The Key that Unlocked Lung Cancer

TRANSCRIPT:

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Dr. Alicia Morgans:  This is the good news about cancer. I'm Dr. Alicia Morgans.

Dr. Charles Ryan: And I'm Dr. Chuck Ryan.

Alicia: We're oncologists and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than there ever has been. And we're here to share that with you.

Chuck: In each episode of this show, we'll talk to one of our colleagues about a new development in cancer treatment or diagnosis. We'll break down what's new, why it matters and how it points the way forward.

Dr. William Pao: Previously, the overall survival of patients untreated was six months, and with chemo was about eight months.  Patients now have a median overall survival of 36 months, plus. It's still not long enough, but it's still a dramatic increase, compared to 2000. 

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Alicia: So, you know, Chuck, I think one of the things that's so stressful about cancers – particularly lung cancer – is that it's really hard to treat and it's a really symptomatic disease, so it causes a lot of trouble and suffering. And it also seems just overwhelming in the number of people it affects and the difficulty in treating it.

But what I think is so exciting is that if you take a big problem and you break it down into manageable pieces and really understand that this lung cancer is different than that lung cancer, which is different than the other lung cancer, we might be able to really, really target our treatments and make big differences, in a big problem, with little steps. 

Chuck: It's a huge point, and thanks for making it. Lung cancer is many diseases, and we've come to appreciate that even more over the last decade or so. And one of the ways that we know that it's different diseases is because of the genes that are mutated or the genes that are present in various subforms. So that's been a really exciting development. 

And we are now, you know, 20, 21 years after some of the initial developments, and it's really with this, uh, retrospective view on 20 years of progress that we can appreciate the good news that's been made here.

Alicia: I'm so excited today to really dig into ways that we can target mutations and break down really complicated cancers so that we can attack them and really treat them so effectively. 

You know, there's nobody better to talk to than your good friend and mine, Dr. William Pao.

Chuck: Your former boss.

Alicia: Yes, of course, that too. 

Chuck: And  my former fellow fellow, we trained together at Memorial Sloan Kettering years ago and have been friends for a long time. He has gone on to do some great, amazing things in his career. Most notably for this episode, he was one of the folks who identified a mutation, as you indicated, in lung cancer that led to the development of a drug, that now hundreds of thousands of people take, probably millions of people will take before all is said and done, and prolongs life, which is amazing.

Alicia: One of the things that we know about cancer just on a fundamental level is that it's a disease of mutations of genetic material or DNA. And it's those mutations, it's those mess-ups that happen in the DNA that make a cancer cell immortal. They can live forever. They can move, they can travel through the body, and they can cause destruction just because of these little errors in their genetic material that give them superpowers. And when we can understand what those mess-ups are, what those mistakes are in the DNA, we can target them. 

And that's what William Pao really helped us to understand. In lung cancer, and I think the field has continued to take that well beyond. So really excited to talk with him about how he made those steps and how he took it all the way to a drug.

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Alicia: William, I wonder if you could tell me a little bit about the story of why you actually got into work on lung cancer, and what it was that drove you to be interested in solving this really complex problem.

William: So I got interested in lung cancer as a medical oncology fellow, for several reasons. One was the outcomes were incredibly poor back in 1999, 2000– 

Chuck: 2000, 2003. 

William: Yeah, where the bar was so low, I felt that translational medicine and science could potentially bring some benefit there. You know, lung cancer is the leading cause of cancer-related death in the United States and worldwide. For patients who unfortunately are diagnosed with stage four lung cancer, the overall survival if you were untreated was basically six months, less than half a year. If you got chemotherapy, it was about eight months. I mean, this is the kind of survival we were talking about at the time. And that was the state of the art treatment.

Chuck: So the only treatment was chemotherapy, the response rates were low, and the survival was eight months.

William: Correct. Less than a year. So, you know, we had to make a change with that.

The second reason was mentorship. As you know, we rotate through different areas and work with different people, during fellowship. And Mark Kris, who was running the thoracic oncology service, took mentorship seriously.

And then the third reason was I was in the laboratory of Harold Varmus, who at the time was working on mouse models of lung cancer. And in the mouse model of lung cancer, he had made what's called an inducible gene expression model, where you can turn on and off an oncogene in the mouse lung. So you could turn on the oncogene in the mouse lung and they would get lung tumors. And you could then turn them off and the tumors would disappear.

Alicia: So you talked about the mice and you could turn basically– turn their cancers on, turn them off. How did you see a way to potentially do that in, in people? Can you tell us that story?

