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A. Dowlati



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    MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)

      14:20 - 15:50  |  Author(s): A. Dowlati

      • Abstract
      • Presentation
      • Slides

      Background:
      PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.

      Methods:
      SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.

      Results:
      104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.

      Conclusion:
      The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-046 - Safety, Clinical Activity and Biomarker Results from a Phase Ib Study of Erlotinib plus Atezolizumab in Advanced NSCLC (ID 5215)

      14:30 - 15:45  |  Author(s): A. Dowlati

      • Abstract

      Background:
      Targeted therapy with erlotinib is effective in reducing tumor burden in EGFR-mutant non-small cell lung cancer (NSCLC). However, resistance to therapy develops almost universally. Atezolizumab, an engineered mAb that inhibits binding of PD-L1 to its receptors, PD-1 and B7.1, has demonstrated promising monotherapy activity in NSCLC. Given that atezolizumab may enhance and perpetuate anti-tumor immunity, we hypothesized that combining atezolizumab with erlotinib may improve both clinical response and durability in EGFR-mutant NSCLC.

      Methods:
      This Phase Ib study consisted of a safety-evaluation stage in patients with NSCLC regardless of EGFR status followed by an expansion stage in TKI-naïve patients with tumors harboring activating EGFR mutations. Patients were enrolled regardless of PD-L1 status. After a 7-day run-in with 150mg erlotinib PO QD alone, patients received 150mg erlotinib PO QD and 1200mg atezolizumab IV q3w. To evaluate immune biology, biopsies were obtained in expansion-stage patients pre-treatment, after erlotinib run-in, at weeks 4-6, and at progression. The primary objective was to evaluate the safety and tolerability of the combination. Secondary objectives included evaluation of the clinical activity per RECIST v1.1. Data cutoff, 11 April 2016.

      Results:
      Twenty-eight patients (safety stage, n = 8; expansion stage, n = 20) who received ≥ 1 dose of erlotinib or atezolizumab were considered safety evaluable. Median age was 61y (range, 47-84); median survival follow-up was 11.2mo (range, 0.8-24.2). The incidence of either treatment-related G3-4 AEs was 39% and for serious AEs, 50%. The most common atezolizumab-related G3-4 AEs were pyrexia and increased ALT. No pneumonitis was reported. No treatment-related G5 AEs occurred. Five patients discontinued atezolizumab due to treatment-emergent AEs. No DLTs were observed. In the expansion-stage population, ORR was 75% (95% CI, 51-91). Disease control rate (CR + PR + SD ≥ 24 weeks) was 90% (95% CI, 68-99), median PFS was 11.3mo (95% CI, 8.4-NE) and median DOR was 9.7mo (range, 4.2-11.7). Increases in intratumoral CD8+ T cells post-erlotinib run-in were observed in 8/13 evaluable paired biopsies. Higher intratumoral CD8+ T-cell prevalence and immune gene expression signatures at baseline were associated with improved PFS.

      Conclusion:
      The combination of full dose erlotinib plus atezolizumab demonstrated a manageable safety profile. While response rates and median PFS for combination treatment appear similar to those observed with erlotinib monotherapy, the addition of atezolizumab to erlotinib may lead to more durable clinical responses in some patients. Additional follow-up is required to evaluate the full potential of this combination treatment. NCT02013219