This is the sixth story in a series that marks the 20th anniversary of the publication of papers on the role of EGFR mutation in lung cancer. This multimedia series is guest-edited by Suresh S. Ramalingam, a lung cancer expert, executive director of Winship Cancer Institute of Emory University, and editor-in-chief of the journal Cancer. The series explores the process of discovery of EGFR mutations in lung cancer, the learning curve for using the drugs that target those mutations, and the unparalleled impact on patients with lung cancer and other diseases.
On Nov. 24, 2003, an article in The Boston Globe told the story of a patient’s remarkable response to gefitinib, a drug that had recently been approved by FDA.
Kate Robbins, a patient of Tom Lynch’s, then a lung cancer expert at Massachusetts General Hospital, remarkably appeared to be disease-free after a year on gefitinib (Iressa). She was one of the lucky few—in most patients, the drug didn’t seem to work.
Before she received gefitinib, Robbins had 16 tumors. After gefitinib, they vanished. “It’s the most amazing thing,” 46-year-old Robbins said to The Globe reporter Raja Mishra, who described Robbins as a woman with “big eyes and a round, girlish face” who talked with “energy and enthusiasm.”
Robbins lived another 18 years. She died in 2021, at age 64.
Reading that news story sparked an idea in Lynch’s colleague Daniel Haber, director of the Mass General Cancer Center, a position he holds today.
Chemotherapy produced responses in about 20% of patients, and the responses were almost always short-lived. So, when gefitinib and erlotinib (Tarceva) were developed, not only were they better tolerated—less toxic than chemotherapy—occasionally, in some patients, they created these unbelievable responses.
“He’s the one who had the aha moment that, ‘I think Tom’s patient’s response is due to a mutation in EGFR kinase domain,’” recalled Lynch, who is now president, director, and holder of the Raisbeck Endowed Chair at the Fred Hutchinson Cancer Center.
At that time, chemotherapy was the main approach to treating lung cancer.
“Chemotherapy produced responses in about 20% of patients, and the responses were almost always short-lived,” Lynch said. “So, when gefitinib and erlotinib (Tarceva) were developed, not only were they better tolerated—less toxic than chemotherapy—occasionally, in some patients, they created these unbelievable responses.
“The problem we had when we first developed them was, we just didn’t know who was responding and why. And it was a big unknown at that point,” Lynch said.
Haber’s suspicions about EGFR led him to sequence several lung cancer specimens from Lynch’s patients who had bounced back after taking gefitinib. Eight of the nine patients had EGFR mutations, a finding reported in the New England Journal of Medicine.
Lynch and Haber’s colleague Jeff Settleman, who is now chief scientific officer for oncology research and development at Pfizer, confirmed how EGFR kinase domain mutation created “an oncogene addiction that underlies the growth of the cancer, and why gefitinib as an inhibitor of the EGFR tyrosine kinase was so effective in that setting,” Lynch said.
More than 20 years later, scientists’ understanding of EGFR-mutated lung cancer has progressed immensely. The field now has many options for patients, including drugs that target rarer mutations, Lynch said.
“The catch is, we still haven’t found a way to cure most patients with EGFR-mutated lung cancer,” he said. “The major gap is resistance—the typical patient still becomes resistant after one to two years, and we need new options.”
Gefitinib received a nod from the FDA Oncologic Drugs Advisory Committee in Sept. 2002, two years before scientists understood why some patients responded to the drug while others didn’t (The Cancer Letter, June 21, 2024). The landmark papers describing the role of EGFR mutations were published in April 2004 (The Cancer Letter, April 30, 2004).
Today, as a cancer center director, Lynch is concerned about the ability to make future discoveries due to decreased funding—both in the governmental and pharmaceutical sectors.
“I worry about the cancer drug landscape becoming more crowded and complex, and the attention of pharma moving to other areas that might be less competitive—such as inflammation, auto-immunity, and obesity—at the same time that the federal government is cutting research funding for cancer,” Lynch said. “The NCI budget is what fuels innovation, and it is very much at risk.”