William: Yeah, so, we would see patients in the clinic. And in particular, there was a middle-aged woman who came from upstate New York to see Mark Kris – I was a fellow at the time. And her local oncologist had actually told her to go to hospice, meaning, you know, he didn't have any other options left.

So she came literally in a wheelchair on oxygen, supplemental oxygen, and told us her story. And she also told us that she had never smoked cigarettes. Now back in 2000, that was a very odd thing to hear because, you know, lung cancer is intimately associated with smoking. Anyway, she came to us, and we were fortunate to have an experimental medicine at the time called gefitinib. 

And so I remember we gave her the prescription. And she called Mark Kris’s office – he told me this later – she called his office literally within three days and said she felt like a new woman. She had stopped using her supplemental oxygen and she was actually out of her wheelchair and felt totally normal.

So this was quite remarkable. We actually asked her to get a chest x ray five days later, after starting. And when you compared her chest x ray pre and post starting that, it was like night and day. So basically, before treatment, she had all this white fluffy stuff in her lungs, which was the cancer, and five days later it was all gone.

So, you know, there's something called the Lazarus, you know, concept, where a patient really comes back almost from the dead. And seeing that really motivated me and a lot of other people who had seen that – rarely – to try to figure out why these patients were benefiting in such a dramatic way.

Chuck: These are the moments that cancer researchers dream of. So why did this happen? Tell us about the target. This was the beginning of the era of targeted therapy that we are still in, and I think you were right there at the cutting edge, and where’d it go from there?

William: Yeah, so basically, their tumors were shrinking in the same way that we saw in the mice. So, we figured there must be something going on there. So, inspired by patients like this woman who had dramatic responses, you know, a number of– it wasn't me alone, many people, including say Vince Miller at Memorial Sloan Kettering, Mark Kris, but also people at Mass General Hospital, Dana Farber Cancer Institute and others– started to really wonder how is this possible? Like, why are certain patients who get this treatment benefiting so dramatically?

I didn't mention that if you gave gefitinib at the time to 10 patients, only one out of 10 patients would have this dramatic response. So one of the first things that was done was to figure out, like, can you identify characteristics of these patients who may benefit?

And so it turned out, as I mentioned, never-smoking history despite having lung cancer was one. Females tended to respond more. And then for some reason that we didn't understand at the time, also people of East Asian descent were more likely. So those were some characteristics that came out. 

And then, most importantly, though, we knew that the target of gefitinib – and there was also a related drug called erlotinib – was supposed to be a gene product called EGFR, or epidermal growth factor receptor. So the logical hypothesis was that maybe there's something altered in the EGFR gene in these patients that might give them increased sensitivity to the drug.

Chuck: With this new medicine, gefitinib, we're not talking about a chemotherapy or even really that toxic of a drug. Tell us about that.

William: So in the late 90s and early 2000s, basically, companies had developed these epidermal growth factor receptor or EGFR tyrosine kinase inhibitors. These were the first time that these had come out in the clinic. So people finally had, for the first time in the world, their hands on targeted therapy that would inhibit the epidermal growth factor receptor. 

So when these molecules were developed, it was just assumed that you give it– if you had, you know, 100 lung cancer patients, 100 colon cancer patients, 100 whatever kind of cancer patients, that most of them would benefit. But as I mentioned, only 10 percent really, had a super response. And the rest of them actually didn't get much benefit at all. 

Alicia: So, William, how do you go from, giving this drug to all people, seeing some people have these amazing Lazarus effects and rising up out of their wheelchairs and, you know, stopping their oxygen, to a situation where you ultimately are testing tumors, giving the treatment to people who you know have a very strong likelihood of benefiting, and really taking lung cancer as a larger concept and carving it up into little groups where we can consider using targeted treatments and having amazing effects in groups of people who are most likely to benefit?

William: Yeah. So basically, observing that these patients had these dramatic responses and knowing some of the characteristics, what we decided, at least at Memorial Sloan Kettering, was: let's try to analyze the tumors in these patients – if we could get tissue – and see if there was something altered in EGFR and also potentially other genes. EGFR, again, was the most likely gene because that was supposed to be the target of the drugs. 

So then in collaboration with the surgeons and the pathologists and people who got tumor specimens, we were able to get a pilot experiment. And then in December of 2003, we actually found the very first, at least for us, a patient who had a mutation in EGFR. 

