SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. With a better understanding of the Immune checkpoints, the gates are now wide open for the development of various immunotherapies. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. Checkmate -063 is a Phase II single arm, open label study designed to evaluate the efficacy of OPDIVO® (Nivolumab) in patients with advanced NSCLC with squamous histology, who had progressed on platinum based therapy as well as at least one additional systemic therapy. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody, which demonstrated an objective response in 20% – 25% of patients with advanced Non Small Cell Lung Cancer, Melanoma and Renal Cell Carcinoma, with favorable toxicities, in previously published studies. This study enrolled 117 patients and two thirds of the patients had previously failed 3 or more treatments and three fourths of patients were within 3 months of completion of their most recent therapy. OPDIVO® was administered as a single agent at 3mg/kg by intravenous infusion every two weeks until disease progression or treatment discontinuation. The primary endpoint was Objective Response Rate (ORR) and exploratory endpoints were overall survival (OS), Progression Free Survival (PFS) and efficacy, based on PD-L1 expression status. With 11 months of minimum follow up, the Objective Response Rate (ORR) was 15% as assessed by an independent review committee and the median duration of response was not reached. These responses were independent of PD-L1 status for patients with quantifiable PD-L1 expression. The estimated one-year survival rate was 41% and median Overall Survival was 8.2 months. The authors noted that an additional 26% of patients had stable disease for a median duration of 6 months, resulting in a disease control rate (ORR+stable disease) of 41%. Approximately 17% of the patients experienced grade 3-4 adverse events which included fatigue, pneumonitis and diarrhea. The authors concluded that the high response rates, median duration of response and disease control rates for Squamous NSCLC, is very promising in this difficult to treat group of patients and phase III trials are underway evaluating OPDIVO® monotherapy in frontline and previously treated patients with Non Small Cell Lung cancer. Ramalingam SS, Mazieres J, Planchard D, et al. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. LBA#3462
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