What Are PD-1 and PD-L1?
Programmed death 1 (PD-1) is an immune inhibitory receptor expressed on several immune cells, particularly cytotoxic T cells. It interacts with two ligands, programmed death ligand 1 (PD-L1) (B7-H1, CD274) and PD-L2 (B7-DC). While PD-L2 is expressed primarily on macrophages and dendritic cells, PD-L1 is expressed on tumor cells, as well as other immune cells. The interaction of these ligands with PD-1 inhibits T-cell activation and cytokine production. Their ligation with PD-1 during infection or inflammation in normal tissue is critically important in maintaining homeostasis of immune response to prevent autoimmunity. Their interaction in tumor microenvironments, however, provides an immune escape for tumor cells by turning off cytotoxic T cells. Thus, blocking these interactions may subject the tumor cells to attack from cytotoxic T cells.
How Is PD-L1 Expression Determined? What Is Its Significance?
PD-L1 expression is measured most commonly by immunohistochemistry (IHC). Tumoral PD-L1 expression status has been shown to be prognostic in multiple tumor types, including melanoma (MEL), renal cell carcinoma (RCC), and non–small-cell lung cancer (NSCLC). In addition, tumoral PD-L1 expression appears to correlate closely with response to anti–PD-1 antibodies. However, no test is uniformly accepted as the standard for quantitating PD-L1 expression. The IHC tests used in clinical trials are proprietary; data on similarities between and among the antibodies used and the assay conditions, staining pattern, threshold for signal detection, and assessment of positivity are not published. The protein expression patterns of PD-L1 on tumor cells, dendritic cells, and tumor-infiltrating immune cells differ, and exact cell type and degree of expression vary between assays. A different methodology for evaluating PD-L1 messenger RNA (mRNA) expression, using an antibody-independent in situ hybridization assay coupled with quantitative fluorescence, showed that increased PD-L1 mRNA transcript was associated with elevated tumor-infiltrating lymphocytes and better clinical outcomes in patients with breast cancer and NSCLC. The role of PD-L1 expression as a biomarker is discussed in this supplement to ONCOLOGY, in the review “Prognostic and Predictive Markers for the New Immunotherapies,” by Drs. Kathleen M. Mahoney and Michael B. Atkins.
Anti–PD-1 and Anti–PD-L1 Antibodies
Several PD-1 and PD-L1 antibodies are in clinical development (Table 1). Overall, they are very well tolerated; most did not reach dose-limiting toxicity in their phase I studies. As listed in Table 2, no clinically significant difference in adverse event profiles has been seen between anti–PD-1 and anti–PD-L1 antibodies. Slightly higher rates of infusion reactions (11%) were observed with BMS-936559 (anti–PD-L1) than with BMS-96558 (nivolumab). In an early stage of a nivolumab phase I study, there was concern about fatal pneumonitis. It has been hypothesized that PD-1 interaction with PD-L2 expressed on the normal parenchymal cells of lung and kidney provides unique negative signaling that prevents autoimmunity. Thus, anti–PD-1 antibody blockage of such an interaction may remove this inhibition, allowing autoimmune pneumonitis or nephritis. Anti–PD-L1 antibody, however, would theoretically leave PD-1–PD-L2 interaction intact, preventing the autoimmunity caused by PD-L2 blockade. With implementation of an algorithm to detect early signs of pneumonitis and other immune-related adverse events, many of these side effects have become manageable. However, it does require discerning clinical attention to detect potentially fatal side effects. In terms of antitumor activity, both anti–PD-1 and anti–PD-L1 antibodies have shown responses in overlapping multiple tumor types. Although limited to a fraction of patients, most responses, when observed, were rapid and durable.
