“Functional Precision Testing”

ests to accumulate and publish their results, and he also encourages patients, patient advocates, and patient foundations to learn more and be involved.

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] Laura Kleiman of Reboot Rx and Ally Perlina of CureMatch both agreed that combining functional precision testing with their services is an opportunity worth exploring. Requests ●Do you have any comments on functional precision testing? ●The value of functional precision testing seems intuitive, yet it’s not widely practiced.

What are the barriers or objections to it?

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“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] — Meeting Notes Brad Power: We're very honored to have Tony Letai of Dana Farber with us. This is very timely. We've been having a conversation over the last weeks about combination therapies with Ally Perlina of CureMatch and Bob Gatenby of Moffitt Cancer Center.

Bob Gatenby adds other treatment strategy considerations that combinatorially make having evidence from randomized clinical trials pretty problematic for some of the more personalized strategies.

Tony has ideas about functional testing that might provide a way out of this conundrum of personalized treatments that include dosing and sequencing of treatments and so little or no evidence from the batches of patients that are required for randomized clinical trials. Tony Letai: I'm a clinician, but I mainly run a cancer biology lab at Dana Farber.

I've been at Dana Farber since roughly 1995 when I was an intern, and I have been there ever since. I'm going to talk about an alternative way of personalizing therapy or choosing the right drug for the right patient. We can have a very open-ended conversation, which can certainly include how you can incorporate this into making novel therapy combinations.

There's always going to be a definite tension between personalizing therapy and assembling novel combinations, which we know are going to be important for long term disease-free survival in a lot of cases on the one hand, and on the other hand verifying safety ahead of time. We can't solve everything, but I acknowledge this tension.

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] This is usually how this goes. This is all about getting information to choose a therapy for the right patient. I like this metaphor, so I'm going to present it to you. I find it analogous to this question.

ut I acknowledge this tension.

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] This is usually how this goes. This is all about getting information to choose a therapy for the right patient. I like this metaphor, so I'm going to present it to you. I find it analogous to this question. Say you're walking along the street with a six-year-old kid. Maybe it's your niece, your nephew, or your grandkid.

I see this little dog, and you want to know, what would happen if I poked that dog with a stick? How would the dog respond? Would it run away? Would it bark? Would it wet itself? Would it bite me? What on earth would it do? How do we answer that question?

If you're a conventional omic person in today's cancer biology world, it's an analogous problem where they're trying to figure out, using genomics, how a complicated system – in their case a tumor, in this case a little dog – how it's going to respond to a perturbation – that's treatment with a drug or some other sort of treatment.

The way omics or modern cancer genomics addresses this problem is: the first thing you do is you kill the dog. Then you sequence the DNA. Or now we're getting more mature: you're sequencing the RNA. You're looking at proteins, metabolites, all these, what I would call static phenomena associated with the tumor at time equals zero – initial condition measurements. You get big, big data sets.

These enormous data sets that people like this gentleman live to analyze. They're often housed at big universities and they take these enormous data sets and do all sorts of classifications and whatnot. And every now and then you actually spit out a suggestion for whether or not a drug works or not; not always, but sometimes you do. What is an alternative to this approach?

I'll summarize what I think the success of this kind of approach is in a little bit, but an alternative approach, if you want to know what happens, if you poke this dog with a stick, how would a six-year-old solve this problem?

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] poke the dog with a stick and then watch what happens. I am a firm believer that we do not do enough of that in cancer biology. Of course, what I'm going to get to with regard to poking it with a stick is actually taking the patient's living tumor cells, exposing them to drugs, and seeing what happens. Why don't we do more of that?

You might ask why we call this functional precision medicine. The omics approach looks purely at static biomarkers. I think of this as looking at dynamic biomarkers. I was originally trained as a physicist. One thing we know is that you can learn a lot from a complicated system by making perturbations to the system, rather than just measuring initial conditions.

But there's already a way to solve it, right?

as originally trained as a physicist. One thing we know is that you can learn a lot from a complicated system by making perturbations to the system, rather than just measuring initial conditions. But there's already a way to solve it, right?