We didn't understand its significance at the time, and you know, scientifically, to publish something like that, we wanted more than just one case, right? If you just publish an N of one, or one example, then people might say, “Oh, well, maybe that's just a fluke.” So then we spent time trying to find more samples, and unfortunately we ended up getting, uh, scooped basically by our colleagues at Harvard including Mass General and Dana Farber who were working very hard on the same problem.

But, you know, science can be a competitive sport, which is good ultimately for patients and for discoveries.

Chuck: So, just to clarify for listeners, EGFR is known to be present on lung cancers, but that wasn't really enough for the patients to respond to the drug blocking it. They really had to have a mutation in the gene that led to the protein that's on the tumor's surface.

And so it was really that discovery that, in a way, came after you had started dosing the patients. And, you know, it was after the drug was really kinda out there.

William: Yes, I mean, in drug discovery you like to think that everything is logical and that we know everything and we know exactly which patients will benefit, but often when we get into the clinic for the very first time, despite all the best knowledge that we have, we find some accidents that, you know, then serendipity, comes into play.

And as you probably know, Louis Pasteur has said, “Chance favors the prepared mind.” So, you have to be able to take advantage of those serendipitous moments. But yes. So it turns out today we know that about 10 to 30%, depending on what geography you're from in the world, lung cancer patients have these EGFR mutations, which are genetically tested for.

And those are the patients who dramatically respond to these drugs. Now, it did take a long time. It took another five years for that to become accepted widely. There were a lot of skeptics, actually, not only from the pharma side, but also from the academic side. And it took a prospective study published in 2009 to firmly establish that EGFG receptor mutations were the best predictor of response to these drugs.

Alicia: So, William, can you tell me a little bit about patients who have EGFR mutations today? What can they expect in terms of their options for treatment? What does their treatment look like? And how long might they be able to stay on treatment? 

We talked before about patients having a life expectancy of 6 months, maybe 8 months if they had some mildly effective chemotherapy. But I don't think things look like that for these patients today.

William: Yeah, I mean, there's been dramatic improvement in overall survival in many patients with lung cancer now, particularly from targeted therapies, such as the ones that we've been talking about that target the epidermal growth factor receptor. 

Today, there are new medicines, I happen to have helped play a role preclinically in the development of one of them, called AZD 9291 at the time, but that's now osimertinib. Which is originally approved in patients with second line plus treatment metastatic lung cancer, and then now it's first line, and now it's even adjuvant. 

The most important thing is where you mentioned previously that the overall survival of patients untreated was six months and with chemo was about eight months. Patients now have a median overall survival of 36 months plus. It's still not long enough. But it's still a dramatic increase, compared to 2000.

Chuck: So compared to chemotherapy, you've quadrupled the survival, basically, over the last 20 years. 

William: Yeah.

Chuck: You made another point though, that the mutation discovery came after the drug was initially invented. And then you made a point that there are new drugs. And I think you skipped over a pretty substantial body of work where you identified that there were mutations that drove resistance to the first set of drugs, which I think is what really exploded the area and made osimertinib the substantially beneficial drug that it is today. And you were involved in that. So tell us.

William: Yeah, so basically after having identified EGFR receptor mutations as the basis for sensitivity, then the next major question became, well, why did patients initially respond but then eventually have their cancers progress?

And here, we were actually learning from our colleagues, who were treating patients with chronic myelogenous leukemia, or CML, where they had the wonder drug called Gleevec, or imatinib, that worked very well. Actually, that's probably one of the first really, effective targeted therapies in cancer. 

And there they had shown that when patients got resistance, they actually got a second mutation in the gene that was being targeted, that somehow blocked binding of the drug or made it less effective. So the logical hypothesis for us was: there must be another mutation in the EGFR gene that is doing the same thing. We just had to prove it.

So long story short is we did indeed find a second mutation. It was a mutation called T790M in EGFR. And other subsequent studies showed that about half of patients had this particular mutation. So that discovery did lead to, ultimately, the approval of osimertinib only 10 years later in 2015.

Chuck: And more recently, it's become something that patients take after surgery to prolong their survival and really reduce the likelihood of a recurrence, correct?

William: Yeah, it's amazing. There was a large study that was presented at ASCO this year, and it was quite remarkable. I actually haven't been in the room when people– when the speaker gets a standing ovation. But after Suresh Ramalingam gave his presentation, the data were so convincing that I think most of the room got up and started clapping, which was quite amazing. And most importantly, you know, it should help patients. 

