Episode 62: Transforming Lung Cancer Treatment using Precision Medicine with Dr. Geoff Oxnard

The Patient from Hell (00:00.138)
Hi, everyone. This is Samira Daswani, the host of the podcast, The Patient from Hell. I have an incredibly cool guest with us today. This is Dr. Oxnard, who, by the way, is a complete underachiever with degrees from Harvard and fellowships at MGH and working at MSK and helping drive research forward. So with this incredible underachiever, I think we're going to be unpacking several themes across both the clinical aspects but also the patient experience piece of oncology.

Dr. Oxnard, thank you for being here with us.

Geoff Oxnard (00:31.563)
Thank you for having me.

The Patient from Hell (00:34.026)
Alright, so the first question for you is how did you come to be an oncologist?

Geoff Oxnard (00:38.475)
I grew up outside, I grew up in New Hampshire, small town. My parents were pediatricians, so I had some interest in being a doctor growing up. Took a couple years off after college. Went to med school at University of Chicago and I met a couple fascinating oncologists. I remember Nick Vogelzang, himself a cancer survivor. I remember being in clinic with him. You know, cancer patients, it's...

It's intense being with a cancer patient. Like there was a lot of weightiness to those moments. I'm generally a pretty positive upbeat guy. And I found that it was the right combination of seriousness and positiveness for a very serious illness. And over the course of my medical training at MGH, I worked with Lecia Sequist, a fantastic lung cancer doc there.

I found that I was engaged by the questions of oncology, the research questions of progress, the opportunity to make an impact with modern science. And so ended up committing myself to oncology at Memorial Sloan Kettering. I have some cancer in the family. My grandfather was a never -smoker or died of lung cancer. And so there, yeah, is a certain personal element. But I think it's also a community of...

of individuals like me who are fascinated by the science and try to bring a positiveness to serious disease every day, day in, day out.

The Patient from Hell (02:06.346)
So I have a slightly dumb question for you. So it always trips me up. You're a thoracic oncologist, but thoracic oncologists and lung cancer doc are effectively the same thing.

Geoff Oxnard (02:18.891)
Yeah, I don't study pulmonology. I don't understand the lung physiology, right? That my oncology training early on focused on lung cancer as disease. At Memorial Sloan Kettering, I worked under Vince Miller, Mark Chris in the thoracic oncology group. And so what I've seen for the past 15 years is lung cancers of all its various diversity, which doesn't mean I don't think there are things that we in lung cancer can learn from what's happening in the rest of oncology.

And so I very much follow the evolving precision therapies in breast cancer or bladder cancer or prostate cancer. Like there are fascinating changes and I think we can learn from that. But what I see in my clinical practice today is lung cancer for the most.

The Patient from Hell (03:03.498)
Got it. Okay, so can you help me understand how we're gonna just do like one -on -one stuff right now? Oncologists are practicing medicine, seeing patients, but you're also doing a lot of science and research. So how do you balance that? How do you go back and forth? What is your approach to it?

Geoff Oxnard (03:15.723)
Sure.

Geoff Oxnard (03:19.787)
Yeah, it's funny. I remember in fellowship, yeah, let me tell you a great anecdote. I had two clinics I was in, all right? I'm not going to tell you the docs, but in one of the clinics, we were seeing patients and I would bring a research idea and the physician would say, look, today's a clinic day. Let's do clinic today. Okay. Research is tomorrow. But in the other clinic, it was always creativity. Every patient led to questions and we were brainstorming all the time. And so I actually find.

that seeing patients feeds my creativity. And so that I'm always curious what's going on today. And then I take those questions to my research the next day fed with energy by the dilemmas I just met the prior day. So when I was in academia, I was at Dana -Farber for almost 10 years. That was a constant interplay. I had a couple of days of clinic. I had several days of research. When you're in academia, you're always submitting grants, trying to get funding to support your...

ever -growing creative research ideas. And so you piece these things together. You're never not a doctor, right? And you'll get a page on a research day or you'll go into the hospital to see a patient on a research day, but they are very much synergistic. And so your research feeds the kind of trials you want to do, which leads to new therapies for your patients. And those patients lead to new curious questions that feed back into your research.

I've since left academia. And so I worked in diagnostics for a few years. I now lead lung cancer clinical development at Lilly. And yet I still maintain a small clinic. I see patients a half day a week. And so it just, it keeps it real that I'm still able to see patients and I can just sort of check my research ideas. I have ideas about what a good therapy should look like and what does impact look like. And those are ideas that I practice in my work at Lilly. But in the clinic, I'm always checking my ideas to say, wait a sec.

