Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

H. Burris



Author of

  • +

    O15 - NSCLC - Chemotherapy II (ID 109)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      O15.06 - Randomized Phase III Trial of Gemcitabine (G)/Carboplatin (C) with or without Iniparib (I) in Patients (Pts) with Previously Untreated Stage IV Squamous Lung Cancer (ID 3322)

      11:25 - 11:35  |  Author(s): H. Burris

      • Abstract
      • Presentation
      • Slides

      Background
      Iniparib is an agent originally thought to function as an inhibitor of the DNA repair enzyme PARP-1, which is overexpressed in squamous lung cancers. Promising phase II activity and safety were reported with iniparib in combination with GC in pts with metastatic triple-negative breast cancer (O’Shaughnessy, NEJM 2011); however, subsequent phase III data were negative. Further study of iniparib’s mechanism of action suggests that this agent induces DNA damage, cell cycle arrest in the G2/M phase, and potentiates DNA-damaging chemotherapies not through PARP inhibition. Herein we report the final results from an international Phase III trial (NCT01082549) of first-line chemotherapy and iniparib in pts with advanced squamous lung cancer.

      Methods
      Pts were randomized 1:1 to GC or GCI. All pts received G 1000 mg/m[2] IV days (D) 1 and 8, and C AUC=5 IV D1 of each 21-D cycle. Iniparib was dosed 5.6 mg/kg IV D 1, 4, 8, and 11. All pts were assessed for response per RECIST 1.1 every 6 weeks. Pts without evidence of progressive disease (PD) or other reason for discontinuation could remain on treatment beyond 6 cycles. Accrual of 780 pts provides 89% power to detect an improvement in survival from 8 months (mos) anticipated with GC to 10.7 mos with GCI (HR of 0.75). Eligibility: Pts with newly diagnosed stage IV (M1a and M1b) squamous lung cancer, ECOG PS 0-1. Exclusion criteria included: history of recent cardiac disease, untreated brain metastases, and treatment for early-stage lung cancer within 12 months of study entry. The primary endpoint was overall survival (OS). Interim analyses for safety and futility were performed by an independent data safety monitoring board.

      Results
      780 pts were enrolled and randomized (GC, 390), (GCI, 390) from March 2010 to May 2012. Baseline characteristics were well balanced between groups (GC/GCI): median age 66 years (21-86); 74%/73% male; 30%/33% ECOG 0; 28%/33% current smokers; 66%/62% past smokers. The median number of cycles for GC/GCI were 4 (1-26)/5 (1-32). Dose reductions, dose intensity, and discontinuations due to tumor progression or adverse events were similar in both arms. The median OS for GC/GCI was 8.9 v. 8.9 months, HR 1.08 (0.92-1.28), p=.348. 1-year OS was 41 v. 40%. The median progression-free survival (PFS) for GC vs GCI was 4.9 v. 4.8 months, HR 0.99 (0.83-1.19), p=.92. The objective response rate (ORR) for GC v GCI was 34 v. 32%, p=.648. The safety profile was similar in both arms; anemia (28/26%), neutropenia (31/35%), thrombocytopenia (27/28%), and fatigue (6/9%).

      Conclusion
      The addition of iniparib did not improve the efficacy of GC in the treatment of pts with advanced squamous lung cancer. Further development of iniparib in squamous lung cancer is not recommended.

      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.

  • +

    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
    • +

      P1.18-020 - Molecular Alterations in Advanced Lung Cancer: Genomic Sequencing in a Community Profiling Program of the Sarah Cannon Research Institute (SCRI) (ID 3357)

      09:30 - 09:30  |  Author(s): H. Burris

      • Abstract

      Background
      In October 2012, SCRI launched a genomic sequencing program at a single community clinical research center in middle Tennessee to explore molecular alterations with proven or potential therapeutic significance for patients (pts) with advanced solid and hematologic tumors. Herein we report the findings from the lung cancer cohort tested to date.

      Methods
      Biospecimens from pts with advanced lung cancer (ECOG ≤ 2) who consented to molecular profiling were tested by Next-Generation Sequencing (NGS) with 1000X average coverage in a CLIA/CAP-certified laboratory. Oncogenic hotspot mutations in 35 genes were tested (copy number variation and translocation were not tested). Results were reported to the treating physician within 12 days of receipt of suitable tissue, and were used to inform treatment decisions. Molecular profiling results were stored in a database to enable correlation with clinical outcomes.

