Whereas vaccines are designed to stimulate tumor antigen-specific immune responses, immune checkpoint inhibitors, in theory, should remove the brakes on most T-cell-mediated immune responses. This mechanism of action has the risk of inducing immune-related reactions.
The activity of immune checkpoint inhibitors in non-small cell lung cancer ( NSCLC ) has been reviewed.
Ipilimumab ( Yervoy ) is a fully human IgG1 monoclonal antibody that binds to CTLA-4 and prevents cytotoxic T-cell downregulation at early stages of T-cell activation. In patients with previously treated metastatic melanoma, Ipilimumab therapy can improve survival.
In the pivotal trial, one-year survival was estimated at 46% of patients versus 22-38% for patients with similar disease receiving other treatment regimens using historical data. Approximately 24% of clinical trial patients with advanced melanoma treated with Ipilimumab were alive at 2 years. Using real-world data, one-year survival rates for patients with advanced melanoma treated with ipilimumab were estimated to be 49–60%.
The activity of Ipilimumab in combination with Paclitaxel and Carboplatin was evaluated in patients with chemotherapy-naïve advanced ( stage 3b or 4 ) NSCLC. Patients were randomized to a concurrent Ipilimumab regimen ( four doses of Ipilimumab plus Paclitaxel and Carboplatin followed by two doses of placebo plus Paclitaxel and Carboplatin ), a phased Ipilimumab regimen ( two doses of placebo plus Paclitaxel and Carboplatin followed by four doses of Ipilimumab plus Paclitaxel and Carboplatin ), or a control regimen ( up to six doses of placebo plus Paclitaxel and Carboplatin ). Ipilimumab or placebo, Paclitaxel, and Carboplatin were administered intravenously once every 3 weeks for a maximum of 18 weeks. Patients without progression received maintenance treatment with either Ipilimumab ( Ipilimumab arms ) or placebo ( control arm ) once every 12 weeks until progression, death, or intolerance.
Antitumor responses were highest in the phased ipilimumab group. Although the numbers were small in the trial, subset analyses suggested phased Ipilimumab significantly improved the activity of chemotherapy in patients with squamous histology and no significant benefit for patients with nonsquamous histology.
Based on the promising results, a phase III study of phased Ipilimumab with chemotherapy has been initiated in patients with stage 4/recurrent squamous non-small cell lung cancer.
Blocking the PD-1 pathway is thought to modulate the activity of T-cells that have become nonresponsive after encountering PD-1 ligands in the tumor microenvironment. There are currently two anti-PD-1 agents in advanced stages of development: Nivolumab and Pembrolizumab.
A) Nivolumab ( BMS-936558 ), a fully human IgG4 PD-1 immune checkpoint inhibitor, is currently being evaluated in two phase III trials for NSCLC after promising phase I data.
In the initial trial, Nivolumab monotherapy was administered to patients with several tumor types, including 129 patients with NSCLC, nearly all of whom had received prior treatment. Patients received one of five different Nivolumab doses, ranging from 0.1 mg/kg to 10.0 mg/kg every 2 weeks for up to 12 8-week cycles.
In NSCLC patients, objective responses were observed in evaluable patients across doses of 1–10 mg/kg and across histologic subtypes in the initial analysis. With extended treatment, the median response duration for the 3 mg/kg dose had not been reached at the time of analysis ( range 16.1+ weeks to 133.9+ weeks ).
Median overall survival across all dose cohorts was 9.2 months for patients with squamous non-small cell lung cancer and 10.1 months for those with nonsquamous non-small cell lung cancer.
At the 3 mg/kg dose, the median overall survival was 14.9 months ( 9.5 months for squamous NSCLC; 18.2 months for nonsquamous NSCLC ), and this dose has been selected for phase III trials.
Data on overall survival rates are limited. Overall survival for NSCLC patients at one and 2 years was 42% and 24%, respectively. One-year survival was 39% for patients with squamous non-small cell lung cancer and 43% for patients with nonsquamous non-small cell lung cancer across all doses.
The tolerability and activity seen with Nivolumab in previously-treated NSCLC patients, including 54% of patients with three prior lines of therapy, was notable and served as the basis for pursuing phase III trials. The trials will evaluate efficacy ( response rate and overall survival ) of Nivolumab versus Docetaxel as a second-line therapy in patients with previously treated advanced stage or metastatic squamous or nonsquamous NSCLC.
Additional phase II studies are also ongoing, with objective response rate as their primary endpoint, testing Nivolumab monotherapy as third-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer, Nivolumab plus Ipilimumab in advanced or metastatic solid tumors, including NSCLC, and Nivolumab following Azacitidine and Entinostat versus oral Azacitidine in patients with recurrent metastatic NSCLC.
A phase I trial is testing Nivolumab as monotherapy, maintenance therapy, or in combination with chemotherapy or targeted agents ( Erlotinib and Bevacizumab ), or with Ipilimumab in patients with stage 3b/4 non-small cell lung cancer.
B) Pembrolizumab ( MK-3475 ) is a humanized IgG4 monoclonal antibody that binds PD-1. A phase I dose-finding study of Pembrolizumab showed a high response rate and durable responses in patients with advanced melanoma. In patients with NSCLC who were previously treated with two systemic regimens, Pembrolizumab was administered at 10 mg/kg every 3 weeks.
In an interim analysis of 38 patients, the objective response rate was 21%, and most responses had occurred by 9 weeks.
A phase II/III study comparing Pembrolizumab and Docetaxel has been initiated in patients with non-small cell lung cancer that has progressed after Platinum-containing therapy. The trial is evaluating a low and high dose of Pembrolizumab, with overall survival, progression-free survival, and safety as the primary endpoints.
Anti-PD-L1 therapies also target the PD-1 pathway by binding one of its ligands, ie, PD-L1.
a) BMS-936559 is a high-affinity, fully human, PD-L1-specific monoclonal antibody which showed activity against advanced non-small cell lung cancer in a phase I clinical trial that included multiple advanced tumor types. Five of 49 evaluable NSCLC patients had an objective response; response duration ranged from 2.3+ months to 16.6+ months. Six of 49 patients had stable disease lasting 24 weeks, and 31% of patients had progression-free survival at 24 weeks.
b) MPDL3280A is another anti-PDL1 antibody, which is a human monoclonal antibody containing an altered nonbinding domain. A phase I dose escalation/expansion study in multiple solid tumor types is being conducted to evaluate dose-limiting toxicities. In an interim analysis of 40 NSCLC patients who had received doses of 1–20 mg/kg, the response rate was 23%, and all responses were ongoing or improving at data cutoff ( range 1+ to 214+ days ). The rate of progression-free survival at 24 weeks was 46%.
Two phase II studies with MPDL3280A are ongoing. One trial is monitoring objective responses and safety in patients with PD-L1-positive locally advanced or metastatic NSCLC receiving MPDL3280A monotherapy. The other study is evaluating response rates and safety of MPDL3280A compared with Docetaxel in patients with advanced or metastatic NSCLC in whom Platinum therapy has failed. ( Xagena )
Davies M, Cancer Management and Research 2014:6: 63–75