PD-1/PD-L1 Immune Checkpoint Blockade: It Just Keeps Getting Better
| Jun 2, 2013
Co-authored by Greg Wolfe, PhD, Senior Consultant
The role of Programmed Death-1 (PD-1) in suppression of antitumor immunity was one of the hottest topics at the 2012 American Society of Clinical Oncology (ASCO) annual meeting and excitement around this topic has only intensified at ASCO 2013 as this story continues to unfold. PD-1 is a key immune checkpoint receptor expressed on activated T-cells and binding of PD-1 to its ligand, PD-L1, results in suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from tumor-specific T-cells. PD-L1, frequently expressed on the surface of tumor cells, binds PD-1 and suppresses the anti-tumor immune response. A number of anti-cancer agents that block the interaction between PD-1 and PD-L1 are now in the clinic. The well-attended clinical science symposium on June 2 entitled “PD1/PDL1: An Effective Target in Melanoma,” featured key advances in the clinical development of several agents.
Merck & Company’s lambrolizumab (MK3475), a humanized monoclonal IgG4 antibody against PD-1 recently made headlines when it received the FDA’s newly debuted breakthrough medication status. Results were presented on June 2 from an ongoing phase Ib study designed to explore the safety and clinical activity of lambrolizumab in patients with advanced melanoma (Ribas et al., Abstract 9009). Patients were administered lambrolizumab every two or three weeks until disease progression or unacceptable toxicity. Data from 135 patients were presented. An independent radiologic review indicated a confirmed overall response rate (ORR) of 38% for all patients; however, at the highest dose level (10 mg/kg) the ORR was 52%, including a 10% complete response rate. Response to lambrolizumab was independent of prior Yervoy®
(ipilimumab, Bristol-Myers Squibb) treatment. The most common drug-related AEs, (mostly grade 1/2) included fatigue (30.4%), rash (20.7%), and pruritus (20.7%). The incidence of drug-related grade 3/4 AEs was 12.6% and included transaminase elevations, renal insufficiency and hypothyroidism. Drug-related cases of pneumonitis (all grade 1/2) were reported in 6 patients (4.4%), and hypothyroidism was reported in 11 (8.1%) (grade 3, n=1; the remainder grade 1/2).
Roche also showcased its entrant in this race, MPDL3280A, a human monoclonal antibody that targets the ligand PD-L1 and inhibits binding to the PD-1 receptor (Hamid et al., Abstract 9010). Safety and efficacy of MPDL3280A was evaluated in patients with locally advanced or metastatic melanoma. Thirty eight patients were evaluable for efficacy. An ORR of 29% was observed (as measured by RECIST). A potential biomarker for response to this class of agents is overexpression of PD-L1. In this study, PD-L1 expression status was determined by immunohistochemistry (IHC) in 30 patients, and ORR in patients with PD-L1-positive tumors was 27% while ORR in patients with PD-L1 negative tumors was 20%. Stable disease was achieved in 87% of patients with PD-L1 positive tumors compared to 20% of patients with PD-L1 negative tumors. Twenty four-week progression-free survival (PFS) in all melanoma patients was 43%. Several additional patients had delayed antitumor activity after apparent radiographic progression and were counted as progressive disease for the above analyses. Forty four patients were evaluable for safety and the most common drug-related AEs, mostly grade 1/2, included fatigue (59%), headache (32%), and diarrhea (30%). The incidence of drug-related grade 3/4 AEs was 36% and included hyperglycemia (9%), elevated ALT (7%), elevated AST (5%) and back pain (5%); no pneumonitis or colitis were observed.
