Tumor Mutation Burden as Biomarker: All-Systems-Go or Too Early?

H. Jack West, MD; Joshua Bauml, MD; Sandip Patel, MD


June 21, 2018

H. Jack West, MD: Hello. I am Jack West, medical director of the thoracic oncology program at Swedish Cancer Institute in Seattle, Washington. Welcome to Medscape Oncology Insights. Joining me today are Dr Josh Bauml, assistant professor of medicine at the University of Pennsylvania in Philadelphia, and Dr Sandip Patel, assistant professor of medicine at University of California San Diego.

We are at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and we have a lot to talk about in the field of lung cancer. One of the stories that has continued to evolve is the role for tumor mutation burden (TMB). In fact, some controversy [has arisen] over the results from CheckMate-227.[1] This study included an analysis of TMB that looked favorable for nivolumab (nivo) plus ipilimumab (ipi) versus chemotherapy in the subset of patients with high TMB (defined as at least 10 mutations per megabase [mb] on the Foundation test). [The question is whether including TMB analysis] should be considered a useful treatment approach.

I see practical limitations in terms of the timing of getting results back and the robustness of the test. I believe that this will be a controversial issue, which was reflected by the range of views in the room [after the presentation]. Josh, does TMB have a place in standard treatment today, and if so, where?

Josh Bauml, MD: In my opinion, at this point, it does not. One of the issues of TMB is that, just like PD-L1, it's a surrogate biomarker. It does not say whether the patient will respond; it is just another reason why a patient may respond. The gold standard to define TMB is whole exome sequencing. There has been very important work to validate foundation medicine as a reasonable surrogate for [whole exome sequencing], as well as MSK-Impact [tumor profiling]. But we don't know whether the different assays that are validated towards whole exome sequencing are validated against each other. There are so many next-generation sequencing (NGS) assays that are used around the country and around the world; I have concerns about how we would use TMB moving forward.

The other issue is what that cut-off will be; 10 mutations/mb is based on the Foundation test. When they extrapolated results based upon whole exome sequencing, they had to use a different cutoff. So how we can apply this in a meaningful sense is really questionable.

We also have to remember that TMB is a surrogate biomarker of response to immunotherapy, period, and not specific to nivo-ipi—any immunotherapy. We have seen data: someone with high TMB is more likely to respond to PD1 inhibition as well.[2] Currently, I don't see TMB as adding anything to what we are doing right now with PD-L1.

West: Sandip, you have a different view, correct?

Sandip Patel, MD: I agree that this is not ready for prime time, by any means. But as we see the overall survival data for TMB 10 mature from CheckMate-227, if there is approval, I believe that this is a biomarker that could become integral. This reminds me of the early days of PD-L1 immunohistochemistry (IHC). We had multiple platforms, searching for which antibody performs it best. Is it tumor staining or immune staining? The Blueprint consortium put together a proposal and looked at this rigorously.[3] Now we better understand PD-L1. It is not a solved science in terms of immunohistochemistry.

That is likely what we'll see with TMB. All of the points are well taken, in terms of TMB being a surrogate endpoint. The PD-L1 IHC in and of itself is a surrogate as well. And so a biomarker, basically, is useful to inform how you can treat a patient. If we do find that when using TMB 10 [mutations/mb] we see an overall survival benefit for nivo-ipi, I believe that it changes the way we look at TMB 10. One other point I should make about PD-L1 IHC and TMB is that these are what we call orthogonal biomarkers, meaning, there are patients who can be PD-L1 zero or TMB high and still benefit from checkpoint blockade.

So the idea that we can have more "chemo-free" options in the front line of the non–small cell treatment space with a different biomarker, this may be something we get from TMB.

West: Although I would say that, while not prohibitively toxic, nivo-ipi does not offer a marked advantage in tolerability relative to a standard chemotherapy approach. But your point is very well taken about TMB and the early days of PD-L1. We were reassured by the consistency of the results, with different trials and different checkpoint inhibitors. I believe that's one of the things that we really need to see more of with TMB—corroboration of this in other studies with different checkpoint inhibitors, clarifying a tipping point with some kind of consistency in a definition of high TMB. One of the other challenges with using [TMB] is that we have other competing options, and several have a survival benefit associated with them, so I would personally prioritize those over TMB right now. Based on what we know, this doesn't mean "not ever" as much as "not now." I believe that we agree more than we disagree on that.

Sandip: One coming attraction is the ability to do this in cell-free DNA. We are looking for [noninvasive] liquid biopsy approaches to finding those seven National Comprehensive Cancer Network biomarkers. The potential to measure TMB in blood—and we've seen some preliminary data presented at ASCO to that effect[4,5]—may one day allow for immunotherapy stratification in the blood itself.

Bauml: But I believe that there are things [we can measure] in the blood for perhaps more direct assessments of the immune system. My concern is that with blood TMB we are moving farther and farther from the actual tumor whole exome. And I don't know how consistent [blood TMB] will be with what we are seeing with these other assays.

West: This is a work in progress, and we have much more to learn. Josh and Sandip, thanks for joining me today. This has been a great discussion. This is Jack West for Medscape. I look forward to joining you for the next discussion.


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