Jack West, MD: Let’s turn also to a big question of, what does TMB mean today? Is this something that you guys are going to be ordering routinely? Should everyone be doing this as part of their initial workup? Jared, what are your thoughts?

Jared Weiss, MD: So, I think we’re getting it by default in a portion of our patients already. There is something of a divide in the nonsquamous patients in how molecular testing is being done, with, I think, academia being wholesale, pretty much sold on next-generation sequencing with advanced bioinformatics, and a community divided, where some are still doing a la carte testing with the advantages of greater speed in some cases and lower cost, but disadvantages of perhaps lower sensitivity for classical changes and less breadth of coverage for rarer changes actionable with off-label drugs and trials.

But TMB, if you’re getting next-generation sequencing with the most common commercial platform used in the United States, as well as most academic platforms, you’re getting TMB anyway. So, for a little over half of our patients with non—small cell, you have that data whether you’re ready to use it or not. I think the harder question is, should squamous patients be offered comprehensive molecular testing for the purpose of getting TMB? I think in clinical practice, we’ve had protocols for years now to get next-generation sequencing on these patients. And if I’m going to be honest about it, I can’t remember if I’ve ever been able to action one as a consequence. So, that’s not really a very satisfying answer. I don’t know that these data are good enough right now that I’m enthusiastic about getting next-generation sequencing in my squamous patients purely to get TMB.

Jack West, MD: Gregory, what do you think?

Gregory J. Riely, MD, PhD: I think TMB is clearly a biomarker. We’ve got all sorts of lines of evidence that say it’s a good biomarker. But I share your reluctance to say it’s a routine today. I think the key thing that I’m waiting for, before I tell everybody you’ve got to test every patient beyond those, as you suggest we already get it on, once we have an FDA approval that says high-TMB patients should get drug X, then I think I would push to get it done more frequently. We get it right now as part of next-generation sequencing. That’s the platform that we’re going to build off of, and we’re just going to expand that when we have an FDA approval in this context. But today, we don’t have that and as a consequence, it’s hard to say that it’s routine.

Jack West, MD: I would even say that the FDA approval, if or when it comes for this, is not necessarily going to be enough for me to say it’s clearly necessary to use or even that valuable to use in clinical practice yet. These data are very provocative and encouraging, especially the potential for a longer-term response. And maybe, particularly in the approximately 16% of patients who have low PD-L1 and high TMB or negative PD-L1 and high TMB, that’s a group where I don’t think we’re hitting it out of the park even with the chemoimmunotherapy. But I would say that the comparisons that are just to doublet chemotherapy just don’t apply that much; the standard has changed. And we shouldn’t be measuring with that yardstick anymore. We are not talking about overall survival yet. So, even if we can, I don’t know that it really means we should. I think it wouldn’t necessarily be wrong, but I don’t know that it matters a lot.

Jared Weiss, MD: I think it matters a lot the direction you asked the question right. So, if you’re a practitioner anxious to implement ipilimumab/nivolumab, maybe you have a super fit, super motivated patient who’s clear to you what they care about is some chance at durable control. If you’re looking at it from this perspective, then at that point it becomes mandatory to get the biomarker before you do it.

Jack West, MD: Yes. Do you…

Charu Aggarwal, MD, MPH: I would add a little bit of sprinkle of reality here.

Gregory J. Riely, MD, PhD: Just a sprinkle?

Charu Aggarwal, MD, MPH: Just a sprinkle. That not all people are actually getting TMB, so at an academic institution like mine, I’m getting next-generation sequencing, but I’m actually not getting TMB in real time. And I think that’s true for probably half of the community practices out there. So, I don’t think we’re quite ready to say, within 2 weeks of seeing a patient, “I’m going to be able to get TMB back. And I’m going to be actually using it in real time to make decisions, and the OS data really come out.” And like you said, until we have an arm that is a triplet that’s being compared with a TMB-driven combination arm, I’m not quite sure that we can flatly say we should get TMB in everyone.

Jack West, MD: Another issue is the fact that we’ve circled this point that TMB is a predictor of some value, pretty consistently, but not necessarily unique to that regimen. TMB may just be a marker for responsiveness to immunotherapy, whatever way you’re delivering it with whatever agent.

Transcript Edited for Clarity