It was previously demonstrated that Bristol-Myers Squibb’s nivolumab, an IgG4 fully human monoclonal antibody against PD-1, is active in metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. On June 2, data were presented from a study that evaluated the combination of nivolumab plus a multi-peptide vaccine administered to patients with unresectable melanoma who failed at least one regimen for metastatic disease (Webber et al., Abstract 9011). Patients were eligible regardless of whether or not they had received prior Yervoy therapy. Nivolumab was administered (1, 3 or 10 mg/kg) IV every two weeks with subcutaneous vaccine administered before each infusion. The ORR for nivolumab plus peptide vaccine was 25% in Yervoy-refractory patients and 24% in Yervoy-naïve patients, with a clinical benefit rate of 46% and 44%, respectively. Durable responses (up to 33 months) were achieved in both Yervoy-naïve and Yervoy-refractory patients. PD-L1 status was determined by IHC. Using the reported cut-off of ≥5% staining as PD-L1-positive, there was a high response rate of 67% in all patients, although responses were also observed in patients whose tumors were PD-L1-negative (<5% staining: 19%). Common adverse events (all grades) included fatigue, injection site reaction, and pruritus and there were few Grade 3/4 adverse events (rash, n=2)
The final paper in this clinical science symposium presented preliminary results from the first Phase I study to evaluate simultaneous blockade of both the CTLA4 and PD-1/PD-L1 immune checkpoints (Wolchok et al., Abstract 9012) in patients with advanced melanoma who had received ≤3 prior therapies. A total of 53 patients who were Yervoy-naïve received IV nivolumab and Yervoy concurrently, every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 additional doses. At week 24, combined treatment was continued every 12 weeks for 8 more doses in patients with disease control and no dose-limiting toxicities. In two sequenced-regimen cohorts, 33 patients who progressed on prior standard Yervoy therapy were treated with nivolumab (every two weeks for up to 48 doses). The confirmed ORR for patients who received concurrent nivolumab and Yervoy was 40%, the majority of which occurred rapidly and exceeded 80% tumor shrinkage. A 53% confirmed ORR was achieved in patients who received 1 mg/kg nivolumab plus 3 mg/kg Yervoy including 3 complete responses and 6 partial responses. All nine of these patients had ≥80% reduction in tumor volume by 12 weeks or at their first assessment. Grade 3/4 toxicities occurred in 53% of patients who received concurrent nivolumab plus Yervoy. The most common Grade 3/4 toxicities were asymptomatic lab abnormalities including elevated lipase, and elevated AST and ALT. The confirmed ORR was 20% for patients who received nivolumab following progression on Yervoy and Grade 3/4 AEs occurred in 18% of patients who received nivolumab subsequent to Yervoy; asymptomatic elevated lipase was the most common Grade 3/4 AE (n=2, 6%). The 1 mg/kg nivolumab plus 3 mg/kg Yervoy dose was chosen to move forward into Phase III trials.
Data presented at the 2012 ASCO annual meeting established the potential of targeting the PD-1/PD-L1 checkpoint as a therapeutic strategy. These agents were shown to be very well tolerated with efficacy in several advanced tumor types. However, many questions were left unanswered about this novel approach to targeting cancer. Some of these questions were answered on June 2. Two of the studies presented demonstrated that progression of melanoma while on Yervoy therapy does not impact efficacy of subsequent PD-1/PD-L1 blockade. In 2012, data was presented that suggested that expression of PD-L1 by tumor cells may serve as a biomarker to identify patients who are likely to respond to anti-PD-1 therapy and those who will not respond. Today we learned that although PD-L1 expression correlates with response, it does not predict response. While PD-L1-positive tumors have a higher rate of disease control, responses are also achieved in patients with PD-L1-negative tumors, albeit at lower rates. Finally, data presented on June 2 demonstrated the feasibility of concurrent blockade of multiple immune checkpoint pathways. Administration of the CTLA4 pathway inhibitor Yervoy plus the PD-1 monoclonal nivolumab resulted in rapid response at rates as high as 53%. The rate, rapidity and depth of responses reported exceed those achieved with either of these agents administered as monotherapy, and the toxicity associated with this combination was manageable. The melanoma market has only recently been transformed, and these data and ongoing clinical development with these agents suggest that it’s set to be transformed even further!