Biomarkers for pembrolizumab in melanoma
With the advent of effective therapy for melanoma, the development and validation of predictive biomarkers has been an important goal of the last several years. The discovery of a single or group of markers predicting response could help define a subset of patients who are more likely to benefit from a particular immunotherapy or combination of therapies. A validated biomarker could also help save a person from exposure to unnecessary cost and toxicity if a treatment is known to unlikely be beneficial. For single agent PD-1 inhibition, such as pembrolizumab therapy, the expression of PD-ligand expression in the tumor was a clear initial candidate for biomarker development. The hypothesis would be that if a patient’s melanoma tumor expresses ligand, which activates the PD-1 pathway, then perhaps this is a relevant therapeutic target for their disease. Tumor cell and intratumoral immune cell immunohistochemical expression of PD-1 ligand has been evaluated as a biomarker in the pivotal studies with pembrolizumab and has been a stratification factor in randomized trials. In the Phase III comparison study of pembrolizumab and ipilimumab, PD-1 ligand tumor expression was evaluated with ~80% of patients in the study defined as positively expressing the ligand (≥1% staining cutoff for positive). In this study, there was a PFS benefit of pembrolizumab over ipilimumab regardless of PD-1 ligand expression pattern. Albeit it was a small subset, evaluation of OS in the PD-1 ligand-negative group showed no difference in OS in subgroup analysis between the arms, suggesting that these patients do just as well with PD-1 inhibition or ipilimumab. There have been a variety of pitfalls to PD-1 ligand expression as an effective biomarker including a disputable expression percentage cutoff, whether to measure tumor cell or immune cell expression, heterogeneity of expression both intratumorally as well as among different metastatic tumors, and a variety of different antibodies used for expression analysis. Finally, there are a significant percentage of patients with PD-1 ligand nonexpressing tumors, no matter the cutoff implemented, who benefit from PD-1 inhibitor-based therapy.
Given the basic biology of immune function with the recognition of antigen as an important trigger for activation of a sustainable immune response, evaluation of tumor antigen production has been another promising biomarker candidate. Melanomas are known to have a very high mutational load, with ultraviolet (UV) radiation inducing hundreds to thousands of point mutations in tumor cell DNA.50 In an exploratory study of patients treated with ipilimumab, whole genome sequencing was done on melanoma tumor samples and matched blood samples to analyze somatic mutations and the neoantigens generated from these mutations. Researchers found that the mutational load and specific neoantigen expression by tumor cells were linked to a benefit from CTLA-4 blockade in these patients with melanoma.51 This concept of higher mutational load creating a broad neoantigen landscape was found in patients with non-small-cell lung cancer as well.52 Mutational load and neoantigen profiling have become the most intriguing biomarker candidates, which have made their way into several prospective melanoma studies.
An additional candidate biomarker profile has been to evaluate the patterns of immune cell infiltration into melanoma tumors. Taube et al53 found that infiltrating immune cells were geographically associated with PD-L1 expression and that immune activity in the tumor milieu was associated with PD-L1 expression in tumor cells and tumor immune infiltrates. Importantly, tumor cell PD-L1 expression correlated highly with the response to anti-PD-1 treatment.53 Another report reported the correlation between tumor infiltrating CD8+ T cells (killer lymphocytes) and tumor radiographic response.54 Patients with higher pretreatment CD8 cell infiltration, as well as PD-1 and PD-L1 expression both inside the tumor and at the tumor margins, had a higher radiographic response.54 In the same report, the pretreatment density of CD8+ T cells was closely associated with clinical response to PD-1 blockade.
Ongoing comparative and combination trials are evaluating many of these new potential biomarker candidates either in all or in a subset of the trial population. This is critically important to build datasets that can tease out the most relevant biomarker to help select appropriate therapy in the future.
Pembrolizumab has become a critical addition to the therapeutic options for the management of melanoma. With a series of clinical trials, which have supported its role as an effective and tolerable agent compared to other standard therapies, it has gained FDA approval and widespread use in patients with advanced or metastatic melanoma. Pembrolizumab has been shown to improve survival outcomes for patients with advanced melanoma making it one of just a handful of agents to be able to do so in this disease. Currently, it is approved in the USA for front-line use in metastatic melanoma and in patients previously treated with ipilimumab and/or BRAF-targeted therapy.
Despite the effectiveness of this new generation of agents, a large subset of patients will still succumb to this disease, which demands further research to improve patient selection for best therapy and evaluation of more broadly effective combinations. The specific utilization of pembrolizumab in melanoma therapy may change in the future to meet these goals as several early combination trials with the agent have shown great potential to be more effective and not sacrifice tolerability. In fact, multiple combinations with a variety of agents could result in positive trial findings, making biomarker discovery and validation critical to identifying what patient population may benefit the most from a particular combination therapy. Despite the large task ahead to further improve therapeutic outcomes, the rapid advances in just the last few years for this disease including the development of pembrolizumab give great hope that these goals are achievable in the near future.
CLC received clinical research funding from Merck, BMS, Novartis, Genentech, and Amgen. The authors report no other conflicts of interest in this work.
Raged M. Abdul-Karim,1 C. Lance Cowey2–4
1Baylor Sammons Cancer Center, 2Melanoma and Genitourinary Oncology Program, Baylor University Medical Center, Sammons Cancer Center Texas Oncology,3Baylor Skin Malignancy Research and Treatment Center, Baylor University Medical Center, 4Developmental Therapeutics Program, US Oncology Research, Dallas, TX, USA
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Source: Cancer Management and Research.
Originally published September 25, 2017.