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| Jun 05, 2012
One of the hottest topics at ASCO this year was the role of PD-1 in suppression of antitumor immunity. A variety of signals regulate T-cell responses and it is well established that tumor cells are able to suppress immune response via distinct immune checkpoints. Proof of concept for targeting these immune checkpoints was provided by the development and commercialization of Yervoy (ipilimumab, Bristol-Myers Squibb), a monoclonal antibody directed against CTLA4 approved for treatment of metastatic melanoma. The launch of Yervoy represented a significant breakthrough in treatment of late stage melanoma where durable responses lasting years are achieved in as many as 20-25% of patients. However, Yervoy’s efficacy comes with the price of toxicity in the form of immune-related adverse events that include skin and gastrointestinal toxicities.
PD-1 is another immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand, either PD-L1 or PD-L2, inhibits immune response and leads to T-cell anergy, exhaustions and death. Many tumors elicit immune responses and are infiltrated by activated T-cells. PD-L1, frequently expressed on the surface of tumor cells, binds PD-1 and suppresses the immune response. A number of agents that block the interaction of PD-1 with PD-L1 are now in early stages of development and some exciting clinical data from these studies were released at ASCO.
Impressive results from a large Phase I study of BMS-936558 (anti-PD-1; Bristol-Myers Squibb / Ono Pharmaceuticals), a fully human anti-PD-1 monoclonal antibody, were presented (Topalian, Abstract CRA2509). Patients (n=296) with advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) or castrate-resistant prostate cancer (CRPC) with progressive disease after 1-5 systemic therapies, were treated with BMS-936558 (dose cohorts of 1, 3, and 10 mg/kg every two weeks in 8 week cycles). The MTD was not identified and expansion cohorts were enrolled at 10 mg/kg in all tumor types. Just 15 patients of 296 (5%) discontinued treatment due to BMS-936558-related adverse events (AEs). The most common AEs were fatigue, rash and diarrhea. Grade 3/4 toxicities occurred in 14% of patients and there were three deaths in patients due to pneumonitis (2 NSCLC, 1 CRC). Overall response rates (ORR) were reported in patients with melanoma (28%), NSCLC (18%) and RCC (27%) and preliminary data suggests that PD-L1 expression in pretreatment tumor biopsies correlates with clinical outcome. Registrational trials are planned in melanoma, NSCLC and RCC.
Preliminary results from the ongoing, first-in-human, Phase 1 trial of BMS-936559, an anti-PD-L1-specific monoclonal antibody were reported (Tykodi, Abstract 2510). Patients with advanced melanoma, NSCLC, RCC, CRC, ovarian, pancreatic, breast, or gastric cancers with progressive disease received BMS-936559 (every two weeks in 6 week cycles). The MTD was not identified and no correlation between AEs and drug dose was observed. Just 12 patients of 207 (6.8%) discontinued treatment due to drug-related AEs. The most common AEs included fatigue, infusion-related reaction, and diarrhea. Grade 3/4 AEs occurred in only 9% of patients and no drug-related deaths were observed. ORR were reported in patients with melanoma (17%), NSCLC (10%), RCC (12%), and ovarian cancer (6%). Durable tumor regressions and prolonged disease stabilization was reported for a proportion of patients with NSCLC, melanoma, and RCC.
These studies demonstrate the potential of targeting the PD-1/PD-L1 checkpoint as a therapeutic strategy. These molecules appear to be very well tolerated and have efficacy in many advanced tumor types. Many questions remain unanswered about this novel approach to targeting cancer including: is efficacy limited to tumors that express PD-L1? If so, PD-L1 may serve as a biomarker to select patients for anti-PD-1 therapy. How durable are responses? Can these agents be utilized in combination with other therapies to improve efficacy? How do these agents compare to CTLA4 inhibitors? This is only the beginning of the road for this class of agents, and many of these questions may be answered in the near future as additional studies are completed with these agents and those also being developed by numerous other pharmaceutical companies. ASCO 2012 was PD-1’s debutant ball, but we may be only a few years away from its coronation.