Lynch spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Transcript
Tom Lynch: Well, I mean, Paul, as you know, from the beginning of my career until 2002, 2003, chemotherapy was the backbone of what we did. Chemotherapy produced responses in about 20% of patients, and the responses were almost always short-lived.
So, when gefitinib and erlotinib were developed, not only were they better tolerated—less toxic than chemotherapy—occasionally, in some patients, they created these unbelievable responses that were so much different than the kind of response you got from chemotherapy. Because when you got a nice chemotherapy response back in the day, you would see some modest shrinkage.
They were almost always partial responses. Very, very rarely did you ever get a complete response to chemotherapy. So, these were truly big advances in terms of what they did.
The problem we had when we first developed them was, we just didn’t know who was responding and why. And it was a big unknown at that point.
Well, with so many groups trying to figure out this issue—the issue is Iressa was on the market; Tarceva was moving towards the market. The question was why were some patients responding and some others weren’t.
And your role, of course, as you’re one of the people who figured out what the biomarker was, what to look for among the responders to Tarceva or otherwise.
So, how did you know where to look? Why did you succeed? There were two groups that succeeded.
TL: Paul, there were at least three groups working on it.
The first finding of an EGFR mutation that I am aware of was in the laboratory of David Carbone from Vanderbilt. It was reported it at an AACR meeting, and they initially thought it was a resistance mutation to gefitinib since it was obtained from a patient who had progressive disease. David was working hard on immunologic approaches to lung cancer and did not pursue the resistance mutation at the time.
The problem we had when we first developed them was, we just didn’t know who was responding and why. And it was a big unknown at that point.
There were three other groups working on this. Our group at MGH led by Daniel Haber, a group at Dana-Farber led by Matt Meyerson, and a group at MSK led by William Pao.
The way we got to it was I had a patient who had a remarkable response to gefitinib, and her story was the focus of a front-page Boston Globe article. Daniel Haber, who at the time was a breast cancer biologist, read the article in The Boston Globe, and he’s the one who had the aha moment that, ‘I think Tom’s patient’s response is due to a mutation in EGFR kinase domain.’
So, one morning in Nov. 2003 he called me and said, “Tom, what do you think?” I said, “Well, you know, Daniel,” I said, “I don’t know.” I said, “I can tell you that that has not been proposed yet.” I said, “But I have plenty of patients who’ve had these responses,” because I had a huge practice at MGH at the time, a large practice of all patients with lung cancer.
I sent Daniel specimens from patients who had a dramatic response, and we were able to sequence nine of them. And of the nine, eight had EGFR mutations who had this remarkable response. And then Jeff Settleman at MGH did the molecular physiology that confirmed how the signaling happened, how EGFR worked, and how this kinase mutation oncogene addiction that underlies the growth of the cancer, and why gefitinib as an inhibitor of the EGFR tyrosine kinase was so effective in that setting.
Dana-Farber was doing work where they were sequencing multiple kinases. And they sequenced and found EGFR mutations in lung cancer specimens.
I see. I’m trying to remember what I knew at that time while this was going on. If you look at the transcript of the Iressa ODAC, Otis Brawley, who was an ODAC member then, mentions EGFR, which was kind of fascinating.
He says, “What about EGFR?” And I think I knew it as well at that time. It didn’t surprise me because I think Bruce Chabner must have told me about this confidentially.
TL: Actually, I don’t think we had discovered this at the time of the ODAC, but perhaps some had a lead.
TL: The next big breakthrough that showed that screening for EGFR mutations was important was done by AstraZeneca and Tony Mok from Hong Kong. Because, as you know, Paul, these mutations are so much more common in Asian patients that all the trials of EGFR inhibitors, they’re almost all concentrated, to some degree, in Asia for accrual.
