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John T Poirier
MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Anna F Farago, Raffaele Califano
- Coordinates: 9/10/2019, 11:30 - 13:00, Colorado Springs (1994)
MS14.05 - DLL3 Targeting Agents (Now Available) (ID 3523)
11:30 - 13:00 | Presenting Author(s): John T Poirier
Delta-like ligand 3 (DLL3) is a single-pass transmembrane Notch ligand that interacts with full-length, unprocessed NOTCH1 in the Golgi apparatus, inhibiting the pathway in cis. DLL3 is selectively overexpressed in the subtype of small cell lung cancer (SCLC) driven by the transcription factor ASCL1 (SCLC-A) that accounts for ~70% percent of SCLC diagnoses (95% CI [60 – 79])1. In one study immunoreactivity was observed in 1,040/1,363 (70.4%) of SCLC specimens, consistent with this incidence2. Overexpression of DLL3 leads to low-level cell surface expression of the protein on the order of 10,000 proteins per cell while expression in normal tissues is restricted to intracellular compartments: the same study demonstrated only low to moderate cytoplasmic or nuclear immunoreactivity in normal adult tissues3. High expression of DLL3 has also been reported in low-grade glioma4,5, neuroendocrine prostate6, and occasionally in other cancer types when neuroendocrine features are present7,8. The exquisitely selective expression of surface DLL3 on cancer cells presents an attractive target for a variety of therapeutic strategies.
Rovalpituzumab teserine (Rova-T; SC16LD6.5) is an antibody drug conjugate consisting of a monoclonal antibody targeting DLL3, a cathepsin-cleavable linker, and a pyrrolobenzodiazepine (PBD) warhead4. The first-in-human clinical trial of Rova-T in recurrent SCLC demonstrated
encouraging activity despite often severe side-effects attributable to the PBD warhead9; however, the phase 2 TRINITY study showed a disappointing 16% objective response rate while reporting a similar toxicity profile (NCT02674568). Subsequently, the phase 3 TAHOE study was halted due to shorter overall survival in the treatment arm. An active phase 3 trial of Rova-T in the maintenance setting (MERU) is ongoing (NCT03033511).
Other DLL3-targeting therapies under active investigation include the bispecific T cell engager (BiTE) AMG 757 (NCT03319940), and a chimeric antigen receptor CAR-T AMG119 (NCT03392064). These agents have shown significant anti-tumor activity in preclinical models of SCLC; however, AMG 119 required direct delivery of the engineered T cells for activity. AMG 757 was therefore the more potent of the two strategies in preclinical models and may therefore be better suited to overcome known barriers to CAR-T activity in solid tumors.
Alternative strategies remain under exploration including the use of 89Zr-SC16, a PET radiotracer, for in vivo imaging and as a companion diagnostic to optimize the selection of patients for treatment with DLL3-directed therapeutic agents. 89Zr-labeled-SC16 antibody successfully delineated normal tissue from subcutaneous and orthotopic SCLC tumor xenografts. Radiotracer accumulation in tumors was directly correlated with the degree of DLL3 expression and, also correlated with response to SC16LD6.5 therapy in SCLC patient–derived xenograft models.
1 Rudin, C. M. et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19, 289-297, doi:10.1038/s41568-019-0133-9 (2019).
2 Huang, R. S. P. et al. Delta-like Protein 3 Prevalence in Small Cell Lung Cancer and DLL3 (SP347) Assay Characteristics. Arch Pathol Lab Med, doi:10.5858/arpa.2018-0497-OA (2019).
3 Sharma, S. K. et al. Non-invasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer. Cancer Res, doi:10.1158/0008-5472.CAN-17-0299 (2017).
4 Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7, 302ra136, doi:10.1126/scitranslmed.aac9459 (2015).
5 Spino, M. et al. Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma. Clin Cancer Res 25, 1261-1271, doi:10.1158/1078-0432.CCR-18-2312 (2019).
6 Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 11, doi:10.1126/scitranslmed.aav0891 (2019).
7 Koshkin, V. S. et al. Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target. Clin Cancer Res 25, 210-221, doi:10.1158/1078-0432.CCR-18-1278 (2019).
8 Ding, X., Li, F. & Zhang, L. Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition. Life Sci 226, 149-155, doi:10.1016/j.lfs.2019.04.024 (2019).
9 Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol 18, 42-51, doi:10.1016/S1470-2045(16)30565-4 (2017).
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.12-15 - PET Imaging of [<sup>18</sup>F]PARP Inhibitor as a Pharmacodynamic Biomarker of Talazoparib in Small Cell Lung Cancer PDXs (ID 1794)
09:45 - 18:00 | Author(s): John T Poirier
Inhibitors of poly-(ADP)-ribose polymerase (PARP) are promising therapeutics for small cell lung cancer (SCLC). We tested whether PARP inhibitor (PARPi) target engagement as measured by a radiolabeled PARP inhibitor ([18F]PARPi) has the potential to predict drug efficacy in vivo.Method
Tumor growth inhibition during daily talazoparib treatment was evaluated in mice engrafted with SCLC patient-derived xenografts to evaluate talazoparib efficacy at multiple doses. Mice were intravenously injected with [18F]PARPi radiotracer at multiple time points after single doses of oral talazoparib to quantitatively assess the extent to which talazoparib could reduce tumor radiotracer uptake and PET/CT activity.
A dose range of talazoparib with differential therapeutic efficacy was established, with significant delay in time to reach 1000 mm3 for tumors treated with 0.3 mg/kg (p=0.02) but not 0.1 mg/kg talazoparib. On PET/CT with [18F]PARPi tumor was among the tissues with the highest radioactivity per gram (1.37 ± 0.15 %ID/g), significantly higher than surrounding lung (0.24 ± 0.05 %ID/g, p = 0.007), bone (0.27 ± 0.05 %ID/g, p = 0.007), and muscle (0.24 ± 0.15 %ID/g, p < 0.002). A reduction in [18F]PARPi uptake after talazoparib dosing was consistent with talazoparib clearance, with reduction in PET activity attenuating over 24 hours. Talazoparib target engagement, measured by maximum tumor PET uptake, increased in a dose dependent manner (3.9% vs. 2.1% ID/g for 0.1 and 0.3 mg/kg at 3 hours post-talazoparib, p=0.003) and correlated with PARP enzymatic activity among individual tumors as measured by total tumor PAR (p=0.04, R=0.62 at 1 hour post-talazoparib).Conclusion
[18F]PARPi PET imaging appears to model PARP inhibitor pharmacokinetics, correlates with PARP inhibitor pharmacodynamics as measured by tumor PAR levels, and differs significantly between therapeutic and subtherapeutic doses of talazoparib. PET imaging using [18F]PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARP inhibitor target engagement in real-time.