Bristol-Myers Squibb Company announced positive results from a randomized phase 2 study evaluating ipilimumab in combination with standard chemotherapy in previously untreated patients with advanced non-small cell lung cancer (NSCLC). The study, known as 041, met the predefined criteria for significant improvement (p-value of <0.1) in immune-related progression –free survival (irPFS), the primary endpoint, over chemotherapy alone. An additional analysis of progression-free survival (PFS), assessed using traditional mWHO criteria1, also reached statistical significance in one of the two dosing schedules that combined ipilimumab with standard chemotherapy. (Abstract #7531)

“Results from this phase 2 study are very encouraging and support further investigation of ipilimumab in NSCLC in large scale phase 3 trials,” said Dr. Thomas J. Lynch, Jr., director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital at Yale-New Haven. “As with melanoma, ipilimumab brings an innovative approach to lung cancer, which is very difficult to treat. These results add to our understanding of the potential of immuno-oncology in the treatment of cancer.”

Ipilimumab is a T-cell potentiator that specifically blocks the inhibitory signal of CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

The 041 study evaluated two distinct regimens of ipilimumab in combination with a chemotherapy regimen that is commonly used to treat advanced NSCLC in the first-line setting compared to the same chemotherapy regimen given alone. The ipilimumab arms improved irPFS by approximately one month compared to the chemotherapy-only arm. Immune-related adverse events reported in the study included gastrointestinal, skin, liver, or endocrine systems.

Planning for a phase 3 study of ipilimumab in the treatment of NSCLC is under way. Ipilimumab is an investigational compound and not currently approved for use by health authorities.

Study results: Immune-related PFS was 5.52 months (hazard ratio, 0.775; p=0.094), 5.68 months (hazard ratio, 0.686; p=0.026) and 4.63 months for the concurrent, phased and chemotherapy-alone groups, respectively. Progression-free survival as assessed by mWHO, a secondary endpoint, was 4.11 months (hazard ratio, 0.882; p=0.250), 5.13 months (hazard ratio, 0.691; p=0.024)) and 4.21 months for the concurrent, phased and chemotherapy-alone groups, respectively. Interim results for overall survival, also a secondary endpoint, were 11.01 months (hazard ratio, 0.962; p=0.429), 11.56 months (hazard ratio, 0.748; p=0.104) and 9.99 months for the concurrent, phased and chemotherapy-alone groups, respectively. Results for survival were based on an interim analysis and follow up continues.

Grade 3/4 adverse events (AEs) were 58%, 52% and 42% for the concurrent, phased and chemotherapy alone groups, respectively, and were reflective of previously reported events for these individual agents. The incidences of Grade 3/4 immune-related AEs were 20% and 15% for the concurrent and phased groups, respectively. Immune-related adverse events were treated with the use of supportive care and systemic steroids using established protocol-specific treatment guidelines.

Study 041 is a multi-centre, randomized, double blind, three arm trial evaluating the efficacy and safety of ipilimumab in combination with paclitaxel/carboplatin compared to paclitaxel/carboplatin alone in previously-untreated patients with Stage IIIb or IV non-small cell lung cancer (n=203). The trial enrolled patients with squamous and non-squamous cell histology. Patients were randomized to receive ipilimumab (10 mg/kg every three weeks) concurrent with the first four cycles of chemotherapy (concurrent regimen), ipilimumab (10 mg/kg every three weeks) in combination with cycles three through six of chemotherapy (phased or sequential regimen) or chemotherapy alone. Ipilimumab was administered in a maintenance schedule (10 mg/kg every 3 months) after discontinuation of chemotherapy and until progression or undue toxicity in the former two treatment arms.