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N. Thatcher



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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA23.02 - Efficacy and Safety of Necitumumab Continuation Monotherapy in Patients with EGFR-Expressing Tumors in SQUIRE, a Phase 3 Study (ID 4283)

      14:30 - 14:40  |  Author(s): N. Thatcher

      • Abstract
      • Presentation
      • Slides

      Background:
      SQUIRE (NCT00981058) demonstrated adding necitumumab (N) to gemcitabine/cisplatin (GC) improved survival in patients with Stage IV squamous NSCLC (SQ-NSCLC). Retrospective analysis revealed consistent treatment effect in favor of patients receiving N monotherapy as continuation after chemotherapy (CT) (GC+N continuation patients) versus continuation therapy-eligible GC arm patients (GC non-progressors). In the EU, N is approved for patients with EGFR-expressing tumors. We repeated the analysis in this patient population.

      Methods:
      Patients with Stage IV SQ-NSCLC were randomized 1:1 for ≤6 cycles of G (1250 mg/m[2] iv, Days [d] 1,8) and C (75 mg/m[2] iv, d1) either with or without N (800 mg iv, d1,8). Patients in GC+N without progression continued N until progressive disease (PD). SQUIRE included mandatory tissue collection. EGFR protein expression was assessed by IHC in a central lab (Dako EGFR PharmDx kit). Analyses were done in EGFR-expressing patients (EGFR >0). Patients who received ≥4 cycles of CT without PD were included. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier method. 95% CIs and hazard ratios estimated using stratified Cox proportional hazards model.

      Results:
      Of 1093 patients (ITT population), 982 patients (89.8%) had evaluable IHC assay results; 935/982 (95.2%) had EGFR>0. GC+N arm continuation therapy patients included 228 patients with EGFR>0 and 194 patients (EGFR>0) were GC arm non-progressors. Baseline characteristics were similar except gender (Males: 81% in GC+N vs 91% in GC arm). CT exposure was balanced. Median OS from randomization in GC+N vs GC was 16.1 vs 14.9 months; HR 0.76 (95% CI, 0.61, 0.95). Median PFS in GC+N vs GC was 7.4 vs 6.9 months; HR 0.81 (95% CI, 0.66, 1.00). Figure 1



      Conclusion:
      In patients with EGFR-expressing tumors, a consistent treatment effect in favor of GC+N continuation maintenance compared to GC non-progressors was observed, similar to ITT population with no unexpected increases in AEs.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03a-025 - Randomized, Double-Blind, Phase 3 Study Comparing Biosimilar Candidate ABP 215 with Bevacizumab in Patients with Non-Squamous NSCLC (ID 6068)

      14:30 - 14:30  |  Author(s): N. Thatcher

      • Abstract

      Background:
      ABP 215 is a biosimilar candidate that is similar to bevacizumab, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic similarity between ABP 215 and bevacizumab has been demonstrated in a phase 1 study. Here we present results from a pivotal phase 3 clinical study in non–small-cell lung cancer (NSCLC).

      Methods:
      In this double-blind, active-controlled study in adults with non-squamous NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel, subjects were randomized (1:1) to receive investigational product (IP; ABP 215 or bevacizumab 15 mg/kg) Q3W for 6 cycles as an IV infusion. Clinical equivalence was demonstrated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) of the objective response rate (ORR; primary endpoint) with pre-specified margin of (0.67, 1.5) Secondary endpoints were risk difference (RD) of the ORR, duration of response (DOR), progression-free survival (PFS), treatment-emergent adverse events, and overall survival (OS).

