title: Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
abstract: BACKGROUND
  PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC).
  
  
  METHODS
  We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947.
  
  
  RESULTS
  Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11-33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9-44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8-58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12-74] of ten patients).
  
  
  CONCLUSIONS
  Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing.
  
  
  BACKGROUND
  MedImmune.
authors: H Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: Scott
authors: S
authors: Antonia
authors: Yale University, Yale Cancer Center, New Haven, CT, USA.
authors: Sarah B
authors: SB
authors: Goldberg
authors: The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors: Ani
authors: A
authors: Balmanoukian
authors: Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors: Jamie E
authors: JE
authors: Chaft
authors: Earle A Chiles Research Institute, Providence Cancer Center, Portland, OR, USA.
authors: Rachel E
authors: RE
authors: Sanborn
authors: MedImmune, Gaithersburg, MD, USA.
authors: Ashok
authors: A
authors: Gupta
authors: MedImmune, Gaithersburg, MD, USA.
authors: Rajesh
authors: R
authors: Narwal
authors: MedImmune, Gaithersburg, MD, USA.
authors: Keith
authors: K
authors: Steele
authors: MedImmune, Gaithersburg, MD, USA.
authors: Yu
authors: Y
authors: Gu
authors: MedImmune, Gaithersburg, MD, USA.
authors: Joyson J
authors: JJ
authors: Karakunnel
authors: Columbia University Medical Center, New York, NY, USA. Electronic address: nar2144@cumc.columbia.edu.
authors: Naiyer A
authors: NA
authors: Rizvi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000613593:durvalumab; C520704:tremelimumab