Abstract
BackgroundThis phase 1b study investigated safety and activity of combined checkpoint inhibition (CPI) with programmed death-ligand 1 (PD-L1) antibody atezolizumab plus cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab in NSCLC. Patients and MethodsEligible patients had previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) or melanoma. A standard 3+3 dose escalation investigated atezolizumab (600-1200 mg IV every 3 weeks) plus ipilimumab starting at 1 mg/kg, administered as a single dose or 4 doses, administered every 3 weeks. The expansion stage included a cohort previously treated with atezolizumab. Patients were monitored for safety and tolerability; response was evaluated every 6 weeks. ResultsTwenty-seven patients were enrolled, 4 with melanoma and 23 with NSCLC; here, we focus on data for the NSCLC population. Three of 23 patients (13.0%) received prior CPI. No dose-limiting toxicities were reported during dose escalation; dose expansion occurred with atezolizumab 1200 mg plus 1 cycle of ipilimumab 1 mg/kg. Most common treatment-emergent adverse events were dyspnea (39%) and cough (35%); treatment-related Grade ≥3 adverse events occurred in 11 patients (48%), most frequently pneumonitis (17%) and amylase or lipase elevation (9% each). Six of 23 NSCLC patients (26%) achieved confirmed responses, 5 of whom (25%) were CPI naive. Median duration of response was 23.0 (95% CI, 3.2-36.9) months overall and 36.9 (95% CI, 2.9-36.9) months in CPI-naive patients. ConclusionPreliminary efficacy of atezolizumab plus ipilimumab was observed in metastatic NSCLC. The combination had manageable toxicity, with a safety profile consistent with those of the individual agents.
Highlights
The growth and proliferation of solid tumors is dependent on their ability to evade immune surveillance and avoid destruction by the immune system.[1]
3 patients received more than one cycle of atezolizumab plus ipilimumab as planned; of the 24 patients who received 1 cycle of the study treatment, 20 had non–small cell lung cancer (NSCLC)
This manuscript will focus on the results in the NSCLC patients; data from the patients with melanoma are available in the online supplement (Supplementary Results)
Summary
The growth and proliferation of solid tumors is dependent on their ability to evade immune surveillance and avoid destruction by the immune system.[1]. In advanced non–small cell lung cancer (NSCLC), inhibition of PD-L1 and its receptor, programmed death-1 (PD-1), has proven to be an important therapeutic strategy in patients with. Advanced disease.[4,5,6,7,8,9,10,11] The PD-L1 or PD-1 inhibitors atezolizumab, nivolumab, and pembrolizumab are approved for first-line use in advanced NSCLC, either alone or in combination with cytotoxic chemotherapy and/or bevacizumab or ipilimumab, and as single agents in NSCLC that has progressed on or after platinumbased chemotherapy. Ipilimumab is an inhibitor of the checkpoint molecule cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and is approved in combination with nivolumab with or without chemotherapy for first-line NSCLC treatment. Atezolizumab, nivolumab and pembrolizumab are recommended for use across lines of therapy by major treatment guidelines.[12,13] the current standard-of-care immunotherapy-based regimens are only effective in a proportion of patients[4,5,6,7,8,9,10,11]; novel strategies are needed to provide therapeutic efficacy for more patients
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