Virtual Library

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    Lunch & Poster Display session (ID 58)

    • Event: ELCC 2019
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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      63P - Real-life experience with the implementation of DLL3 staining and the subsequent treatment with rovalpituzumab tesirine in heavily pretreated SCLC patients (ID 530)

      12:30 - 13:00  |  Presenting Author(s): Maximilian Johannes Hochmair  |  Author(s): Christoph Weinlinger, Hannah Fabikan, Renate Koger, Dagmar Krenbeck, Florian Huemer, Oliver Mark Illini, Melisa Kulaksiz, Arschang Valipour, Otto Chris Burghuber

      • Abstract

      Background

      Around 15% of newly diagnosed lung cancer patients are characterized as SCLC mostly with extensive stage disease. While SCLC may be responsive to 1st or 2nd line chemotherapy, there is no approved drug for the 3rd line with guidelines recommending best supportive care. Rovalpituzumab Teserine (Rova-T) is a novel first–in-class antibody-drug conjugate and targets the delta-like protein 3 (DLL3), a newly discovered target highly expressed in SCLC and other high-grade neuroendocrine carcinomas. ROVA-T showed an encouraging single-agent anti-tumor activity and manageable safety profile in Phase 1 and 2 studies. The present study is a retrospective analysis to evaluate DLL3 testing and real-life experience with ROVA-T for patients with an unmet medical need after failure of at least 2 systemic treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Methods

      DLL3 Immunohistochemistry (VENTANA DLL3 (SP347) Assay) was performed for 68 Patients with high grade neuroendocrine carcinoma (61 SCLC and 7 LCNEC). The percentages of stained tumor cells was determined - TC-counts of < 25% were interpreted as negative, counts of ≥ 25 to < 75% as positive and ≥75% as highly positive. 16 patients were eligible for treatment with Rova-T and received at least 1 of 2 planned cycles with a dose of 0.3 mg/kg.

      20c51b5f4e9aeb5334c90ff072e6f928 Results

      DLL3 staining was seen in most of the patients with high grade neuroendocrine carcinoma, 49 specimens (72.1%) were interpreted as highly positive, 10 specimens (14.7%) were considered positive. 9 (13.2 %) were considered negative, 4 (5,9%) of them showed no staining for IHC. All eligible patients had an ED with an ECOG of 0-1. 2 of the treated patients were DLL3 negative, 4 positive and 10 were highly positive. Of the 2 planned cycles 7 patients received both and 9 received only one due to disease progression or adverse events. Overall, 4 patients (25%) showed a PR, 4 (25%) had SD and 8 developed disease progression (50%). Side effects were manageable.

      fd69c5cf902969e6fb71d043085ddee6 Conclusions

      DLL3 staining is frequent in SCLC patients but further studies are needed to proof it to be a useful predictive biomarker. Rova-T seems to be an option for ED SCLC patients in later lines with a high unmet need for treatment and showed a clinical benefit in selected patients with a manageable safety profile.

      b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study

      The authors.

      213f68309caaa4ccc14d5f99789640ad Funding

      Has not received any funding.

      682889d0a1d3b50267a69346a750433d Disclosure

      All authors have declared no conflicts of interest.

      cffcb1a185b2d7d5c44e9dc785b6bb25

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    09 - Session 6: Targeted Therapies (ID 9)

    • Event: SCLC 2019
    • Type: General Session
    • Track:
    • Presentations: 1
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      A DLL3-targeted Theranostic (ID 09.03)

      17:20 - 19:00  |  Author(s): J.T. Poirier

      • Abstract
      • Slides

      Abstract not provided

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    12 - Session 9: Recent and Ongoing Clinical Trials (ID 12)

    • Event: SCLC 2019
    • Type: General Session
    • Track:
    • Presentations: 1
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      DLL3 BiTE® AMG 757 (ID 12.06)

      11:40 - 12:10  |  Author(s): Taofeek Owonikoko

      • Abstract

      Abstract not provided

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    09 - Antibody Drug Conjugate (ID 09)

    • Event: TTLC 2019
    • Type: General Session
    • Track:
    • Presentations: 1
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      Rovalpituzumab Theranostics (DLL3) (ID 09.07)

      18:15 - 19:15  |  Author(s): J.T. Poirier

      • Abstract
      • Slides

      Abstract not provided

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    MINI 27 - Biology and Other Issues in SCLC (ID 152)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI27.09 - A DLL3-Targeted ADC Effectively Targets Pulmonary Neuroendocrine Tumor-Initiating Cells to Result in Sustained Tumor Regressions (ID 2533)

      16:45 - 18:15  |  Author(s): L.R. Saunders, A.J. Bankovich, W.A. Anderson, M. Aujay, S. Bheddah, K.A. Black, R. Desai, P. Escarpe, J. Hampl, A. Park, A. Laysang, D. Liu, J. Lopez-Molina, M. Milton, M. Pysz, H. Shao, M. Torgov, S. Williams, O. Foord, P. Howard, J.T. Poirier, M.C. Pietanza, P.P. Massion, C.M. Rudin, R.A. Stull, B.S. Slingerland, S.J. Dylla

      • Abstract
      • Presentation
      • Slides

      Background:
      Pulmonary neuroendocrine tumors such as small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC) remain among the most deadly malignancies and are increasing in incidence. Patient-derived xenograft (PDX) tumors provide excellent models to study tumor biology and discover tumor-initiating cell (TIC) populations. Novel therapies that target and eradicate TIC represent a promising strategy to improve survival. An effectively targeted antibody-drug conjugate (ADC) carrying a cell-cycle independent toxin should result in significant anti-tumor activity and eliminate TIC.