      Results:
      A total of 642 subjects (ABP 215 [Arm 1], n=328; bevacizumab [Arm 2], n=314) were randomized. Demographic and baseline characteristics were balanced between arms. There were 128 (39.0%) responders in Arm 1 and 131 (41.7%) responders in Arm 2. The RR for ORR was 0.93 (90%CI, 0.80–1.09). The RD for ORR was −2.90% (90%CI, −9.26%–3.45%). Among the responders the estimated median DOR was 5.8 months in Arm 1 versus 5.6 months in Arm 2. The estimated median PFS in Arm 1 was 6.6 months versus 7.9 months in Arm 2; the analysis included all 256 PFS events, 131 (39.9%) in Arm 1 and 125 (39.8%) in Arm 2. The safety population included 324 treated subjects in Arm 1 and 309 in Arm 2; 139 (42.9%) subjects in Arm 1 and 137 (44.3%) in Arm 2 experienced grade ≥3 TEAEs. TEAEs leading to IP discontinuation affected 61 (18.8%) subjects in Arm 1 and 53 (17.2%) in Arm 2; 85 (26.2%) subjects in Arm 1 and 71 (23.0%) in Arm 2 experienced at least one serious AE; 13 (4.0%) in Arm 1 and 11 (3.6%) in Arm 2 had a fatal TEAE. OS analysis included 79 deaths, 43 (13.3%) in Arm 1 and 36 (11.7%) in Arm 2. Binding antibodies developed during the study in 4 (1.4%) subjects in Arm 1 versus 7 (2.5%) in Arm 2; no subject tested positive for neutralizing antibodies.

      Conclusion:
      The study met the primary and secondary objectives demonstrating that ABP 215 and bevacizumab are clinically equivalent.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03b-035 - EGFR FISH as Potential Predictor of Necitumumab Benefit with Chemotherapy in Squamous NSCLC: Subgroup Analyses from SQUIRE (ID 5708)

      14:30 - 14:30  |  Author(s): N. Thatcher

      • Abstract

      Background:
      Necitumumab (Neci) is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). In the SQUIRE trial (NCT00981058), the addition of Neci to gemcitabine plus cisplatin (Gem-Cis) in squamous cell lung cancer resulted in a significant advantage in terms of overall survival (OS), but the expression of EGFR assessed by immunohistochemistry was not able to robustly predict the benefit from Neci. In a post-hoc analysis of SQUIRE, EGFR gene copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of Neci. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy (HP) vs gene amplification (GA) as both were included in the “FISH-positive” category.

      Methods:
      Suitable specimens from SQUIRE patients underwent FISH analysis. Probe hybridization was performed in a central laboratory and each sample was analyzed using the Colorado EGFR scoring criteria. FISH was considered positive in cases of HP (≥40% cells with ≥4 EGFR copies) or GA (EGFR/CEP7 ≥2 or ≥10% cells with ≥15 EGFR copies). The correlation of granular FISH parameters with clinical outcomes was assessed.

      Results:
      FISH analysis was available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with HP and 41 (7.4%) with GA. The outcome data for HP and GA are reported below:

      HIGH POLYSOMY GENE AMPLIFICATION
      Neci+Gem-Cis (N=89) Gem-Cis (N=78) Neci+Gem-Cis (N=22) Gem-Cis (N=19)
      Median OS in months (95% CI) 12.58 (11.04-16.00) 9.53 (7.16-12.48) 14.78 (10.02-31.51) 7.62 (4.99-16.10)
      Hazard ratio within subgroup (interaction model) 0.77 (0.55-1.08) p = 0.133 0.45 (0.21-0.93) p = 0.033
      Interaction p value 0.189
      Median PFS in months(95% CI) 6.08 (5.59-7.59) 5.13 (4.24-5.72) 7.36 (4.27-11.40) 5.55 (2.79-8.34)
      Hazard ratio within subgroup (interaction model) 0.70 (0.50-0.99) p = 0.044 0.69 (0.33-1.45) p = 0.334
      Interaction p value 0.980


      Conclusion:
      The OS benefit from the addition of Neci to Gem-Cis appeared to be more pronounced in the small subset of patients with GA when compared to HP, but the same trend was not observed for PFS. The potential predictive value of different EGFR FISH parameters should be evaluated in future studies.