NEW YORK (GenomeWeb) – A new study in Clinical Cancer Research has shown that certain cancer patients with altered PD-L2 expression may do better when treated with PD-1 targeting immunotherapy regardless of their levels of PD-L1, which is the current biomarker of choice for this class of drugs.
Both PD-L1 and PD-L2 are binding partners of PD-1, and so both have the biologic potential to impact in some way the activity of PD-1 axis therapies. However, most investigations so far have focused on PD-L1.
In the study, researchers from Merck conducted a retrospective analysis of PD-L2 levels from patients with head and neck cancers in a clinical trial of the cancer immunotherapy Keytruda (pembrolizumab). The results demonstrated that a combination of PD-L2 and PD-L1 protein expression was associated with both higher response rates and longer survival compared to levels of PD-L1 alone.
Interestingly, Merck senior principal scientist Jennifer Yearley said that the company is not planning on advancing a PD-L2 test to serve as a complementary or companion diagnostic to the drug, because the firm is currently in the middle of validating a broad gene-expression assay with NanoString Technologies, which includes PD-L2, PD-L1, and a variety of other immune-related analytes.
According to Yearley, the recognition that PD-L1 alone is an imperfect biomarker for response to Keytruda and drugs like it has been well established at this point. Though the marker is predictive of a higher likelihood of response, some individuals who test results suggest wont respond in fact do, and vice versa.
For Keytruda in lung cancer , the US Food and Drug Administration approved a traditional companion PD-L1 assay, an immunohistochemistry test called PD-L1 IHC 22C3 pharmDx, developed by Agilent Technologies subsidiary Dako. But recognition that PD-L1 doesn't perfectly stratify patients for immunotherapy reponse has contributed to the emergence over the past two years of a completely new regulatory category for tests approved for other similar drugs — so-called complementary diagnostics.
Yearley said that she and her colleagues were interested in the potential added value of PD-L2, based mainly on the fact that so little was known about it despite the recognition that it was also a binding partner to PD-1.
"We know that PD-1 has two ligands — two binding partners — but the greatest amount of effort, by all parties really, had gone into PD-L1 and there was extremely little data on PD-L2, whether it was likely to be relevant, what the expected levels would be in different cancers, etc.," she said.
"We felt that it was really important to get an understanding of the relative prevalence because [this protein] has the ability to bind to PD-1 and potentially regulate T-cell activity. … Then, once we started our background investigation in archival tumors and saw how common this was, it raised the possibility that there could be clinical relevance to expression in the context of PD-1 axis therapies," she added.
According to Yearley, just developing a way to test for PD-L2 took a great amount of effort and time for the Merck team.
"There weren't good tests, good reagents, so this took a very concerted undertaking to be able to test this in a sensitive and reproducible fashion," she said.
Once the group had developed an assay, they began by studying archival tumor samples (more than 400 of them) from a variety of cancers including renal cell carcinoma, bladder, melanoma, non-small cell lung cancer, triple negative breast cancer, gastric carcinoma, and head and neck cancers.
PD-L2 was expressed widely across these cancers, although expression appeared to vary significantly between tumor types: gastric cancer and triple-negative breast cancer showed generally moderate to high levels of expression, whereas expression in renal cell carcinoma was predominantly low, for example.
Based on these results, Yearley said the group decided it was important to evaluate what clinical effect, if any, there might be for higher levels of PD-L2 in the context of cancer immunotherapy treatment.
For the cohort of head and neck cancer patients in the Keytruda trial the team reported on, the overall response rate for patients whose tumors were positive for both PD-L1 and PD-L2 was 27.5 percent, more than twice the 11.4 percent rate for patients whose tumors were positive only for PD-L1, the authors reported.
PD-L2 positivity was also associated with longer overall survival compared to PD-L1 alone: 303 days and 109 days, respectively.
Yearley said that Merck's work with NanoString is moving down a path to potential approval as a companion diagnostic.
With Keytruda now also approved for use in patients with microsatellite instability and/or mismatch repair deficiency, a dual testing scenario appears to be emerging, in which patients could be eligible for Keytruda or other similar drugs based either on evaluation of things like MSI and hypermutation, or based on immune-based tests like the NanoString panel.
Indeed, researchers have suggested that to best guide the use of immunotherapies, clinicians will need a multipronged approach that addresses a tumor's mutational richness and immunological foreignness, a patient's general immune status, immune cell infiltration into tumors, and the absence or presence of specific checkpoints.
Yearley agreed, saying that the evidence so far suggests that while there may be overlap between the two testing areas emerging for Keytruda — MSI/mismatch repair deficiency and immune-associated gene expression —  their predictive ability is not superimposable and each appears to have independent value.