What do patients really want? What are patients really up for? What kind of therapies make an impact versus not? And so very much my practice and my cancer research are hand in hand.

The Patient from Hell (05:24.458)
Okay, so let's maybe talk a little bit about your research, because you've definitely had an arc to your own research over the last many years, right? You've sort of focused in on rare mutations as sort of an area for now a couple of decades, if I understand it right. Can you talk to us why rare mutations? How does that intersect with lung cancer? And how does that influence your patient care?

Geoff Oxnard (05:44.459)
I would say I entered oncology right when precision cancer care was undergoing change. I remember hearing about EGFR in my residency at MGH when I got to fellowship memorial. There had just been the description of the first resistance mutation in EGFR T7 90M And so I just zoomed in and I said, wait a sec, that's weird. Let's figure out resistance and what it means, the biology of resistance.

the behaviors, the treatments of resistance. And that focus on EGFR and T7 90M started defining my early years in academia. And then spiraled, right? Other kinds of resistance, other kinds of genomic alterations and what's happening in lung cancer was an arc from, in pure cancer care, one size fits all, doublet chemotherapy, the same bad outcomes no matter who you are.

to a place of incredible precision and right sizing of therapy, depending on the individual. And so over this time of my training, but really my faculty years, every year there was a new nugget, a new molecular subtype being identified. It felt like if you were persistent, you could discover the next fascinating subtype of lung cancer. Every patient in front of you could be something new to be discovered, which would be good for them in that it led them to the new therapy.

and led to more creative research as an investigator. Does that answer your question?

The Patient from Hell (07:14.794)
Okay, it does, but of course it sparks more questions for me. I apologize. You use a couple of technical words that I definitely want us to define. Our audience definitely skews nerdy, but I think we need to define a couple of things. The first one I would love for you to give a definition of is actually resistance. So I don't think we've spoken about it so far on our podcast ever. So what do you mean by resistance? And why is that fascinating?

Geoff Oxnard (07:41.643)
Sure. I mean, it starts with precision therapy, if I may, right? That once you have defined a specific molecular subtype, you've tried to sort of sift through the randomness of cancer care to find a group of patients who are going to behave in a similar way. Let's go into that for a moment, if I may, OK? EGFR mutations. If you give an EGFR inhibitor in the original studies to

The Patient from Hell (08:04.266)
course.

Geoff Oxnard (08:10.379)
a bunch of patients on average with lung cancer, they live a couple months longer, but 10 % of those patients have fantastical responses that can last for a year or two or more. And so when you are a lung cancer patient, which are you looking for, by the way, to live on average two months longer or to have a fantastical response that can work for years? And of course, people are looking to be that.

outlier. They're looking for a dramatic effect from therapies is the sense that I get from talking to patients. And what we realize is that you could figure out which are those patients by profiling. And so in fact, you can find the EGFR mutation and therefore say, oh, wait, I don't have to guess empirically what the therapy is right for you. I can actually know based on this fingerprint that if you get an EGFR inhibitor, you're going to have a much more favorable outcome and I can right size your therapy.

This is amazing in practice. I saw a patient a couple years ago at Boston Medical Center where I see patients. He was Asian, heavy former smoker, diagnosed with squamous lung cancer, metastatic to brain, skin, dangerous looking cancer. And I, because I'm a believer in profiling and precision therapy, I sent NGS on this patient, next generation sequencing, to look at the characteristics of his tumor's genes. There are many doctors who don't believe

Next generation sequencing is necessary for squamous lung cancer. They say, no, squamous lung cancer you can treat empirically. It's the non -squamous ones that have the EGFR mutations. This patient had an EGFR mutation. Now, the chance of him having an EGFR mutation was 1%. But I believe in testing all of my patients, and so I found that 1%. And so whereas in an empiric world, I would have given him chemo and immunotherapy, in a precision world, I gave him an EGFR inhibitor, and he's been on it for years now.

You know, still with setbacks and he's been on chemo since then and radiation, but completely changed the story. Okay. He now a couple of years in has developed resistance, which is that after a couple of years on his EGFR inhibitor, his cancer starts to grow again. And when the cancer grows again, after a predictable course on targeted therapy, you can go back and revisit the tumor and ask what's new, what's different. And in his case, honestly, I've not figured it out.

Geoff Oxnard (10:26.443)
I've sent a couple liquid biopsies. I tried to get a biopsy. It wasn't big enough. I've not actually gotten a really good piece of his tumor to characterize the biology of his resistance. But sometimes in doing this, what you do is you find something new. You find an extra mutation that maybe you can target. And so I've had a patient start as EGFR and they develop MET. And then I give them a MET inhibitor with their EGFR and they respond. And they develop resistance again. And now they have another MET mutation on top of their original MET mutation.