      Results
      As of May 31 2013, a total of 594 tumor samples were profiled, 143 (24%) of which were from pts with lung cancer. 23% (33/143) of the lung samples were inadequate for assay. Of the 110 lung samples with sufficient tissue, 47 (43%) were found to have at least 1 identifiable mutation: 30 (27%) single mutations and 17 (16%) multiple mutations. The mutation frequency by histology was adenocarcinoma 63% (34/54 pts), squamous 19% (4/21 pts), large cell 67% (4/6 pts), and small-cell 8% (1/13 pts). The most frequent mutations from this 35-gene panel were KRAS and EGFR (18% and 14%, respectively). Other genetic alterations identified included STK11 6%, MET 5%, RUNX1 4%, FGFR3 3%, BRAF 2%, MEK1 2%, PIK3CA 2%, WT1 1%, SMO 1%, KIT 1%, GNAS 1% and FGFR4 1%.

      Breakdown of KRAS and EGFR Mutations
      Gene Codons Tested Mutation Codons Detected Number of Mutations % of Detected Mutations
      KRAS 12, 13, 61, 146 12 19 95%
      61 1 5%
      EGFR 709-719, exon 19 deletion, 768-790, exon 20 insertion, 833, 858-861 769 2 13%
      796 1 7%
      833 1 7%
      852 1 7%
      858 3 20%
      Deletion 7 40%
      Insertion 1 7%

      Conclusion
      This program confirms the feasibility of molecular profiling in the community setting to assist medical oncologists in treatment decisions for pts with lung cancer, including enrollment in clinical trials.

  • +

    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P2.11-005 - Randomized Phase II Study of Pemetrexed v. Pemetrexed/Bevacizumab v. Carboplatin/Pemetrexed/Bevacizumab in Patients with Previously Untreated Advanced Non-Squamous Non-Small-Cell Lung Cancer and Poor Performance Status (ID 894)

      09:30 - 09:30  |  Author(s): H. Burris

      • Abstract

      Background
      Pemetrexed (Pem) and bevacizumab (Bev) have each been shown to improve survival in patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC) (Scagliotti JCO 2008, Sandler NEJM 2006). Recent evidence suggests these agents can be safely combined and given with carboplatin (Cb) in the first-line setting with encouraging activity (Patel, ASTRO 2012). However, the efficacy and safety of these agents in pts with poor performance status (PS) are unknown. Herein, we report a prospective randomized phase II study of first-line pem v. pem/bev v. cb/pem/bev in pts with advanced NSCLC and poor PS.

      Methods
      Key eligibility included: pts with newly diagnosed advanced non-squamous NSCLC (IIIB or IV), an Eastern Cooperative Oncology Group (ECOG) PS of 2, and measurable disease per RECIST v.1.1. Pts were randomized 1:1:1 to receive either Pem 500mg/m[2] IV (Arm 1), Pem 500mg/m[2] IV and Bev 15mg/kg IV (Arm 2), or Pem 500mg/m[2] IV, Bev 15mg/kg IV, and Cb AUC=5 IV (Arm 3). Cycles were 21 days, with reimaging every 2 cycles. Pts on Arm 3 received a maximum of 4 cycles (12 weeks) of Cb. All pts continued Pem or Pem/Bev until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.

      Results
      Between June 2009 and May 2013, 155 pts were randomized. Summary demographic data are available for 142 pts (median age: 72 years, adenocarcinoma, 80%, males, 59%) in Arms 1, 2, and 3; 97%, 98%, and 88% of pts were current or former smokers, respectively. The most common treatment-related grade 3/4 toxicities are presented below. ORRs for Arms 1, 2, and 3 were 15%, 24%, and 40%, respectively. While modest efficacy was observed in Arm 1, recent data (Lilenbaum, et al. 2012) suggesting a significant OS advantage in pts receiving Pem in combination with Cb vs. Pem alone led to closure of this arm in early 2013. A subset analysis examining pts older or younger than 70 years found that the younger population treated on Arm 1 had inferior ORRs to older pts treated on Arm 3 (7% v. 26%, respectively).