      Methods:
      Whole transcriptome sequencing was performed using TIC isolated by fluorescence-activated cell sorting from SCLC and LCNEC PDX tumors. Quantitative RT-PCR, microarray analysis of PDX tumors and cell lines, and mining of publically available transcriptome and proteome datasets were executed to validate that prospective targets, such as Delta-like protein 3 (DLL3), were highly expressed in neuroendocrine tumors, but limited in their expression in normal tissues. DLL3-specific monoclonal antibodies were generated and used to determine protein expression by immunohistochemistry, flow cytometry and ELISA. Select DLL3-specific antibodies were conjugated to a cell-cycle independent pyrrolobenzodiazepine (PBD) dimer toxin and evaluated for their ability to internalize and mediate cell killing. Finally, established SCLC and LCNEC PDX tumors were treated in vivo with a lead anti-DLL3 ADC (i.e. SC16LD6.5). Limiting dilution assay (LDA) serial transplantation experiments were executed to assess the impact of SC16LD6.5 on TIC.

      Results:
      Elevated expression of DLL3 mRNA was discovered in TIC of SCLC and LCNEC PDX tumors and confirmed in additional distinct primary SCLC and LCNEC tumor samples and PDX tumors. In contrast, little to no mRNA expression was detected in vital organs and other normal tissues outside of the brain. DLL3-specific antibodies confirmed protein expression on the cell surface in both primary SCLC and LCNEC tumors and in PDX tumors initiated from patients with these diseases, whereas protein was scarce in normal tissues. SC16LD6.5 rapidly internalizes and localizes to late endosomes, and treatment of 10 SCLC and 2 LCNEC PDX tumor models resulted in significant and durable tumor regression with a median time to progression benefit of 75 days versus 16 days with standard-of-care (SOC: SCLC, cisplatin/etoposide; LCNEC, cisplatin). During the course of these in vivo studies, many mice were cured as tumors often did not recur despite being followed for 120+ days post-randomization and treatment. LDA experiments executed using tumors actively responding to SC16LD6.5 provided further functional evidence that the common lack of tumor recurrence following treatment resulted from effective targeting of DLL3-expressing TIC. In vivo efficacy strongly correlated with DLL3 protein expression, and responses were observed in PDX tumor models initiated from patients with both limited and extensive stage disease and independent of their sensitivity to SOC.

      Conclusion:
      The DLL3-targeted ADC, SC16LD6.5, effectively targets and eradicates TIC in SCLC and LCNEC PDX tumors. SC16LD6.5 (i.e. rovalpituzumab teserine) is currently concluding Phase 1b trials and is a promising first-in-class therapeutic for the treatment of high grade pulmonary neuroendocrine tumors.

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    OA05 - Treatment Advances in SCLC (ID 373)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      OA05.03 - Single-Agent Rovalpituzumab Tesirine, a Delta-Like Protein 3 (DLL3)-Targeted Antibody-Drug Conjugate (ADC), in Small-Cell Lung Cancer (SCLC) (ID 4648)

      14:20 - 15:50  |  Author(s): D.R. Spigel, M.C. Pietanza, T.M. Bauer, N. Ready, D. Morgensztern, B.S. Glisson, L.A. Byers, M.L. Johnson, H.A. Burris, F. Robert, T.H. Han, S. Bheddah, N. Theiss, S. Watson, D. Mathur, B. Vennapusa, D.K. Strickland, H. Zayed, S.J. Dylla, S.L. Peng, R. Govindan, C. Rudin

      • Abstract
      • Presentation
      • Slides

      Background:
      SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.

      Methods:
      Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.

      Results:
      Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop

      Conclusion:
      Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.

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    JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)

    • Event: WCLC 2017
    • Type: Joint Session IASLC/CSCO/CAALC
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      JCSE 01.17 - The Correlation of DLL3 Expression with High-Grade Pulmonary Neuroendocrine Carcinoma Clinicopathologic Features and Prognose (ID 10913)

      07:30 - 11:30  |  Presenting Author(s): Li-Xu Yan  |  Author(s): Y. Liu, J. He, D. Luo

      • Abstract
      • Slides

      Background:
      Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.

      Method:
      A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).

      Result:
      No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1



      Conclusion:
      Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.