I gave them a different EGFR -MET combination. We wrote that patient up a couple of years ago. She actually got to another clinical trial and then another clinical trial. Young woman, she found me on Twitter a couple of years ago saying, hey, I'm still doing great. Got married, wanted you to know. And so even these individual cases of resistance and persistence, overcoming resistance sometimes plays out for many, many years.

The Patient from Hell (11:22.506)
Can you define empiric? I think we've used it a couple of times in this conversation and I think it's important for us to define it because I think any type of oncology, there's pros and cons to empiric based treatment, right? Presence of data.

Geoff Oxnard (11:33.963)
The best example of empiric is if you show up with a urinary tract infection, your doc's going to give you Bactrim or Cipro because Bactrim and Cipro tend to work. They're not going to test every urine specimen to know exactly what bacteria is in there. They're going to say, well, you know, on average Bactrim seems to work. And if it doesn't work, let me know and I'll get you something different. Okay. Precision is actually looking at the exact bug that's in the urine and the exact resistance spectrum that's in that bug to say, wait a second.

for your urinary tract infection, back from the doctor to work, I need to use Cafflex or whatever, okay? And for urinary tract infection, I would say it's, you know, empiric is fine. But for lung cancer, as the diversity, or it's often fine, to be treated, I don't treat a lot of urinary tract infections, so that's the most I know about UTIs, okay? But for lung cancer, the genomic diversity is so crazy in its evolution that precision testing has become an absolute critical part of how we treat lung cancer.

And so, you know, a lung cancer comes in and, you know, based on its clinical features, you say, well, it looks like it's going to respond to chemo. I think, you know, maybe immunotherapy is going to work because this patient used to smoke. Like clinical features are only so good, but through molecular testing, you can add now predictability to your guess. And that predictability means now, oh, wait, I just found an ALK mutation last week, this ALK rearrangement.

leads to a range of ALK inhibitors and a much more predictable outcome. Not perfectly predictable. This patient's next generation sequencing also found a couple other mutations that maybe they're a lot more high risk. Maybe this patient's gonna develop resistance earlier. It maybe changes how close I monitor or how I anticipate it's gonna play out. But fundamentally, the ALK rearrangement now defines the biology for this person. And only, you know,

4 % of patients have an ALK arrangement, but by finding it, I can get them to a pill that can be very well tolerated and potentially create a more predictable course of therapy one, resistance therapy two, clinical trial three, a whole different course of how their cancer could play out.

The Patient from Hell (13:48.426)
Dr. Akshay, I have a practical question for you. So one of the things we've heard from other thoracic oncologists just in the course of our broader work is we've heard two sides of this. We've heard NGS is super important. We should order it for all the reasons you're mentioning. It gives you predictability. It enables you to find the right treatment at the right time, right? Because there is this notion of what is the right treatment for this specific patient. We've heard that. The downside we've heard is NGS just takes time.

God, it takes anything between 10 days to four weeks. So if I'm a patient, given the patient you were describing, cancers everywhere, super aggressive in the brain, that from a patient lens, it can one feel very, very nerve wracking to say, oh yeah, let's wait for, I don't know, four weeks to see the results come back when it's a 4 % chance. We're talking about a small set of patients where it is actually helpful.

So one, I'd love for you to talk about that. And the second thing I would love for you to touch on is what happens when, let's say I just have a lot of symptoms and I have to start chemo tomorrow. So there's two sides of it. One is there's a logistical problem and the other one is a symptom issue. The patient is just honestly too sick. So.

Geoff Oxnard (15:07.371)
Several things to respond to that. First off, you should know that as my career evolved, I focused both on the therapies and on the testing. I became an expert of actually diagnostic tools we use to get patients tested. And I spent a lot of time, especially working on liquid biopsy, right? Finding resistance mutations is frustrating because you have to biopsy the patient's tumor to get a piece of it out. But if you could just find that floating DNA, liquid biopsy.

now you can profile them. And over the course of my career, I spent a lot of time working on liquid biopsy. I actually first went to a diagnostics company. I worked for three years at a company that developed tumor testing, liquid testing. And so I will say today, those that evolved to such a stance that in the US at least, tissue NGS is FDA approved, liquid biopsy is FDA approved. Liquid biopsy is a pragmatic, accessible NGS that any patient can get with advanced disease.

Medicare pays for liquid biopsy, insurance companies pay for liquid biopsy, right? So there's no reason why a patient shouldn't be able to get NGS. A liquid biopsy is not a perfect specimen. It's the wisps of DNA that you can find in a cancer patient's blood, and it might be falsely negative. And so, you know, sometimes a liquid biopsy, while accessible and pragmatic, might miss something. A negative liquid biopsy may need tissue on backup.