MEL is among the first types of solid tumors in which nivolumab has shown promising antitumor activity. In a phase I study across all dose levels, nivolumab resulted in an objective response rate (ORR) of 28% (95% confidence interval [CI], 19–38) in patients with advanced MEL who had no prior ipilimumab treatment. Responses were adjudicated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, with modification. A recently updated analysis in 107 MEL patients confirmed these responses and suggested potential survival benefit.[9,10] The ORR was 32% (95% CI, not reported [NR]). The median duration of response was 99.4 weeks (range, 17.0+ to 117.0+). More than half (11/21) of responding patients who discontinued therapy for reasons other than progressive disease responded for more than 24 weeks. The 1-, 2-, and 3-year overall survival (OS) rates were 63% (95% CI, 53–71), 48% (95% CI, 38–57), and 41% (95% CI, 31–51), respectively. Median OS was 17.3 months (95% CI, 12.5–36.7). Survival analysis by type of response suggested that patients who had immune-related responses, such as reduction in the target lesion in the presence of new lesions or following initial progression, had similar OS to patients with RECIST responses.[9,10]
Nivolumab in patients who were pretreated with ipilimumab was tested as part of a “sequential cohort” of an ongoing phase I trial. Nivolumab was given at two dose levels (1 mg/kg and 3 mg/kg every 2 weeks). Of 33 patients, ORR by RECIST criteria was 31% (95% CI, NR). The 1-year survival rate was 70% (95% CI, NR). The residual plasma concentration of prior ipilimumab at the start of nivolumab appears to have an influence on response to nivolumab. An ipilimumab concentration ≥ 7.255 μg/mL (the median) was associated with greater ORR to nivolumab (57.1% vs 14.3%).
Pembrolizumab (MK-3475, lambrolizumab) is a humanized immunoglobulin G (IgG)-4 kappa antibody against PD-1. In KEYNOTE-001, the safety and antitumor activities of pembrolizumab were tested in the largest-ever phase I study of patients with metastatic MEL (N = 411). This study began with ipilimumab-naive (IPI-N) and ipilimumab-treated (IPI-T) patients, and later implemented a randomized dosing comparison of 2 mg/kg vs 10 mg/kg in ipilimumab-refractory (IPI-R) and IPI-N patients. Among patients evaluable by RECIST 1.1, overall ORR was 34% (95% CI, 29–39). The ORRs were 40% (95% CI, 32–48) in IPI-N patients and 28% (95% CI, 22–35) in IPI-T patients. The 1-year OS rate was 69%; median OS has not yet been reached. A subgroup analysis suggested that a tumor size smaller than the median of 90 mm was an independent predictor of response.
In the randomized comparison of 2 mg/kg vs 10 mg/kg of pembrolizumab in IPI-R and IPI-N patients, there was no statistically significant difference between the ORRs for the two cohorts by either RECIST 1.1 (independent central review) or immune-related response criteria (investigator review). In the IPI-N cohort, the ORRs by RECIST 1.1 were 33% (95% CI, 20–49) vs 40% (95% CI, 26–56) in the 2-mg/kg and 10-mg/kg arms, respectively (P = .4835). In the IPI-R cohort, the ORRs were 26% in both arms (95% CI, 17–37 in the 2-mg/kg arm and 95% CI, 17–36 in the 10-mg/kg arm). According to Kaplan-Meier estimates of OS in IPI-N patients, 1-year OS rates were 72% (95% CI, 15–NR) and 64% (95% CI, 10–NR), and in IPI-R patients, they were 58% (95% CI, 11–NR) and 63% (95% CI, NR)—in the 2-mg/kg and 10-mg/kg arms, respectively. Given favorable benefit-risk profiles at both doses, 2 mg/kg every 3 weeks was recommended for future investigation. The most common immune-mediated adverse event of any grade was hypothyroidism (~8%). There was a < 1% incidence of grade 3 or 4 pneumonitis, hepatitis, colitis, or hypophysitis reported.
Pidilizumab is a humanized anti–PD1 IgG1 kappa with binding affinity at 20 nM. A phase II study in MEL patients showed ORR (by investigator review) of 7% in IPI-N patients and 5% in IPI-T patients. The rate of immune-related stable disease was 37%. The 12-month survival rate was 64% (95% CI, 55.6–72.0). Pidilizumab is being investigated in hematologic malignancies.
