Challenges of Molecular and Immune Testing in Lung Cancer, and Implications of Liquid Biopsies

New York—At the 2019 Perspectives in Thoracic Oncology meeting, Marc Ladanyi, MD, Chief of Molecular Diagnostics at Memorial Sloan Kettering Cancer Center (MSKCC), New York, spoke with Oncology Learning Network about the challenges of molecular and immune testing in lung cancer, and the implications of liquid biopsies in therapeutic management.

Can you discuss the role of the pathologist in negotiating challenges of molecular and immune testing in lung cancer?

Pathologists are now faced with requests for PD‑L1 testing, which is done by immunohistochemistry, as well as growing demands for tumor mutational burden (TMB) testing, which is done by large‑panel next-generation sequencing (NGS) testing, usually of tumor tissue.

One practical thing that you might want to keep in mind is that it's usually different pathologists who are doing those 2 types of testing. The PD‑LI1 HC is typically done by lung pathologists, whereas the TMB testing is done by the molecular pathologists.

There are a lot of challenges with PD‑L1 immunohistochemistry. I don't do it, personally; I'm on the molecular side.

There are the challenges of different antibodies, different scoring criteria, and the overall challenge of a 1% cutoff, which is a very liberal cutoff by most pathology standards.

TMB is still evolving as a biomarker. There's a lot of evidence for it, definitely in the context of single‑agent or combination immunotherapy. The picture in situations that combine immunotherapy and chemotherapy is a little less clear in terms of TMB's effect on survival metrics.

We're still looking for the best combination of biomarkers for immunotherapy. Some people feel like the real question is “Which patients are so unlikely to benefit from immunotherapy that they should be spared a trial of immunotherapy?”

For instance, in most (or almost all) studies, patients with low TMB-negative PD‑L1 have had extremely minimal benefit from immunotherapy. That might be a subgroup that could be offered another option, obviously chemotherapy.

It's already accepted that patients who have a targetable kinase mutation should be treated with the appropriate kinase inhibitor first, and in general show poor responses to immunotherapy.

In a way, it's easier to predict who's not going to respond to immunotherapy than to exactly predict who will.

How has the use of molecular testing in lung cancer evolved in recent years?

Lung cancer is definitely the poster child of molecular testing in solid cancers. We've seen a rapid growth in the number of biomarkers that you have to test for routinely in patients with lung cancer.

This has driven the development of panel testing (ie, testing everything at once). It has driven the development of large‑panel, NGS‑based testing. The one drawback of that is that with large‑panel NGS‑based testing it takes a couple of weeks to get results. Therefore, there's also now been a growth in what I would call “ultra-rapid testing” for the FDA-approved targets, which is the model that we use at MSKCC.

What are the implications of liquid biopsies in therapeutic management?

Liquid biopsies are an extremely attractive option for a lot of good reasons, but maybe also for some of the wrong reasons.

If a patient already has tissue available for testing, it would clearly be better to test the tissue. If a patient is already scheduled for a procedure in the very near future that will procure tissue, that may be preferable, too, because aside from the large‑panel NGS testing (which takes longer), there are also rapid assays that can give you an answer very quickly for the critical FDA-approved indications.

We're still figuring out what's the most appropriate and cost-effective use of liquid biopsy testing. Liquid biopsy testing, because it's so easy to procure the sample and send it off, has the potential to blow up medical costs. The reimbursement, especially for repeated testing, is unclear—there is a chance that patients could face out‑of‑pocket expenses.

There's still a lot of uncertainties about what's the best utilization of liquid biopsy testing, but there's no denial that it's here to stay and that it's very beneficial in certain scenarios that get you to the answer faster and more cheaply than scheduling a patient for a biopsy.