Still, I think because it's FDA approved, reimbursed and accessible, everyone should be able to get NGS. The question is when, when is the right time to get NGS? And do you treat first and get the NGS later? Do you treat while you're getting the NGS? How do you integrate the NGS into your practice pattern so that the results deliver in a timely fashion? And so you are right that

I have definitely seen patients where I need to urgently get started on treatment. What I will often do, you know, I meet a patient with advanced cancer. I say, I'm worried about your cancer. We got to get going. How long do you think it takes to get that patient going on therapy? I mean, for small cell lung cancer, I'll just hospitalize them the next day and start them on chemo, right? But for non -small cell lung cancer, I'm getting a PET scan, I'm getting a brain MRI, I'm getting their symptoms managed, I'm getting insurance.

Geoff Oxnard (17:28.971)
approval, I'm getting their PD -L1 status, you know, it takes a couple of weeks. It takes a couple of weeks to get these things going. And so that first day I meet them, I'm getting a lot of things going and I'm sending NGS. And then where I work at BMC, there is a rapid profiling in -house for tumor. There's a send out liquid biopsy. I can get results back in two weeks. So that, but I will, I'll still put the plan in motion. You know, I think our path leads us.

to chemoimmunotherapy, let's say. But in parallel, let's get some testing started. And what I might need to do is pivot, right? In a highly symptomatic never smoker, I might start with chemotherapy. And then during the course of their first cycle of chemotherapy, I'll get a signal back, oh my goodness, you have EGFR. Oh, we can adjust your plan as follows. We can add it on, we can shift it. And so I think,

It's not like there's only one decision point in oncology, right? There are multiple decision points. One of the things that I'm doing is seeing my patients earlier. So the patient that I just saw on Friday was scheduled for his biopsy today or tomorrow. So I was seeing him four days before his biopsy, but trust me, he had lung cancer, lung mass, small brain tumors. He was doing okay. He was not heavily symptomatic, fortunately. And I said, okay.

We need the biopsy, we need XYZ and let's send off this liquid biopsy in hopes of finding a mutation. And so I think that we can build our practice patterns in a way that make these more routine and more timely. But I won't deny, I have started patients on therapy without a result where I've said, you know what, a liquid biopsy was negative or the tissue specimen failed. And I just, the key thing in that patient you have to do is.

tuck them away in your chart as un -genotyped. This is a patient that's been started on empiric therapy, but they're un -genotyped. And I think I'm going to need to go back and answer this question again a few months down the line. And I think that's the case in a lot of cancers actually, where maybe the profiling doesn't impact first line decision like in lung cancer, but it impacts second line. And so you're going to have to be ready to go back and ask this question again. I'm not making light of it. Like there are so many decisions to make in oncology and...

Geoff Oxnard (19:55.691)
there is a diagnostic burden of having extra tests. Like I'm not looking for extra tests just for fun, but I do think for lung cancer, this is critical. And what I would just do is say, you know, along with your creatinine and your CBC and your brain MRI and your PET scan is your NGS. And you send it off and the results will come back at some point in a way that allows you to adjust your plan.

The Patient from Hell (20:24.554)
So it actually I wasn't reacting to the over testing scenario. It was more of one of our very, very early episodes. We spend a lot of time talking about decision making and oncology and how it's analogous to chess.

And just as an example game doesn't have to be chess as the main game, but this came straight from my surgeon actually during my lumpectomy. And I was going into the decision for lumpectomy, mastectomy and breast cancer. And I remember him telling me, he's like, look, you have to think of this as a game of chess. We make a move, cancer makes a move. We make a move, cancer makes a move. And it sounds like what you're trying to do early on in the lung cancer diagnostic pathway is to figure out where the pieces are sitting.

It's like, what does the full chestwood look like for us to make the right move? And maybe we don't know what the full chestwood looks like, but we're starting to make a move waiting for the pieces to fall into place. It's what it sounds like.

Geoff Oxnard (21:07.339)
So.

Geoff Oxnard (21:18.123)
So a great example of that is in resected lung cancer. So a lung cancer patient presents, they have it surgically removed, and they get adjuvant chemo. And for that patient, there are a few adjuvant precision therapies. We're trying to learn for breast cancer. And so you now can get adjuvant immunotherapy, and you can get adjuvant EGFR therapy, which is FDA approved. And you.

