title: 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.
abstract: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen.
  
  
  
  We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer.
  
  
  
  Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells).
  
  
  
  Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.
  
  
  
  Stemcentrx Inc.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Pietanza
authors.affiliation: Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Ready
authors.affiliation: Washington University School of Medicine in St Louis, St Louis, MO, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgensztern
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Tae H
authors.initials: TH
authors.lastname: Han
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Bheddah
authors.affiliation: Ventana Medical Systems Inc, Tucson, AZ, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Theiss
authors.affiliation: Ventana Medical Systems Inc, Tucson, AZ, USA.
authors.forename: Sky
authors.initials: S
authors.lastname: Watson
authors.affiliation: Ventana Medical Systems Inc, Tucson, AZ, USA.
authors.forename: Deepan
authors.initials: D
authors.lastname: Mathur
authors.affiliation: Ventana Medical Systems Inc, Tucson, AZ, USA.
authors.forename: Bharathi
authors.initials: B
authors.lastname: Vennapusa
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Hany
authors.initials: H
authors.lastname: Zayed
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Satwant
authors.initials: S
authors.lastname: Lally
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Strickland
authors.affiliation: Washington University School of Medicine in St Louis, St Louis, MO, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Dylla
authors.affiliation: Stemcentrx Inc, South San Francisco, CA, USA.
authors.forename: Stanford L
authors.initials: SL
authors.lastname: Peng
authors.affiliation: Tennessee Oncology PLLC, Nashville, TN, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015996:Survival Rate
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; C496666:DLL3 protein, human; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000620223:rovalpituzumab tesirine