IPILIMUMAB OF NO USE IN SCLC

Abstract and Introduction

Abstract

Background Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).

Design Patients (n = 130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m²)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.

Results Phased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64; P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.

Conclusion These results suggest further investigation of ipilimumab in ED-SCLC.

Introduction

Combination chemotherapies are the current standard of care for extensive-disease-small-cell lung cancer (ED-SCLC).^[1,2] Despite high initial tumor responses to these therapies, recurrence occurs rapidly with median overall survival (OS) ranging from 8 to 11 months.^[1,3] Phase 3 trials over the past 30 years evaluating the combinations of cisplatin or carboplatin with different third generation cytotoxic agents as first-line treatment have shown no incremental improvement in OS,^[1,3] underscoring the need for novel treatment strategies.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation, is an anticancer target of current interest.^[4–7] Ipilimumab, a fully human anti-CTLA-4 monoclonal antibody, blocks the interaction of CTLA-4 with its ligands (CD80/CD86). This blockade augments T-cell activation and proliferation, leading to tumor infiltration by T-cells and tumor regression.^[8–14] Early clinical trials with ipilimumab have shown durable tumor responses in multiple cancer types.^[15–18] Two phase 3 studies have demonstrated ipilimumab as the first agent to significantly improve OS in patients with metastatic melanoma.^[19,20] Adverse events (AEs) occurring in ≥15% of patients included pruritus, rash and diarrhea, and most AEs were managed by the drug-specific treatment guidelines.^[19,20]

SCLC patients with immune-mediated Lambert-Eaton myasthenic syndrome appeared to stay longer in limited disease state and have improved survival.^[21] Long-term survivors of SCLC were found to have a higher ratio of antitumor effectors T cells to regulatory T cells compared with those who had recurrent disease.^[22] These observations suggest that agents such as ipilimumab that act by promoting antitumor immunity may delay tumor growth in patients with SCLC. This randomized phase 2 study was undertaken to evaluate the activity of ipilimumab in combination with paclitaxel/carboplatin versus paclitaxel/carboplatin alone in patients with ED-SCLC. The rationale for combining ipilimumab with chemotherapy was based on preclinical studies showing that chemotherapeutics induce the release of tumor-specific antigens initiating T-cell activation and sensitize tumor cells to T-cell-mediated killing [23–29], and that certain chemotherapeutics enhance the antitumor activity of an anti-CTLA-4 monoclonal antibody.^[30,31]

Paclitaxel/carboplatin was chosen as comparator in this study, because this combination is a common standard of care for non-small-cell lung cancer (NSCLC) patients, the larger of the two cohorts in this trial,^[32,33] and also because the long-term efficacy of paclitaxel/carboplatin in ED-SCLC was comparable with that of cisplatin/etoposide, the commonly used chemotherapy combination in ED-SCLC.^{[3, 34, 35]}

Since the timing of chemotherapy administration relative to immunotherapy has been shown to affect outcome [29, 36, 37], ipilimumab was combined with carboplatin/paclitaxel using two alternate regimens. In the concurrent regimen, ipilimumab was administered concurrently with paclitaxel/carboplatin, allowing ipilimumab to be present at the earliest phase of chemotherapy-induced antigen release. In the phased regimen, paclitaxel/carboplatin alone was administered followed by ipilimumab/paclitaxel/carboplatin, allowing for antigen release to occur before ipilimumab exposure.

The study enrolled patients with ED-SCLC as well as those with advanced NSCLC, and was designed to analyze each cohort separately. Results for the ED-SCLC cohort are presented here. The NSCLC cohort is reported elsewhere.^[38]