There's even published evidence around adjuvant ALK therapy and there are others under investigation. But do you need all of the NGS, you know what I mean, for that stage two lung cancer, right? Do you need all the other 10 different targets in lung cancer? And I've had a doctor say to me, well, the patient has stage three disease. They have a 90 % chance of their cancer coming back and being incurable, okay?

but I'm not gonna send the NGS until it comes back and I know it's incurable. And I was like, look, man, if it's 90 % chance, I think it's okay to send the NGS today and have that data for you down the line, right? So like in breast cancer, profiling of ER, PR, HER2 is just any stage, any cancer, do it. But in lung cancer, there's this strange, like it's like we're bad at chess.

Instead of collecting the information upfront and saying, I'm going to have this ready so I can pull the trigger when you are at your sickest and your cancer comes back. That's the way I practice, right? But there are some who haven't quite caught on to that chess move yet. And we actually published a paper with Nate Pinnell a couple of years back trying to look at this exact idea of preparedness, that by testing people before they've recurred,

then if they have recurrence, you are better able to get them in a timely fashion onto the right therapy instead of the wrong therapy. And so I don't disagree. There is some chess, but it's hard to plan many steps down the line. And then certainly with a patient who's hoping for a cure, you're focused on positive. And sometimes it's hard to prepare for recurrence, which is not where we wanna focus.

The Patient from Hell (23:25.706)
Yeah. Yeah.

The Patient from Hell (23:33.61)
So let's actually zoom in on the hoping for cure because in just in the prep for this conversation, we were talking about hoping for cure in breast cancer versus lung cancer and how the patient populations have very different expectations upfront. And I remember you telling me that breast cancer patients just demand more from treatment. And I'd love for you to talk about that. Like why did you say that? And like, why is lung cancer different?

Geoff Oxnard (23:58.347)
Yeah.

Geoff Oxnard (24:02.411)
When I was at Dana -Farber, I was the lead of a study called Alchemist, which was a big multi -center NCI study investigating precision therapies as an evolution of our adjuvant therapy in resected lung cancer, like has been done for many, for a long, long time in breast cancer. And we wrote a paper led by a colleague, Ken Keele, in GM Oncology, where we looked at, in this population treated across the U .S. at NCI sites.

What is their use of adjuvant therapies? All these patients had enrolled into alchemists said, I want testing. I want to know if I'm a candidate for precision adjuvant therapies. And yet when we look at the standard therapies they're getting, that standard adjuvant therapy for a node positive resective lung cancer is cisplatin plus venereal bean, or it's certainly a platinum doublet, four cycles of a platinum doublet. Only four cycles here, okay? Like, I mean, but still platinum is something real.

the adoption was incredibly variable. And it was like 50 % of patients are actually getting adjuvant platinum. And a whole bunch of other patients are not. Now, older patients might not be getting the adjuvant therapy, higher risk patients are more likely to get the adjuvant therapy. There is some diversity. But if I talk to a doc who focuses on breast cancer and say, how many of your patients decline the adjuvant, you don't get the adjuvant therapy, they say everyone gets the adjuvant therapy, right?

Now breast cancer patients are generally fitter, often younger, don't have the same comorbidity as lung cancer patients. And yet there is, there's sort of this acceptability to not go the full distance for this lung cancer patient, often because they have illness. But, but I, I'm confused. It's a little bit interesting how that is. I think even in advanced lung cancer, there are many patients with advanced lung cancer who present already too sick for treatment. There's a meaningful portion of lung cancer patients.

who just never get therapy or they present too sick for their most aggressive treatments. And so, you know, the diseases are very different, but the differences in the diseases means that our practice patterns are biased in certain ways, but they're changing. And so I have an anecdote I want to share with you. I met a patient about a year ago, I think, a middle -aged male, black, he came in with what looked like metastatic lung cancer. He was getting sick. And he said to me, doc,

Geoff Oxnard (26:29.323)
You know, my mom had lung cancer eight years ago. And I would just say many lung cancer patients have lung cancer in the family and they have seen how terrible it can be. And it brings a degree of somberness, sometimes nihilism to how they approach their disease. And so I'm ready for what he's going to say next. And he says, she got one of these fancy new immunotherapies and now she's cured. So I'm really hopeful.

