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

Abstract

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.

Figure 1:

Pharmacokinetics of ALT-803 after subcutaneous administration

Figure 2:. Post-hoc clinical activity of ALT-803 in combination with nivolumab

(A) Best observed response for 21 patients given ALT-803 in combination with the US Food and Drug Administration (FDA)-approved dose of nivolumab (3 mg/kg then 240 mg flat dose after change in FDA approval). Upward arrows indicate the patient had a 180% increase in size of tumour by RECIST and is out of scale for the figure. (B) Best response by patient versus duration of treatment on study. Upper red line is more than 20% over baseline tumour burden; lower red line is less than 30% from baseline tumour burden, both measured by RECIST criteria. RECIST=Response Evaluation Criteria In Solid Tumors. *Progression due to a new lesion. †Target lesion decrease of 27%, but met RECIST 1.1 criteria for partial response.

Figure 3:. Immune correlates of patients given ALT-803 in combination with nivolumab

(A) The change in peripheral blood numbers of NK cells (CD56^bright/dimCD16+CD3–), CD8-positive T cells (CD8+CD3+), and CD4-positive T cells (CD4+CD3+) in relation to pre-treatment assessment (appendix p 10 provides additional details). (B) Ki67 induction in immune cell subsets, measured in patient number 7 after the addition of ALT-803 treatment to ongoing nivolumab treatment. (C) Change in Ki67 concentrations (MFI) in lymphocyte subsets at day 4 versus pretreatment. Each symbol indicates one patient and colours indicate best response as depicted in the figure legend. Changes for NK cells and CD8-positive T cells differed significantly from 1, and all pairwise comparisons were statistically significant. (D) Serum interferon γ and interleukin-6 concentrations were measured longitudinally and the fold change was established in relation to pre-treatment assessment. Each line represents one patient. (E) Upregulation of HLA-DR on CD11c-positive cells was assessed by determining the fold change in percentage of HLA-DR-positive cells at day 4 versus pretreatment. Each symbol indicates one patient and the colours indicate best response. Fold changes differed significantly from 1. (F) T-cell receptor (TCR) immunosequencing of pretreatment peripheral blood mononuclear cells of the first seven trial patients. (G) Longitudinal analysis of TCR repertoire of first seven trial patients graphed as Morisita index. NK=natural killer. MFI=mean flouresence intensity. C=cycle. W=week. D=day. *p<0·01. **p<0·001. ***p<0·0001.