Chuck: When you're in a conference and there's 4,000 doctors and you're doing a presentation, and they get up and give a standing ovation, it's because they know that the hundreds of patients that they're going to be able to treat are going to benefit from these therapies. 

And the numbers just keep magnifying and it's an overwhelmingly good feeling as a doctor to see progress in the field like this. And for it to go from an idea in mice, et cetera, to literally hundreds of thousands of people who are out there, walking around, living lives because of the work that you did, it's– it's amazing. So what's next for lung cancer?

William: Since the initial discovery of EGFR mutations, there have been discovery of more, what are called “driver mutations,” or more of these same types of mutations. So now we can even segment lung cancer into multiple different subtypes, you know, one driven by this gene, another one driven by this gene and so on.

And I think virtually all of those– most of those genes that are druggable now, have drugs that are available. And so, I would recommend, you know, the patients definitely get their tumors tested genetically because they may be eligible for one of these targeted therapies. 

Then, immunotherapy has been a big breakthrough also. We didn't really talk about that, but that's where therapies allow the immune system, or reactivate the immune system, to recognize cancers, and to then attack those cancers. And that has been a huge breakthrough and patients are living longer because of that as well. 

But there's still patients who are not benefiting. There's still subsets of patients who do not have a targetable mutation, so to speak. So we need to just continue to do more research and also figure out how to help patients, again, live longer with a better quality of life. But I'm very optimistic that there are going to be new breakthroughs coming, you know, every year.

Alicia: When you think about the good news in cancer and you think about looking forward, what is your vision for tomorrow and for patients who are still to come?

William: Right, well, I think that the pace of research and drug development is ever faster. And I would call this the biological century, really, because, we're understanding more and more about processes of biology, we've also got established protocols or ways of doing clinical trials now and so on, and, and a lot of scientists working on the problem.

So I'm very optimistic that there'll be more breakthroughs faster, than ever before. In my book, you'll see that some of the arcs of the stories take a hundred years, right? From the original clinical description to a breakthrough, maybe 40 years later to another breakthrough 30 years later, and then finally a drug like another 30 years later. But the pace of drug discovery is ever-accelerating and so I'm very optimistic that there'll be new breakthroughs. for various kinds of cancers, in the years to come.

Chuck: Well William Pao, I've known you now for 25 years. We were fellows together at Memorial Sloan Kettering and it's– I'm really proud to know you. I'm proud of the work that you've done, and can only imagine the pride you must feel thinking about all the people who are out there living lives and doing interesting things –  raising families, being parents and friends etc – who are alive today because of your work and the work of the teams that you've been a part of. 

And that is a good news story. And it's also the middle of a good news story, which is to say we've seen the beginning and we're now seeing more and more progress. And we can only hope that we'll see further acceleration of benefit for those patients who face a lung cancer challenge. So thank you for joining us on this podcast, we're really proud to have talked to you.

William: Thanks a lot, Chuck. Thanks, Alicia. It was a great opportunity to be with you guys. And obviously, I have the equal respect for you guys and what you're doing in prostate cancer and other areas.

Alicia: Thank you. 

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Chuck: Lung cancer is the leading cause of cancer death in American men and women. And I believe – if I'm not mistaken – the leading cause of cancer death worldwide. So any progress on this scale is going to impact hundreds of thousands, if not millions of lives. And for those of us who have dedicated our careers to cancer research, this is the stuff that we dream of, uh, working on something that has such a huge impact.

Alicia: As usual, William just says some things that are so exciting, so amazing and really encouraging about where we're going. 

Chuck: Yeah. William’s had a great career, made a huge impact in the lab. He discovered this mutation led to a treatment for lung cancer. Then he was head of oncology at Vanderbilt and actually held leadership positions in research and development at both Roche and Pfizer. Now he's got his own startups, a biotech company. And on top of all that, has his book Breakthrough: The Quest for Life-Changing Medicines released in January 2025 from One World Books, and I really enjoyed reading it in preparation for this interview.

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Alicia: Thanks for listening to the good news about cancer. I'm Dr. Alicia Morgans, a medical oncologist at Dana Farber Cancer Institute in Boston.

Chuck: And I'm Chuck Ryan, also a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. 

Thanks to Lilly for support of the show.

Alicia: Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post production by Jose Miguel Baez. And there's a whole lot more good news to talk about, so make sure you subscribe to this show wherever you listen to podcasts.

Chuck: And if you liked the show, share it with someone you think might find it interesting. 

We'll be back again soon with more good news about cancer.