And Tony’s group published the IPASS study in NEJM in 2009. That study showed that if you had an EGFR mutation, it made sense to get gefitinib upfront, and if you didn’t have an EGFR mutation, it made sense to get chemo upfront.
That was very, very important and that got the whole testing of people upfront underway and established that as the way to go.
TL: The patients that we discovered it in were the patients responding to Iressa, correct. And then we started screening everybody upfront.
But it was not trivial in 2004 to do that, because sequencing then was not like it is now. It took a long time—sometimes six to eight weeks. You couldn’t always wait six weeks with a patient with lung cancer for the results to return because the cancer grows so fast. In some patients, you couldn’t wait for the sequencing and you just had to treat them with chemotherapy to start with.
TL: We probably treated 150 patients in my group at Mass General. Dr. Panos Fidias treated many of them. We saw that many responded—around 10-15%.
TL: No. Actually, AstraZeneca made the drug available in a broad compassionate use study. This enabled us to treat patients and get the drug quickly as we collected data.
TL: It was terrific.
TL: Well, I was at ODAC. I was at the ODAC, but I don’t believe we had the mutation data at ODAC.
TL: No, we didn’t.
But what we found was these patients in the compassionate use trial. See, the reason that ODAC carried the day was for the first time ever, patients with lung cancer could get up and say, “I had this unbelievable response.”
And the thing that made it incredible was there were very, very few chemotherapy patients, if any, who any company could bring out who could testify on behalf of their drugs because they weren’t doing well.
So, you finally had this patient population of people who presented themselves to ODAC, and the committee was overwhelmed by these incredible responses in lung cancer. We never ever saw that before.
TL: There was like a 32-year-old woman. I remember her. She got up and talked.
TL: She was incredibly young. It was incredibly compelling.
TL: Yes, I was in the room for that ODAC. It was a very dramatic day. It really was.
Yeah, I keep asking Otis. He can’t remember why he knew to ask why aren’t you looking at the EGFR? It’s interesting. I don’t know where he heard it, but he knew it. He was the only person who mentioned the EGFR in just that way.
So, how would you describe the present landscape for EGFR?
TL: Well, I think, Paul, a couple of things have happened. One is we’ve widely embraced molecular profiling of lung cancer. So, lung cancer, among solid tumors, is genomically profiled probably the most extensively of any of the solid tumors.
The catch is we still haven’t found a way to cure most patients with EGFR-mutated lung cancer. The major gap is resistance—the typical patient still becomes resistant after one to two years, and we need new options.
And we now routinely get not just EGFR, but remember, EGFR was the first of many of the important actionable mutations. ALK being one, ROS1 being another, BRAF being another, RAS being another.
And as you know now, we have osimertinib. We also have fourth-generation inhibitors, and we now have specific drugs that are actionable against rarer mutations, including exon 20 mutations. The field has continued to evolve and to develop additional compounds that work in those settings.
The catch is, we still haven’t found a way to cure most patients with EGFR-mutated lung cancer. Maybe some patients are cured, but they’re very rare, Paul. Very rare to cure patients who’ve got stage 4, EGFR-mutated lung cancer.
The place where it’s going to make the biggest difference, we now know that giving the drugs after surgery are important. And so, adjuvant therapy after surgery seems to make a big difference, or after chemoradiotherapy in stage 3 disease, and this was shown in the past several years, that you are increasing the long-term survival rate.
Roy Herbst and Suresh Ramalingam have both published studies which suggest that anti-EGFR TKI therapy can dramatically improve outcome after treatment of earlier stage disease. It is even possible to think that some of these patients are cured.
TL: The major gap is resistance—the typical patient still becomes resistant after one to two years, and we need new options.
And so, understanding resistance is still important, and understanding how to overcome resistance to improve the cure rate is still the biggest challenge in metastatic disease.