I was not prepared for that. Right? He has heard the new story of lung cancer. His mom was one of the first, you know, populations on the early immunotherapy trials. She had a fantastic outcome. She's off therapy now. She comes into the appointment. She looks amazing. And, and he has heard the optimism. He's heard the good news and he wants a piece of that. His cancer is getting worse. We get him started on treatment. He has some side effects. He started to respond.

his cancer melts away. And a year later, he's on immunotherapy having a home run response. And I hope that he might be like his mom eight years down the line. And I think, you know, this is a crazy coincidence to have two individuals. And I think in my academic days, I would have wanted to figure out exactly what about this family. But my guess is just that the story is changing. We are expecting more from our lung cancer therapies and some patients are gaining dramatic benefit. And we even talk.

in hushed circles about using the C word, the cure word for some lung cancer patients who've had dramatic response. But what it means is now when a patient comes into me and I find an EGFR mutation and I know they're going to be able to live on a pill for a number of years and then need chemo, I'm almost not satisfied. I want even more. And so as our therapies get better,

we elevate our expectations and we are chasing, I would say, the good outcomes that we are starting to see in HER2 positive breast cancer now with our lung cancer patients. And so our targeted therapies are going to early disease, our immunotherapies are going to early disease, and we are being more aggressive in how we treat lung cancer. And the question I think only is how do we do it in the way to make sure everyone participates in this progress and we don't leave anyone out.

The Patient from Hell (28:51.05)
I want to underscore two things you said, and I'd love for you to talk about it. Because I'm with you on the story of lung cancer is changing. We sort of have this inflection point where the entire narrative is getting restructured almost. And it is starting to feel, I'm assuming I'm not, I don't want to give that all, but I'm assuming it starts to feel what happened in the early years of her septum.

right, which is you're starting to get new data, there is new evidence that you know what, these patients actually might be living longer. We're still waiting for cure to come into the picture. It sounds like it's almost like the early days of like the Herceptin movement in breast cancer. My question for you though is on the point of nihilism. Because I think this is the second time in a lung cancer conversation I've heard that word and both the times it kind of blows my mind.

Because we're in the community a lot. We talk to patients all the time. And I'd love for you to talk about it from a clinician perspective, because what does that look like in the clinic? When a patient walks in, what are they doing? What are they saying that you're like, this is nihilism?

Geoff Oxnard (30:00.491)
Um...

I will say, yeah, okay, I want to say one thing before I answer your question, which is I am worried that the positiveness I've just described to you, lung cancer patients aren't hearing. Like people haven't gotten the message at how it's changing. I feel like everyone got the message that lung cancer, that breast cancer treatment had evolved and the treatments got better. It's almost, I mean, there are lung cancer survivors out there and they need to go share those spread the word, right?

that we're doing a better job. I'll admit it's still, you know, devastating for many, many patients. And so maybe haven't gotten the inflection point quite yet to have it kept on. And so what does nihilism look like? I saw a patient on my calendar in clinic who didn't come in. I called up and I said, Hey, we have an appointment today. You know, she's just been given a diagnosis of lung cancer. She's home, she's unwell. And she said, I just didn't think it was worth coming in.

And I was like, no, no, I have plans for you. Like we're gonna do this and we're gonna do that and we're gonna get you to therapy. And I managed to convince her, but it took some convincing for her to even come in and get care. And I think that's because of her pain and because of the support system she had, because of lots of things. But I also wonder if there is a willingness because of the stigma around lung cancer to say,

You know, I brought this on myself. I mean, awful things that a patient thinks to themselves when they're struggling with symptoms. And so we, you know, I spent a lot of my research time in Dana -Farber trying to think about like, how do I unpack just the stigma around it? We wrote a paper about young lung cancer, you know, lung cancer patients under the age of 40, familial lung cancer, so much we've learned about lung cancer that is different than the narrative.

Geoff Oxnard (32:00.779)
that started the lung cancer story about tobacco associated lung cancer, it's way more complicated than that. And yet patients aren't willing to tell the people around them that they have lung cancer because of the stigma. And so I think the stigma is a major burden in lung cancer and that stigma, I believe, contributes to some nihilism. And so all we can do is make sure we see the progress, share the news that our treatments are getting better.

and there's potential for dramatic impact.

The Patient from Hell (32:34.474)
I can definitely relate and I'll give you an analogy as to why breast cancer has shifted the story in the US. It's a very US centric story. And I'm not even sure that if you think back and I only know this from having read a lot about Dennis Lehman's books, I had her to post a breast cancer. So Herceptin, I literally owe my life to that drug. Like it's one of those drugs where like I owe my life to that drug. I know the data to know that I owe my life to Herceptin.

So I went down the rabbit hole of like reading about the evolution of herceptin and how it comes to market. And you're right about the patient population. Breast cancer patient population has over the last couple of decades been very vocal, very loud, demanding of like new therapies. So there is that patient driven pressure almost on the industry to come up with better drugs.

But at the same time, if you look at what happens in the first few years of Herceptin, there's a lot of pushback. There's a lot of skepticism. There's a lot of like, will this work, will this not work? There's a lot of like, we don't know if this is going to change the story. Right? So I feel as though where, so Herceptin today versus Herceptin when it came out, I suspect that lung cancer is probably closer to when Herceptin just came out versus today, because it's been on market for a while. So there has been this like, we just have one more data around it. People have gone through it.

