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R. Mosher

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    MA09 - Immunotherapy Combinations (ID 390)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA09.10 - A NaPi2b Antibody-Drug Conjugate Induces Durable Complete Tumor Regressions in Patient-Derived Xenograft Models of NSCLC (ID 5769)

      14:20 - 15:50  |  Author(s): R. Mosher

      • Abstract
      • Presentation
      • Slides

      The sodium-phosphate transporter NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug conjugate (ADC) development in this disease. However, NaPi2b is also expressed at high levels in type II alveolar cells, raising the potential for normal tissue toxicity with this approach. XMT-1536 is an ADC comprised of a humanized antibody against NaPi2b and approximately 15 auristatin-derived payload molecules per antibody conjugated via a multivalent hydrophilic polymer (Fleximer). The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin-derivative that is capable of bystander effect killing.

      The anti-tumor activity of XMT-1536 was evaluated in seven patient-derived xenograft models of NSCLC adenocarcinoma, chosen for high NaPi2b-expression and representing a spectrum of oncogenic driver mutations prevalent in NSCLC adenocarcinoma (including tumors without oncogenic drivers). The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study.

      At the 3 mg/kg dose, XMT-1536 was active in 6/7 models: complete tumor regression in 3 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 3 of the 4 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60. The antibody component of XMT-1536 is cross-reactive with cynomolgus NaPi2b with similar affinity as human NaPi2b. XMT-1536 was well tolerated up to 5 mg/kg (4294 mg/m[2] auristatin payload equivalents), the highest dose tested. There was no body weight loss, no clinical observations attributable to XMT-1536, and no evidence of neutropenia. On pathology, there was minimal mixed inflammatory cell infiltrate in the lung in 1 high dose animal at each necropsy time point, but no evidence of significant lung toxicity. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.

      These results indicate XMT-1536 can achieve durable tumor regressions in murine patient-derived NSCLC adenocarcinoma models at doses associated with good tolerability in cynomolgus monkey, and support evaluation of XMT-1536 in patients with NSCLC.

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