MPDL3280A is an IgG1-engineered, anti–PD-L1 antibody. A phase I study in 38 patients with metastatic MEL reported a 39% ORR (95% CI, NR), with 43% achieving a 24-week progression-free survival (PFS). Both patients with cutaneous (33%) and mucosal (25%) MEL responded. Patients with PD-L1–positive status by IHC had a 27% ORR (95% CI, NR). Similarly, patients with a negative status had a 20% ORR (95% CI, NR). An additional 60% of patients with PD-L1–positive tumors had stable disease, suggesting that PD-L1–positive patients are more likely to derive clinical benefit. No grade 3 or 4 pneumonitis or treatment-related deaths occurred. Based on these findings and a potential synergy with vemurafenib, a phase Ib study is currently testing the safety and tolerability of this combination in patients with BRAF V600E mutations (National Cancer Institute ClinicalTrials.gov ID NCT01656642).
BMS-936559 is a fully human, anti–PD-L1, IgG4 monoclonal antibody. In a study of 1-, 3-, and 10-mg/kg doses in metastatic MEL patients, 9 of 52 (17%; 95% CI, 8–30) achieved objective responses. Three patients achieved a complete response (CR). Five of 9 responding patients had an objective response lasting beyond 1 year. In addition, 14 of 52 patients (27%; 95% CI, 16–41) had stable disease lasting at least 24 weeks.
MEDI4736 is an engineered IgG1 kappa monoclonal antibody with triple mutations in the Fc domain to remove antibody-dependent, cell-mediated cytotoxic activity. It has shown high affinity and selectivity for PD-L1 and, reportedly, no binding to PD-L2. In its dose escalation study of doses ranging from 0.1 mg/kg every 2 weeks to 15 mg/kg every 3 weeks, no dose-limiting toxicity or drug-related deaths were seen. Tumor regression was seen in multiple tumor types, including MEL, NSCLC, RCC, and colorectal cancer (CRC). Segal et al reported the results of a multiarm expansion study using a dose of 10 mg/kg every 2 weeks in 44 patients with MEL (uveal and cutaneous). Although an analysis of antitumor activity in MEL patients has not been reported, preliminary data suggest that several patients with both cutaneous and uveal MEL remained in the study beyond 12 weeks, and no serious adverse events have been reported.
In light of their promising activity as single agents, several combinations of anti–PD-1 and anti–PD-L1 antibodies have been studied. A preclinical study has shown that dual immune checkpoint blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 resulted in more pronounced antitumor activity than either single blockade alone. Wolchok et al reported the clinical activity of concurrent administration of nivolumab and ipilimumab in 53 patients with advanced MEL; the resulting ORR was 40% (95% CI, 27–55) (by modified World Health Organization [WHO] criteria), and responses were “rapid and deep.” In an updated survival analysis, Sznol et al reported 1- and 2-year OS rates of 85% and 79% (95% CI, NR), respectively; median OS was 40 months, and median PFS was 27 weeks. This study added another cohort of 40 patients who received nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 1 mg/kg every 3 weeks for 4 more cycles, then 3 mg/kg every 2 weeks for up to 48 cycles. Results confirmed clinical activity, with an ORR of 43% (95% CI, NR). Responses were seen regardless of PD-L1 tumor expression status or BRAF mutation status.
Nivolumab in combination with multiple peptide vaccines in IPI-R or IPI-N MEL patients was well tolerated. This study also found that increased peripheral blood regulatory T cells and decreased antigen-specific T cells were associated with progression.The clinical benefit of adding a vaccine remains to be seen.
A phase I/II study of MEDI4736 in combination with a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) or with trametinib alone is ongoing (NCT02027961). Other immune modulatory agents, such as interferon (IFN) alfa-2b, are combined with various anti–PD-1 and anti–PD-L1 antibodies in ongoing clinical trials.
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