TL: So, the initial findings were that the T790M mutation, the secondary mutation called T790M, was very important in resistance. And then we found inhibitors like osimertinib that work against T790M.
And again, we’re now looking at drugs that target MET, because drugs that target MET also appear to overcome some of the resistant phenotypes.
But this, again, that’s the area of investigation that we’re all looking at now.
TL: Unfortunately, Paul, I am not active in the world of EGFR research now. Instead, I am working hard to lead Fred Hutch in Seattle.
So, I am no longer an investigational lung cancer doc. I enjoyed it. It was fantastic. It was probably the most productive thing I’ve done in my career, but I’m running a large institution now.
TL: I think this is an unbelievable time to be entering cancer research. Okay? Now I’m going to guess that you and I are pretty close in age. I won’t tell you the exact number.
TL: Okay. So, I’m turning 64 in a couple of weeks. Okay? So, we’re pretty darn close.
But if you think about what we’ve seen in our careers, it has been remarkable.
I worry about the cancer drug landscape becoming more crowded and complex, and the attention of pharma moving to other areas that might be less competitive—such as inflammation, auto-immunity, and obesity—at the same time that the federal government is cutting research funding for cancer.
However, I think if you met a 30-year-old doctor right now who is entering oncology, he or she has way more to learn, and so much more is going to happen in their career than has happened during the course of our careers in cancer.
The ability to apply AI to understanding molecular abnormalities is going to be extraordinary. The ability to model protein-protein interactions to come up with drugging targets will be something that used to take years is now going to take a weekend. So, I think you’re going to see great advances.
It will still require clinical trials, and clinical trials still take a long time to do. There’s no really getting around the fact that it’s going to take some time to do the trials, but I think we’re going to see consistent and steady progress in cancer over the next 50 to 75 years.
And my prediction is that cancer will be a very controllable disease. By the time someone who’s born today turns 75, cancer will be a very different threat to them than it is today.
You’ll still have early-stage cancers that need surgery and need radiation, it might need some other therapies, but it’s not going to have the same dramatic negative impact it has now if you or I were to find out we had a glioblastoma or a pancreas cancer. Because that news that you’ve got pancreas cancer isn’t much different now, Paul, than it was in 1965. And so, that’s going to change. It’s going to happen.
So, I think for young people, I couldn’t imagine a part of medicine that would be better than going into this.
TL: Well, you worry a little bit about the time that we’re getting close, and I worry about a couple of things. One, I worry that companies are beginning to think about other areas other than cancer.
Companies are beginning to think of obesity as being a great place to be working in. They see inflammation as a great place to be working in. And don’t get me wrong—those are definite areas that need attention. But Big Pharma and biotech can’t take their eye off of cancer. They’ve made too much progress there.
The NCI budget is what fuels innovation, and it is very much at risk.
And I get worried the feeling is, well, it’s crowded, it’s hard. And so, I worry about the cancer drug landscape becoming more crowded and complex, and the attention of pharma moving to other areas that might be less competitive—such as inflammation, auto-immunity, and obesity—at the same time that the federal government is cutting research funding for cancer.
And so, the NCI budget last year, for the first time since 2012, the actual budget at the NCI decreased.
That’s a problem for us, because the NCI budget, and you know this better than anybody, the NCI budget is what fuels innovation, and it is very much at risk.
These companies are created based off the incredible discoveries that are made at NIH-funded laboratories. And there isn’t a substitute for NIH money.
So, the two biggest threats are focus of pharma and biotech and funding from the NCI.
TL: Yeah. The reason I’m not doing lung cancer research anymore is because I’m spending all my time with the following problem: if I have a fully funded NIH investigator here at Fred Hutch, we still have to raise nearly 25% of the cost of research to support their lab.
So, I’ve got to come up with other ways to cover that gap for the cost of research. And we do. We find other ways to cover that gap, okay. But I’m just saying it’s challenging.
TL: I think this is great. I think we covered most of it.
