Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC

Abstract

ObjectivesOur aim was to evaluate the safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive-stage SCLC.MethodsPatients with chemotherapy-naive extensive-stage SCLC were treated with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and immune-related response criteria. The primary end point was 1-year progression-free survival (PFS) according to RECIST. Secondary end points included PFS according to immune-related PFS and overall survival. Autoantibody serum levels were evaluated and correlated with clinical outcomes.ResultsA total of 42 patients were enrolled between September 2011 and April 2014; 39 were evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95% confidence interval (CI): 7.4–30.4]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95% CI: 5.5–7.9). Median immune-related PFS was 7.3 months (95% CI: 5.5–8.8). Median overall survival was 17.0 months (95% CI: 7.9–24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved an objective response by RECIST and 28 of 33 (84.8%) achieved an objective response by the immune-related response criteria. All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity.ConclusionsIpilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation.

Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy

“…Clinical studies revealed that the recommended dose of ipilimumab in phased combination with chemotherapies was identified as 10 mg/kg and had a better treatment benefit in combination with chemotherapeutic agents, such as carboplatin, etoposide and paclitaxel in patients with lung cancer [94][95][96] and advance melanoma [97,98]. Moreover,combining radiotherapy and ipilimumab was feasible and well tolerated with limited toxicity for solid tumors [99].…”

Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer

“…5 Consistent with these concepts, immune checkpoint inhibitors have shown some activity in SCLC. [6][7][8][9][10] Ipilimumab, a fully human immunoglobulin G1 monoclonal that blocks CTLA-4, 11 showed a trend to improved overall survival (OS) when combined with standard chemotherapy in a phase II trial. 6 Although the confirmatory phase III failed to confirm an improvement in OS, 2 combination of anti-CTLA4 and anti-PD1 agents showed a significant antitumor activity in SCLC patients in second line of treatment, particularly when ipilimumab is included in the regime.…”

“…Despite this, there is a subset of patients who benefit from immunotherapy and have long-term outcomes when this strategy is used. 2,9 Predictive biomarkers to select patients who will benefit from immunotherapy are therefore urgently needed. In SCLC additionally, the limited tissue available for biomarker studies 14 makes blood-based tests particularly interesting and relevant.…”

<p>Temozolomide Combined With Capecitabine In The Treatment Of Mixed Neuroendocrine Carcinoma Of The Lung With Poor Tolerance After Repeated Radiochemotherapy: A Case Report And Literature Review</p>

“…A cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitor, ipilimumab, is the first immune target drug used for SCLC. In the exploratory analysis of phase II clinical trials of combined chemotherapy using ipilimumab, 13 it was found that patients with a high expression of antibodies before treatment may benefit from this regimen. A meta-analysis 14 indicated that ipilimumab improved the PFS (six months: RR=1.16, P=0.02; one year: RR=1.39, P=0.02) and six-month immunerelated PFS (irPFS) (RR=1.60, P=0.004) in 1084 SCLC patients.…”