ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.
- Wrangle JM Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Velcheti V Cleveland Clinic, Cleveland, OH, USA.
- Patel MR Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA.
- Garrett-Mayer E Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Hill EG Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Ravenel JG Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Miller JS Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA.
- Farhad M Earle A Chiles Research Institute, Portland, OR, USA.
- Anderton K Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Lindsey K Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Taffaro-Neskey M Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Sherman C Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Suriano S Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Swiderska-Syn M Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Sion A Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Harris J Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Edwards AR Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Rytlewski JA Adaptive Biotechnologies, Seattle, WA, USA.
- Sanders CM Adaptive Biotechnologies, Seattle, WA, USA.
- Yusko EC Adaptive Biotechnologies, Seattle, WA, USA.
- Robinson MD Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
- Krieg C Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA.
- Redmond WL Earle A Chiles Research Institute, Portland, OR, USA.
- Egan JO Altor BioScience, Miramar, FL, USA.
- Rhode PR Altor BioScience, Miramar, FL, USA.
- Jeng EK Altor BioScience, Miramar, FL, USA.
- Rock AD Altor BioScience, Miramar, FL, USA.
- Wong HC Altor BioScience, Miramar, FL, USA.
- Rubinstein MP Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. Electronic address: markrubinstein@musc.edu.
- 2018-04-10
Published in:
- The Lancet. Oncology. - 2018
Aged
Antineoplastic Agents, Immunological
Antineoplastic Combined Chemotherapy Protocols
Carcinoma, Non-Small-Cell Lung
Female
Humans
Lung Neoplasms
Male
Middle Aged
Neoplasm Staging
Nivolumab
Proteins
Time Factors
Treatment Outcome
United States
English
BACKGROUND
Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC.
METHODS
In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing.
FINDINGS
Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks.
INTERPRETATION
ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC.
FUNDING
Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.
Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC.
METHODS
In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing.
FINDINGS
Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks.
INTERPRETATION
ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC.
FUNDING
Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1016/S1470-2045(18)30148-7
- PMID 29628312
- Persistent URL
- https://sonar.ch/global/documents/47502
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