title: Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.
abstract: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC).
  
  
  
  In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing.
  
  
  
  Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression.
  
  
  
  Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting.
  
  
  
  Merck KGaA and Pfizer.
authors.affiliation: Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: gulleyj@mail.nih.gov.
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.affiliation: Sarah Cannon Research Institute Tennessee Oncology, North Nashville, TN, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.affiliation: Hematology Oncology Associates of the Treasure Coast, Port St Lucie, FL, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Iannotti
authors.affiliation: West Cancer Center, Memphis, TN, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Chandler
authors.affiliation: Department of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Deborah J L
authors.initials: DJL
authors.lastname: Wong
authors.affiliation: Virginia Piper Cancer Institute, Minneapolis, MN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leach
authors.affiliation: Institute for Translational Oncology Research, Greenville, SC, USA.
authors.forename: W Jeff
authors.initials: WJ
authors.lastname: Edenfield
authors.affiliation: Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Hans Juergen
authors.initials: HJ
authors.lastname: Grote
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Anja von
authors.initials: AV
authors.lastname: Heydebreck
authors.affiliation: EMD Serono, Billerica, MA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chin
authors.affiliation: EMD Serono, Billerica, MA, USA.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuillerot
authors.affiliation: University of California-Davis, Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004417:Dyspnea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000009:adverse effects; D008049:Lipase / Q000097:blood; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017671:Platinum Compounds / Q000627:therapeutic use; D011014:Pneumonia / Q000139:chemically induced; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced; D066066:Response Evaluation Criteria in Solid Tumors; D019233:Retreatment
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017671:Platinum Compounds; D008049:Lipase; C000609138:avelumab