      Grade 3/4 Toxicity Arm 1 (N=48) Arm 2 (N=49) Arm 3 (N=45)
      Hematologic
      Hemoglobin 5 (10%) 1 (2%) 5 (11%)
      Leukocytes 0 1 (2%) 4 (9%)
      Neutrophils 3 (6%) 4 (8%) 8 (18%)
      Platelets 0 2 (4%) 10 (22%)
      Non-hematologic
      Anorexia 1 (2%) 0 0
      Cardiac ischemia/infarction 0 1 (2%) 0
      CNS ischemia 0 1 (2%) 1 (2%)
      Deep vein thrombosis 0 1 (2%) 1 (2%)
      Dehydration 2 (4%) 2 (4%) 0
      Diarrhea 0 2 (4%) 1 (2%)
      Dyspnea 0 2 (4%) 2 (4%)
      Fatigue 10 (21%) 9 (18%) 9 (20%)
      Epistaxis 0 1 (2%) 0
      Hypertension 0 2 (4%) 2 (4%)
      Muscle weakness 4 (8%) 3 (6%) 4 (9%)
      Nausea 0 0 2 (4%)
      Proteinuria 0 0 1 (2%)
      Pulmonary embolism 1 (2%) 1 (2%) 2 (4%)
      Vomiting 0 2 (4%) 1 (2%)

      Conclusion
      This is the largest prospective trial of bevacizumab in poor PS pts with advanced NSCLC. All three regimens were safe and well-tolerated. ORRs with Pem/Bev +/- Cb were encouraging and comparable to historical outcomes in patients with better PS. PFS and OS data will be presented.

  • +

    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P3.11-014 - Safety, pharmacokinetics, and activity of the anti-NaPi2b antibody-drug conjugate DNIB0600A: A Phase I study in patients with non-small cell lung cancer and platinum-resistant ovarian cancer (ID 1477)

      09:30 - 09:30  |  Author(s): H. Burris

      • Abstract

      Background
      NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter highly expressed in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). DNIB0600A is an antibody-drug conjugate consisting of a humanized anti-NaPi2b IgG1 monoclonal antibody and the anti-mitotic agent MMAE.

      Methods
      This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to patients (pts) with non-squamous NSCLC or platinum-resistant, non-mucinous OC. A traditional 3+3 design was used for dose escalation followed by expansions in NSCLC and OC at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue by immunohistochemistry (IHC). Anti-tumor activity was evaluated per RECIST 1.1.

      Results
      As of 1 May 2013, 65 pts have enrolled (35 NSCLC; 30 OC), median age 62 (range 39-85), PS 0-1, median number of prior regimens 2 (1-8) in NSCLC pts, and 5 (1-12) in OC pts. Pts received a median of 4 (range 1-25) doses of DNIB0600A. One pt experienced a DLT (Grade 3 dyspnea) at 1.8 mg/kg; however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Two patients had Grade 1 and 2 infusion-related reactions. The most common related AEs (all grades) were fatigue (55%), nausea (35%), peripheral neuropathy (32%), decreased appetite (29%), vomiting (25%), alopecia (20%), and diarrhea, dysgeusia, headache, and pain (each 15%). The majority of these AEs were Grade 1 and Grade 2. Two patients had serious AEs (SAE) which led to discontinuation (dyspnea; dehydration and hyperglycemia). Four other related SAEs (nausea, upper respiratory tract infection, abdominal pain, and headache) were noted in 2 pts. Preliminary PK results support a q3w dosing regimen with no accumulation observed. Expansion at 2.4 mg/kg was selected based on cumulative safety data and a benefit/risk assessment performed at time of expansion. Exposures of analytes monitored were dose-proportional over all dose levels, and no PK difference was observed between NSCLC or OC pts. Approximately 60% of NSCLC and 90% of OC pts expressed high levels (IHC 2+/3+) of NaPi2b. Anti-tumor activity with DNIB0600A was associated with tumor NaPi2b expression for both NSCLC and OC. Of the 40 pts with NaPi2b IHC Score of 2+ or 3+, treated at dose levels 1.8-2.8 mg/kg, 10 pts had a confirmed partial response (PR); 2 of 18 NSCLC and 8 of 22 OC pts, respectively. Additionally, 3 NSCLC and 3 OC pts have unconfirmed PRs. No pt was enrolled with NaPi2b IHC Score of 1+; no pt responded among the 13 pts with NaPi2b IHC Score of 0, treated at dose levels 1.8-2.8 mg/kg

      Conclusion
      DNIB0600A administered q3w has an encouraging safety, tolerability, and PK profile and evidence of anti-tumor activity in NSCLC and OC pts whose tumors express NaPi2b detectable by IHC. This data supports further clinical evaluation of DNIB0600A in NSCLC and OC together with a companion diagnostic.