCO 2015, A#8002 10) Brahmer, NEJM 2015

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    ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)

      H. West

      • Abstract
      • Presentation
      • Slides

      Background:
      Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.

      Methods:
      Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.

      Results:
      Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1



      Conclusion:
      CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.

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    ORAL 03 - New Kinase Targets (ID 89)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL03.04 - Discussant for ORAL03.01, ORAL03.02, ORAL03.03 (ID 3292)

      H. West

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 33 - ALK (ID 145)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)

      H. West

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).

      Methods:
      North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.

      Results:
      At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1



      Conclusion:
      Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-084 - A Phase 2 Study of TH-4000 in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI (ID 2209)

      H. West

      • Abstract
      • Slides

      Background:
      While EGFR-TKI therapy is initially effective for patients with EGFR-mutant NSCLC, eventual resistance to EFGR-TKI therapy is expected. For patients with non‑T790M resistance to EGFR-TKIs, the optimal treatment is unclear. Sensitizing mutations in EGFR are often heterozygous with co-expression of both wild type (WT) and mutant EGFR. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that EGFR-mutant NSCLC with WT EGFR present is associated with a poorer response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of EGFR-TKI resistance. TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, mutant EGFR and HER2. Hypoxic tumor targeting using TH-4000 may allow a greater therapeutic index with greater intratumoral TKI levels and less dose-limiting systemic toxicity seen with current EGFR-TKIs. In xenograft models of EGFR-mutant NSCLC that co‑express WT EGFR, TH-4000 reverses resistance to current EGFR-TKIs, and is effective as a single‑agent. A Phase 1 study was conducted in patients with advanced solid tumors; the maximum tolerated dose (MTD) of TH-4000 administered as a 1-hour weekly intravenous (IV) infusion was established at 150 mg/m[2]. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue.

      Methods:
      A multicenter Phase 2 trial was initiated to evaluate the safety and activity of TH-4000 as a single‑agent in patients with EGFR‑mutant, T790M-negative Stage IV NSCLC progressing on an EGFR TKI. Hypoxia PET imaging with [18F]-HX4 and molecular analyses of tumor tissue and plasma are incorporated in the study design to identify potential predictors of response to treatment. The primary endpoint is response rate. Secondary endpoints include progression-free survival, duration of response, overall survival, pharmacokinetics and safety, as well as evaluation of imaging, serum, and tissue biomarkers that may be associated with tumor response. Up to 37 patients will be enrolled with recurrent EGFR-mutant Stage IV NSCLC which has progressed while on treatment with EGFR-TKI, absence of EGFR T790M mutation, measureable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients must also have adequate pre-therapy tumor tissue available to enable tumor biomarker assessment. TH-4000 (150 mg/m[2]) is administered weekly by IV infusion over 60 minutes. The study design incorporates a Simon two-stage design (alpha = 0.10; beta = 0.10). Recruitment is ongoing.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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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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      P2.01-099 - nab-Paclitaxel as Maintenance Therapy in Patients with Squamous Cell NSCLC (ABOUND.sqm) (ID 3122)

      H. West

      • Abstract
      • Slides

      Background:
      Patients with squamous cell (SCC) non-small cell lung cancer (NSCLC) may be at risk of poorer outcomes and have fewer treatment options than those with other histologies. Furthermore, no randomized studies have demonstrated the benefit of maintenance therapy in these patients. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) demonstrated a 68% improvement in the overall response rate (ORR; 41% vs 24%; P < 0.001) and a trend toward improved overall survival (OS; median, 10.7 vs 9.5 months; HR 0.890; P = 0.310) compared with solvent-based paclitaxel plus C in a subset of patients with advanced SCC NSCLC (Socinski et al. Ann Oncol. 2013;24:2390-2396). An exploratory analysis of the phase III trial demonstrated that therapy with nab-P/C beyond 4 cycles of first-line treatment was effective in the subset of patients with SCC NSCLC who did not progress (from the time of randomization, median progression-free survival [PFS] and OS were 6.8 and 13.8 months, respectively), and no new safety signals were noted (Socinski et al. IASLC 2013 [abstract 3438]). In the open-label, multicenter phase III ABOUND.sqm trial, the efficacy and safety of nab-P maintenance therapy after nab-P/C induction therapy will be evaluated in patients with advanced SCC NSCLC.

      Methods:
      During the induction part of the study, approximately 540 patients will be treated with 4 cycles of nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus IV C AUC 6 on day 1 every 21 days. Patients with a complete response (CR), a partial response (PR), or stable disease (SD) will be eligible for maintenance. In the maintenance part of the study, approximately 260 patients will be randomized 2:1 to nab-P 100 mg/m[2] on days 1 and 8 every 21 days plus best supportive care (BSC) or BSC alone until disease progression. Patients will be stratified by disease stage (IIIB vs IV), response to induction therapy (CR/PR vs SD), and ECOG performance status at the end of induction (0 vs 1). Key eligibility criteria include histologically or cytologically confirmed stage IIIB/IV SCC NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and preexisting peripheral neuropathy grade < 2. ClinicalTrials.gov identifier NCT02027428.

      Key Endpoints
      Primary PFS from randomization into the maintenance part of the study
      Secondary Safety OS from randomization into the maintenance part of the study ORR during the induction and maintenance parts of the study
      Exploratory Correlation between pretreatment tumor characteristics and response to treatment Association between changes in tumor characteristics and acquisition of resistance to therapy at the time of treatment failure during maintenance Correlation between genetic polymorphisms and treatment efficacy and/or toxicity Healthcare resource utilization during the maintenance part of the study Changes in quality of life


      Results:
      Not applicable.

      Conclusion:
      Not applicable.

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