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    OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)

    • Event: WCLC 2017
    • Type: Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      OA 08.02 - The Correlation of DLL3 Expression with High-Grade Pulmonary Neuroendocrine Carcinoma Clinicopathologic Features and Prognoses (ID 7961)

      11:00 - 12:30  |  Presenting Author(s): Li-Xu Yan  |  Author(s): Y. Liu, J. He, D. Luo

      • Abstract
      • Presentation
      • Slides

      Background:
      Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.

      Method:
      A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).

      Result:
      No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1



      Conclusion:
      Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.

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    EP1.12 - Small Cell Lung Cancer/NET (ID 202)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.12-22 - The Expression and Prognostic Roles of PD-L1, PAPR1 and DLL3 in Small Cell Lung Cancer (Now Available) (ID 866)

      08:00 - 18:00  |  Presenting Author(s): Tao Tian  |  Author(s): Xiao Fu, Mengjie Liu, Zhiping Ruan, Xuan Liang, Kejun Nan, Yu Yao

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine tumor with limited treatment. Recently chemotherapy combined with anti-PD-L1 therapy was approved for SCLC. PARP1and DLL3 inhibitor are under clinical trials but the data revealed that these agents benefit a proportion of SCLC patients. Which patient can benefit from anti-PD-L1, PARP1 and DLL3 inhibitor therapy and whether combination of these agents can improve the survival of SCLC are unknown. We aim to examine the expression and prognostic roles of PD-L1, PARP1 and DLL3 and to analyze the correlation between them and clinicalpathological factors.

      Method

      All protocols were approved by the Ethics Committee of Xi'an Jiaotong University and informed consent was signed. FFPE samples were obtained from Department of Pathology at The First Affiliated Hospital of Xi'an Jiaotong University from 2011 to 2018. SCLC was confirmed in all patients by surgical pathology and graded by AJCC TNM staging system. The expression of PD-L1, PARP1 and DLL3 were detected by immunohistochemistry as previously described. The association between PD-L1, PARP1, DLL3 and clinicalpathological characteristics was performed by χ2 test. The survival curves were analyzed by the log-rank test and Cox proportional hazards model.

      Result

      Except for CYFRA21-1 and DLL3, no correlation between PD-L1, PARP1 and DLL3 and clinicalpathological factors were noticed (Table 1).

      Table 1. Correaltion between PD-L1, PARP1, DLL3 and clinialpathological factors in SCLC patients
      PD-L1 negative PD-L1 positive χ2 P PARP1 negative PARP1 positive χ2 P DLL3 negative DLL3 positive χ2 P
      Age
      <60 11 12 17 6 8 15
      >=60 8 13 0.42 0.56 17 3 0.80 0.74 7 11 0.07 0.79
      Gender
      Male 14 21 28 7 15 28
      Female 4 4 0.27 0.70 6 2 0.10 1.00 3 5 0.10 1.00
      Smoking status
      Smoker (including previous smoker) 12 15 23 4 10 17
      Never-smoker 6 10 0.20 0.76 11 5 1.64 0.26 5 11 0.15 0.70
      Central or Peripheral
      Central 11 16 21 6 10 17
      Peripheral 7 9 0.04 1.00 13 3 0.07 1.00 5 11 0.15 0.70
      CEA level
      CEA normal 9 12 16 5 7 14
      CEA high4 4 7 9 2 4 7
      Unknown 9 2 5.68 0.06 9 2 0.13 0.90 4 7 0.04 0.98
      CYFRA21-1 level
      CYFRA21-1 normal 7 11 14 4 5 13
      CYFRA21-1 high 5 7 9 3 9 3
      Unknown 6 7 0.16 0.92 11 2 0.03 0.83 4 9 7.54 0.02
      NSE level
      NSE normal 2 0 1 1 0 2
      NSE high 10 17 21 6 11 16
      Unknown 6 8 3.04 0.22 12 2 0.79 0.49 4 10 1.73 0.42
      TNM stage
      TNM stage 1-2 10 13 13 10 6 17
      TNM stage 3-4 7 12 0.19 0.66 16 3 3.73 0.05 9 11 1.69 0.19

      We also demonstrated that PD-L1 predicts poor prognosis (HR=0.26, P=0.01), while either PARP1 or DLL3 has no correaltion with prognosis in SCLC patients (HR=0.40, P=1.39 and HR=0.07, P=1.29 respectively).

      Interestingly, we found SCLC patients with negative PD-L1 and PARP1, negative PD-L1 and DLL3 performed the best survival (Figure 1).
      layout 1.jpg

      Figure 1. Overall survival of SCLC patients with different expression patterns of PD-L1 and PARP1, PD-L1 and DLL3.

      Conclusion

      PD-L1 is a negative prognositc factor in SCLC.

      Different expression pattern of PD-L1 and PARP1, PD-L1 and DLL3 lead to significantly different prognosis in SCLC.

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    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
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      MS14.05 - DLL3 Targeting Agents (Now Available) (ID 3523)

      11:30 - 13:00  |  Presenting Author(s): John T Poirier

      • Abstract
      • Presentation
      • Slides

      Abstract

      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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