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J. Infante



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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      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 - 16:30  |  Author(s): J. Infante

      • 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.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      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 - 16:30  |  Author(s): J. Infante

      • 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.