More Biomarkers Needed in Cancer Immunotherapy

Nick Mulcahy

April 11, 2019

ORLANDO, Florida — Cancer immunotherapies that target the cell programmed death (PD) pathway and related ligands (L) have established new standards of treatment in multiple tumor types.

Nonetheless, selecting patients for treatment using the widely employed PD-L1 biomarker has "key limitations," including heterogenous results based on the location of the tumor tissue sample, said Jarushka Naidoo, MBBCh, a medical oncologist at the Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

As a result, various investigators are hard at work seeking additional biomarkers to help identify the best candidates for immune checkpoint blockade, Nadioo told an audience here at the 2019 annual meeting of the National Comprehensive Cancer Network.

Naidoo reviewed results with at least 10 "emerging" biomarkers during her presentation and said the field was a "very crowded space."

However, despite this multitude of biomarkers, "right now, we are only thinking of PD-L1," she said about the practice of oncology and testing.

What the NCCN Endorses

During her presentation, Naidoo reviewed the NCCN guidelines for biomarker testing for US Food and Drug Administration-approved cancer immunotherapies.

In cisplatin-ineligible bladder cancer, there are two different types of PD-L1 biomarkers in use. With atezolizumab (Tecentriq, Genentech), PD-L1 immunohistochemistry (IHC) is used, with immune cells needing to total >5% of the tumor area. With pembrolizumab (Keytruda, Merck), a PD-L1 combined score is used, with the percentage of immune cells plus the percentage tumor cells divided by the percentage of tumor cells; the total score needs to be >10%. "It’s kind of complicated," said Naidoo.

In advanced non-small cell lung cancer (NSCLC), when EGFR/ALK-negative status is unknown, there are varying percentages of PD-L1 needed, based on the line of therapy. For first-line pembrolizumab, a PD-L1 IHC score (tumor cells only) of >50% is needed.  For second-line NSCLC, to use pembrolizumab, a PD-L1 IHC score (tumor cells only) of >1% is needed. "These cut-offs and their relevance are debatable in the new era of chemotherapy plus immunotherapy," added Naidoo.

In renal cell carcinoma and metastatic melanoma, there is no requirement for PD-L1 testing, as the biomarker is not predictive of response. Therefore, all relevant patients are given immune checkpoint blockade.

In colon cancer and endometrial cancer, to use related cancer immunotherapies, microsatellite instability (MSI) and DNA mismatch repair (MMR) testing are required, which represents the only endorsed biomarker outside of PD-L1 for this class of drugs, said Naidoo.

The NCCN guidelines for biomarker testing for immunotherapy are a "rapidly evolving space" that are "likely to change every couple of months," added the Johns Hopkins oncologist.

Tumor Mutational Burden

Currently, there are three broad categories of biomarkers for cancer immunotherapy, said Naidoo.

She explained that, first, there are biomarkers "that tell us the tumor is inflamed," such as PD-L1 high status. Second, there are biomarkers that reveal the "immunogenicity of the tumor — that is, how likely is it to engender an immune response," such as tumor mutational burden (TMB). Third, there are factors of the "host environment," the most recently emerging category. This includes elements outside of the tumor, such as the microbiome, which may indicate if a patient will more likely respond to immunotherapy.

TMB is the most advanced biomarker in terms of clinical development, but falls short of full utility at this time, said Naidoo.

"Tumor mutational burden is a measure of the accumulated areas of mutations in DNA that is present in tumors [and] that is collectively counted and expressed as a number," she said.

"TMB really is where PD-L1 was a couple of years ago in terms of the need to harmonize the different methods, the different cut-off values," she added. "There is still work to be done in TMB."

Additionally, in her NCCN presentation, Naidoo described at least 10 other biomarker types currently under study. The use of biomarker combinations seems inevitable, she suggested.

"The question then becomes, which ones go together?" Naidoo asked.

NCCN audience member David Spangler of eviCore Healthcare asked Naidoo who will pay for all of this potential biomarker testing.

Nadioo gave a self-described "facetious" answer: "I’m hoping you’re going to pay for it."

She continued: "There’s a lot of technology out there and we have to look and see which ones are the most beneficial."

Finally, she ended on an upbeat note about biomarker testing: "The more we use it, the cheaper it will get."

Naidoo has disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 2019 Annual Meeting. Presented March 23, 2019.

Follow Medscape’s Nick Mulcahy on Twitter. For more from Medscape Oncology, follow us on Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.