A lot of women have gone through it, so I suspect part of it is evolution. But the point on stigma... Go ahead. I can see you're ready to respond. Go ahead.

Geoff Oxnard (34:06.347)
No, I mean, if there's something that we haven't perfected in lung cancer, it is that a lot of our progress in the early years was rare genotypes that were enriched in never smokers, sometimes young patients. And so there are still doctors across large swaths of the US who have never seen an elk, even though they've been looking, because their patient population is enriched in different ways.

And so I'll just say, I'm excited that the next difficult targets we're tackling in lung cancer. And we have many of these programs at Lilly are focused on KRAS and a different flavor of genomic subtypes that actually are more enriched in smokers. And so I am, I hope that pharma can be part of the solution, right? That they, there's this constant evolution of our expectations and then pharma needing to step up and meet those expectations with new therapies, right? And so it has been a, it's a very heady time in pharma where,

where it's harder to develop drugs because our treatments are getting so much better, right? And then we're demanding more of our therapies to say, how can I develop an even better, even cleaner, even smarter, even more effective treatment? So I think there's an ecosystem that expects the most from all of us. And my hope is that still trickles down to continually evolve that lung cancer story.

The Patient from Hell (35:26.378)
So now that we went there, you opened the can of worms. I have two questions for you. And this is going to tie back to an earlier comment in the conversation around outliers small patient populations. So you're at Lilly. You're talking about this new story of lung cancer. And we're talking about these mutations. These mutations are common, but not super common. So you're talking about a relatively small set of patients.

where it will give that huge, huge growth, like curve differential, right? Like you're talking about a patient population where if they had that mutation and you had a drug that targeted that mutation, it changes the story for that patient. So I'm fully bought in on targeted therapy. My question to you though is if you are wearing a Lily hat, that's a very small number of patients.

So how do you think about finding that patient? How do you think about coming up with a trial on that patient? How do you think about bringing a drug to market in the patient? Mission is, of course mission, but pharma is not a nonprofit, right? Pharma is a business. So like, how do you think about that when it comes to bringing drugs to market in a small cohort of patients?

Geoff Oxnard (36:42.795)
Better be a great drug.

You know what I mean? Right? Like if you're targeting a rare population, it better be really effective. Don't start developing a drug in a rare population that's modest. And I would say that for common cancer types, we're actually okay with, sometimes okay with modest stepwise improvements. Oh, you know, it's not a dramatic difference, but it's something, right? Every little thing counts.

The Patient from Hell (36:50.058)
Yeah.

Geoff Oxnard (37:12.939)
But if you need to be doing a large randomized trial to detect the effect size, that's not a good fit for rare populations. And so I think one excitement is that if your drug looks like a home run, there are now regulatory paths for accelerated development where you can demonstrate dramatic effect with smaller numbers of patients. And so honestly,

I would say that regulators have been a real partner in this and in the whole space of accelerated approval. Accelerated approval is not always panned out, right? Some drugs with accelerated approval have since been withdrawn because their promise did not follow through. But for other drugs, it created very early access for really, really effective therapies. But I'm not an economist, I would guess, if you want me to ask the economics of all this. It's a little bit outside of my expertise, except to say that...

when you're focusing on something rare, you want to make sure that you have a, it's feasible, right? It better be feasible to enroll that trial. You better be able to find the patients. And then there better be a real dramatic of an effect to make the whole endeavor worthwhile.

The Patient from Hell (38:24.554)
No, I wasn't looking for an economic answer. I was looking for the answer you just gave, mostly from a clinical development perspective, right? Because in the cancer community, once you enter the community, there's a lot of clinical enrollment questions. There's a lot of, like, how do you find the right patient? Does a patient want to join a trial? We open up a whole new part of the patient experience. And I imagine that in some of the populations you're talking about, even in the patient stories you've shared today, right?

this patient had to go on trial and then we found something else and we switched the trial. Right. So in the, in the clinical practice that you've been describing in the lung cancer population, I've already in, just in this conversation, heard you mentioned trials a few times. So as a modality of care, I can tell you an early stage breast cancer. Yes, there are trials and yes, it's part of the equation, but the, the clinical perspective on it is very different, right? Because we have known and we're going to put known in quotes again, known.

treatment modalities that are validated for years and years and years and years and years. So the impetus for a patient to go into a trial, very different than I would imagine why we have with lung cancer, which is the impetus to enroll in a trial is actually an option you may not have today. So I'd love to talk about that a little bit, because I suspect that that's also going to be playing into the process of clinical development, the processing of patient, doing research, et cetera.

