Immunotherapy is rapidly changing the treatment landscape for non-small cell lung cancer (NSCLC). Two inhibitors of programmed cell death 1 (PD-1), nivolumab (Opdivo) and pembrolizumab (Keytruda), are now standard of care options for second or later lines of treatment in patients with advanced stages of NSCLC. Inhibitors of the PD-1 ligand (PD-L1) are also under development. There is as much excitement as there are unresolved issues with the use of these agents, and patient selection based on PD-L1 expression is a frequent source of confusion.
Trials for Nivolumab
Nivolumab was first approved by the U.S. Food and Drug Administration for the treatment of squamous NSCLC after failure of first-line chemotherapy. A clinical trial of 272 patients demonstrated better response rates and survival in patients who were randomized to receive nivolumab compared to docetaxel (response rates: 20% versus 9% and median survival 9.2 months versus 6.0 months, respectively) (N Engl J Med 2015;373:123-35). PD-L1 expression was not prognostic or predictive of benefit in this clinical trial.
When nivolumab was tested in a single-arm clinical trial for 117 patients with refractory squamous NSCLC, there were higher response rates seen when 5 percent or more tumor cells expressed PD-L1 compared to patients whose tumors expressed less (Lancet Oncol 2015;16(3):257-65); however, the use of archival specimens, and the number of patients without evaluable specimens limited conclusions about the predictive nature of PD-L1 expression as a biomarker in these trials.
The FDA later expanded approval for nivolumab to include all NSCLC subtypes after failure of first-line chemotherapy, based on a larger clinical trial that randomized 582 patients to nivolumab or docetaxel and required tissue for enrollment but not randomization (N Engl J Med 2015;373:1627-39). In this trial, PD-L1 expression was strongly predictive of clinical outcomes, yet objective responses were still observed in 9 percent of patients without detectable PD-L1 who were treated with nivolumab. Thus, the 28-8 pharmDx antibody for PD-L1 has been approved by the FDA to help physicians select which patients may benefit most from treatment with nivolumab, but PD-L1 expression is not a requirement to receive nivolumab.
Pembrolizumab received accelerated approval from the FDA for second or later line treatment of patients with NSCLC whose tumor cells express PD-L1. The 22C3 pharmDx antibody for the detection of PD-L1 was approved as a companion diagnostic to select patients who are most likely to benefit from pembrolizumab. In two clinical trials, the greatest benefits in terms of responses and survival were observed in patients with NSCLC whose tumors had 50 percent or greater expression of PD-L1 (N Engl J Med 2015;372:2018-28, Lancet 2015;S0140-6736(15):01281-7. doi: 10.1016/S0140-6736(15)01281-7. [Epub ahead of print]). Regardless, approximately 8 percent of patients without detectable PD-L1 responded to pembrolizumab in one of these trials (N Engl J Med 2015;372:2018-28), whereas the other trial excluded patients without any expression (Lancet 2015;S0140-6736(15)01281-7. doi: 10.1016/S0140-6736(15)01281-7. [Epub ahead of print]).
There are many potential reasons for the discrepancies in the use of PD-L1 as a predictive biomarker for PD-1 inhibitors. First, there is a second ligand of PD-1 (PD-L2) that may also result in immunosuppression and is not detected by antibodies that recognize PD-L1. Second, the dynamics of PD-L1 expression may limit or enhance its detection when archival specimens are used; however, a survival benefit was seen regardless of whether archival or new specimens were analyzed for PD-L1 in a clinical trial with pembrolizumab (Lancet 2015;S0140-6736(15)01281-7. doi: 10.1016/S0140-6736(15)01281-7. [Epub ahead of print]). Third, the heterogeneity of PD-L1 expression raises concerns about the use of PD-L1 in selecting patients for immunotherapy. PD-L1 expression in lung cancer is often focal within a tumor and confined to the tumor-stromal interface (JAMA Oncol 2016;2(1):46-54). Biopsies of early-stage NSCLC lesions frequently underrepresent PD-L1 expression compared to that by matched, fully resected tumors (Ann Oncol 2016;27:147-53). The concordance of PD-L1 expression between biopsies and fully resected tumors improves with the number of biopsy cores analyzed. Detection of PD-L1 expression also may be limited by intertumoral heterogeneity. In patients with multifocal lung cancer, there is poor agreement of PD-L1 expression between fully-resected, independent primary lesions as defined by genomic approaches (Clin Cancer Res 2015). In contrast, there is much better agreement of PD-L1 expression between related, intrapulmonary lesions. Overall, these data suggest small biopsies or analysis of a single lesion may not accurately detect PD-L1 expression.
PD-L1 expression is not only dynamic and inducible by cytokines such as interferon-γ, but it is also expressed by immune cells and negatively regulates the establishment of memory T cell populations. Despite PD-L1 expression by tumor cells, it is hypothesized that PD-1 axis inhibition may not be effective in the absence of an endogenous anti-tumor immune response (Cancer Res 2015;75:2139-45). In fact, in a clinical trial of the PD-L1 inhibitor atezolizmuab, PD-L1 expression by tumor-infiltrating immune cells was one of the strongest predictors of clinical benefit (Nature 2014;515:563-7).
Furthering Treatment Decisions
Many questions still remain as to which specimens to test for PD-L1, which diagnostic test to use for its detection, whether PD-L1 expression by one diagnostic test is concordant with another, and whether expression by one diagnostic test predicts responses to any PD-1 or PD-L1 inhibitor. At this time, the evidence strongly supports that detectable PD-L1 expression, especially in the presence of tumor-infiltrating immune cells, enriches for responses to PD-1 inhibitors. However, given the heterogeneity and dynamics of expression, there are patients without detectable expression who may benefit from PD-1 inhibition. Physicians ultimately have to balance the potential risks and benefits of immunotherapy against those of other cytotoxic therapies in their recommendations to patients, but PD-L1 expression can facilitate these decisions.Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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