If you've listened to anything from the NCI, from big cancer centers around the world, including my own at Dana Farber, this problem of choosing drugs for patients, we've kind of got it licked, right? We know that we do precision medicine: we take the patient's tumor, we sequence it, and it's going to spit out a mutation that tells us to use a particular drug.

As you can see, in this famous graphic the NCI uses, this is how you do precision medicine. You see it's very persuasive because there's this DNA chain. You can see for these different patients, there's a blue asterisk or purple asterisk there, then a green dot there, and an orange dot there, all these different parts on a DNA double helix.

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] patients, they're all served by this. Everyone gets a drug out of all this. This approach was tested in the NCI-MATCH trial. You may have heard that they took people with advanced, solid tumors, all across the US, and did a genomic test, some kind of sequencing, to find mutations, then assigned them to different treatment arms.

It started out with around 10 treatment arms, and then grew to something like 30 as new knowledge increased. It's worth considering: How well did this work? This was the National Cancer Institute using a general approach for advanced cancer patients doing the sequencing that we've been told is the way to do precision medicine. Let's talk about what we mean by “work''.

What I mean by “work'' is: how many patients got a drug that helped them? I could tell you if you look at a lot of the publicly available information from the NCI- MATCH trial – and I encourage you to look into this yourselves – you won't find a lot of information about how many drugs were found that actually helped patients.

You find a lot of information about logistics, how many people were sequenced, how many sequences there were, and so forth, but not so much about patient response. But I'll show you what I know and what I could find in the publicly available information.

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] As you see, they enroll big numbers. They were able to sequence like 7,000 people. But what's really important to recognize is how many of those patients after sequencing made it to a treatment arm. That is how many patients had a mutation identified that actually was relatable to an arm that had a drug assigned to it. Only 16% of the patients even made it to a treatment arm of these 30 treatment arms. How did those patients do?

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11]

. That is how many patients had a mutation identified that actually was relatable to an arm that had a drug assigned to it. Only 16% of the patients even made it to a treatment arm of these 30 treatment arms. How did those patients do?

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] Well? It depends on the treatment arm, and for the most part, there's no publicly available information on what I would consider the most important result of this trial. Maybe it'll come out eventually, but here's what we do know. Here's maybe about 10 different treatment arms.

You can see they have different letters as they sort of advanced through the alphabet and then needed more. The “ORR” is the overall response rate. That's an objective response rate based on shrinkage of the patient's tumors. This means a patient went to a group of patients who had a mutation identified, went to a treatment arm, and then got a drug.

If you look at these numbers, you might have anticipated that number would be a lot higher, based on what we know about genomically- directed precision medicine. Recognize that this overall response rate is only for the 16% that even made it to a treatment arm. My point in presenting this is not to tell you that genomics is useless.

In a lot of patients it can be very helpful, but the ceiling on how many patients actually benefit from this is lower than I think many of us consider. And if you take in all cancer patients getting genomic tests, it's not that nobody benefits. Some people certainly benefit.

I can list EGFR-mutant lung cancers, or BRAF- mutant tumors, whether it's melanoma or colon cancer or something like that, or patients with TRK mutations in a wide variety of diseases, that certainly benefit, but that's not most cancer patients. In fact, we're probably down in the single digits percents for patients who actually benefit from these genomic analyses.

I'm saying this just to indicate that, yes, there is room for improvement. There is a need for additional methods to assign drugs to patients. If we rely purely on genomics, we're tying one hand behind our back. It's not a useless test, but it definitely needs help. So what's my proposal?

“Functional Precision Testing” (Tony Letai, MD, PhD) [#11] Something that we talk about called cancer functional precision medicine. It's a very simple idea. You take a drug, you put it on a bunch of tumor cells, and then you figure out a smart assay to see what happens.

This is what we use even today as the gold standard in microbiology, except for in that case, you are usually trying to kill a bacterium. If you have a blood infection,urine infection, or pneumonia, your doctor will try to culture the bacteria causing that infection. We'll grow it in a Petri dish, really fast, treat it with all the drugs, and let's see which one works best.

And that's how we choose. That's still the gold standard for what the best antibiotic is.