Geoff Oxnard (39:48.939)
Yeah, when your, when your trials, when your therapies are less effective, clinical trials aiming to improve upon it are more compelling. Uh, that being said, trial participation, isn't something the U S is great at. Uh, in fact, many trials are out enrolled by ex -US countries. And we're actually trying to understand that better at Lilly to figure out if we can evolve that a bit. Um,

You know, there are incredibly smart people who have thought about this a lot. And sometimes it's the patient just says, no, this consent form's too painful. Okay, shorten the consent form. Or the scheduling is too difficult. Okay, make the schedule easier. Or the copays are too complicated, right? Okay, we'll cover all your copays. Or we'll pay for all the study therapies, right? Lily is launching some new efforts in this regard. Or sometimes...

But often it's just, I've heard it said, sometimes the studies just haven't gone to where the patients are, right? And that we need to make sure our trials are going to where the neediest patients are. We need to make sure we're enrolling not at coastal ivory towers, but actually out there across America where patients are sick with lung cancer. And so I do think if we...

with trials that are meaningful, that are feasible, that are well supported, and that are sort of as a team built to leverage the existing infrastructure or build the infrastructure to make it possible, we can get trials everywhere. But we still need to think about what are the intangibles that are getting the way of patients saying yes to clinical trials. But I can't disagree with you at all that when...

you know, if we acknowledge fundamentally while we have therapies in lung cancer, we have vast, so many more therapies in lung cancer than we used to have. And yet fundamentally they're unpredictable, they're unreliable so often and we can do better. And so that requires what the optimism to say, I've got options for you, great. And I wish I could do better. How about we consider this clinical trial? I would say randomization is something that.

Geoff Oxnard (42:09.963)
many parts of the world are comfortable with. U .S. patients often aren't as open to the loss of control that comes with randomization. And yet, I think there's still ways to design a study that make it hard for a patient to say no and good for all people involved.

The Patient from Hell (42:28.202)
Dr. Oxnard, I'm watching the clock a little bit and had a couple of ways that we could wrap up this conversation. But I think just given the last few minutes of this conversation, I would love for you to wrap up by telling us why you went from full clinical practice to industry.

Like what drove that decision? And as a, I'll tell you where I'm coming from, right? There's especially in today's day and age, there's a lot of conversation happening in the patient population around new therapies, the cost of therapies, et cetera, right? And as a clinician, you have a unique perspective on it because you are seeing patients. You have been in the lab.

You're doing research and now you've joined industry. So I would love to hear from your perspective, kind of how you see painting the next generation of oncology, but wearing a different hat.

Geoff Oxnard (43:16.363)
Sure. First, I didn't go from full clinical care to industry, right? That in fact, my experience at Dana -Farber was slowly less clinic, more research. And I was always developing ideas and taking them to industry and saying, you know, you should really do this next. And they wouldn't always listen to me. And I was like, wait a second, why aren't they listening to me? Okay. And I had a certain moment, I was like, wait, if I want to change,

how we develop drugs, how we develop diagnostics, I have to just go join them. And I'm so blessed to be able to do that in a way that still includes patient care. It is such an incredible privilege to still have a small clinic. But I think that so often what I'm doing right now is leveraging the same skills as I used at Dana -Farber, just on the other side of the table.

You know, do I miss it? I miss it terribly. I miss the education. I miss my patients terribly.

Geoff Oxnard (44:24.843)
I miss the patients I left behind, but I believe that I'm investing my time in a different kind of impact. I love the teamwork of industry. I love that we really are all together on the same mission, the same look of success. And I love that I'm on a team where we're expecting massive impact, right? Like I want to make sure I'm at a company where we are shooting for the stars. And I'm learning. I'm learning a whole bunch of new stuff.

Honestly, a lot of it is learning that I, you know, maybe I'd learned a lot of academia and I said, what's the next thing I can learn? But I think about going back all the time, right? I very much think we live together in an ecosystem and I go to the same meetings and I say all the same academic docs I used to see, and it's just, we team up in a different way now. So I think I'm in the same world, just a different flavor, honestly. And you know, did I make the right decision? I mean, it's good for me.

But every time a fellow walks in the clinic at Boston Medical Center, oh, am I excited. I get to do a little bit of teaching. I love it. So it's a lot of the same stuff that drives me as used to drive.

The Patient from Hell (45:36.266)
Thank you for sharing that. I can sense the passion, the optimism, and I appreciate you sharing this new story of lung cancer and what we're going to see unfold in the next five to 10 years. Thanks for being a guest on this podcast.