PD-1/PD-L1 inhibitors
Introduction
Antibodies blocking PD-1 and PD-L1 have demonstrated durable responses in a number of different advanced malignancies. The PD-1/PD-L1 checkpoint is operative in peripheral tissues and serves as a negative regulator of T-cells to help control local inflammatory responses and maintain self-tolerance. PD-1 is expressed on activated T-cells, natural killer cells, and B-cells [1]. Its two known ligands are PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 is constitutively expressed on a subset of macrophages, but may be rapidly upregulated in a number of different tissue types and by tumors in response to interferon-gamma and other inflammatory mediators [2, 3, 4]. PD-L2 is expressed on macrophages and dendritic cells, though it's impact on surveilling T-cells is not as well understood [5, 6]. PD-L2 expression by tumors as a mechanism of immune evasion has also been described. In addition to ligating PD-1, PD-L1 can also bind CD80 on activated T-cells. The observed differences in clinical activity and types of immune-related adverse events between anti-PD-1 and anti-PD-L1 may be attributable to the interaction between PD-L1 and CD80, as well as a suspected second receptor for PD-L2 [7].
A number of agents targeting both sides of the PD-1/PD-L1 interaction are currently in clinical development, Table 1. This review covers the first landmark trials reported in 2012 that employed these agents to treat multiple different solid tumor types, as well as summarizes the response rates by tumor type from subsequent trials. Most tumors are thought to display antigens that can be recognized by T-cells, though some are thought to be more ‘immunogenic’ than others; for example, mismatch-repair deficient colorectal carcinomas have a high mutational density and thus a greater likelihood of generating a strongly antigenic mutation, and melanomas display melanocyte-specific antigens that are readily recognized by the immune system. It was anticipated that tumor types such as these would be most likely to respond to this therapy, and one of the more exciting developments has been the dramatic clinical responses in patients with less immunogenic tumor types such as non-small cell lung cancer (NSCLC). The remarkable results observed in these trials have resulted in recent FDA approvals for pembrolizumab and nivolumab (both anti-PD-1 antibodies) for the treatment of advanced melanoma in late 2014 and nivolumab for the treatment of non-small cell lung carcinoma in early 2015.
Section snippets
The first studies demonstrating anti-tumor efficacy with anti-PD-1/PD-L1 in multiple solid tumor types
The first-in-human report of anti-PD-1 in solid tumors included 39 patients with advanced melanoma, NSCLC, renal cell carcinoma (RCC), prostate, and colorectal cancer who had received MDX1106 (nivolumab). Anti-tumor activity was observed, and PD-1 receptor occupancy studies indicated a longer than anticipated half-life for the agent [8]. These findings were pursued in a larger cohort of 296 patients, and objective responses (OR) as defined by RECIST with modifications [9] were observed in 26 of
Melanoma
The results of two Phase 3 clinical trials for anti-PD-1 monotherapy in patients with melanoma have recently been reported. The first trial employed nivolumab as a first-line therapy for 418 treatment-naïve patients with unresectable melanoma whose tumors were BRAF wild type. Patients were randomized to receive either nivolumab or chemotherapy with dacarbazine. The one-year analysis demonstrated an overall survival of 73% for the nivolumab patients versus 42% for those who received dacarbazine (
Immune-related adverse events
PD-1/PD-L1 checkpoint blockade is normally well-tolerated. Drug-related adverse events that are common to both anti-PD-1 and anti-PD-L1 agents include pruritus, fatigue, and loss of appetite. Immune related-adverse events (irAE) such as dermatitis, hypophysitis, colitis, and hepatitis have been reported for this class of agents, and in general are managed with corticosteroids and when essential, interruption of treatment. In the initial reports on nivolumab and BMS-936559, 14% and 9% of the
PD-L1 expression as a biomarker
One of the key observations in these studies has been the association between PD-L1 expression in the tumor microenvironment and the response to therapy. This feature was first highlighted by Topalian et al., in 2012, who observed that out of 42 patients studied with multiple different solid tumor types, 36% who had PD-L1 detected on the surface of tumor cells by immunohistochemistry demonstrated an OR to nivolumab, while no patients who were PD-L1 (−) demonstrated a response [10]. In a follow
FDA approval
These data have led to the US Food and Drug Administration's (FDA) approval in 2014 of pembrolizumab and nivolumab for the treatment of advanced melanoma. Specifically, both are approved for patients who are refractory to ipilimumab and BRAF inhibitors (if the patient's tumor harbors a BRAF-mutation). In early 2015, the FDA also extended the approved use of Nivolumab to include NSCLC patients who have failed platinum-based chemotherapies. Breakthrough designations have also been granted for the
Future directions
Potential differences in either efficacy or safety profiles between the agents blocking PD-1 and those blocking PD-L1 will likely require head-to-head trials before being fully elucidated. Future clinical development of either agent will involve identifying additional tumor types likely to respond to therapy, for example, Merkel cell carcinoma [46] and cervical carcinoma [47]. Combination with other checkpoint agents has also demonstrated remarkable results, in the case of nivolumab and
Conflict of interest
JMT receives research support from Bristol-Myers Squibb and is a member of advisory boards for Bristol-Myers Squibb.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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