May 2024 marked the 20th anniversary of the publication of papers on the role of EGFR mutation in lung cancer. This is a seminal event that changed the history of this disease and that can be traced back to one reason why cancer mortality has been declining in the United States.
The Cancer Letter and the Cancer History Project explore this development in a comprehensive multimedia series consisting of opinion pieces, our real-time coverage, historical documents, and interviews with scientists, clinicians, drug regulators, and cancer survivors.
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.
This is the second story in a series that will explore the process of discovery of the EGFR mutation, the learning curve for using the drugs that target it, and the unparalleled impact on patients with lung cancer and other diseases.
On Sept. 24, 2002, when I showed up at a meeting of the FDA Oncologic Drugs Advisory Committee, I had a pretty good idea that the drug on the agenda—AstraZeneca’s Iressa (gefitinib)—was having a surprising effect on some patients in third-line non-small cell lung cancer.
I knew also that the drug was being given out widely—to nearly 20,000 patients worldwide—through an expanded access program.
Alas, no one knew how to identify potential responders and how to explain their response.
There was considerable hypothesizing about an epidermal growth factor receptor mutation, some playing a role in determining response, but publication of the papers conclusively establishing the link between specific mutations in EGFR and clinical response to gefitinib was still a year and seven months away (The Cancer Letter, April 30, 2004; May 31, 2024).
Today, as the field of oncology marks the 20th anniversary of publication of the papers identifying the role of the EGFR mutations that were mostly seen in either exon 19 or 21 as targets in non-small cell lung cancer, it’s humbling to look back at Iressa’s first date with ODAC and the profound dilemmas the application presented to the committee.
My real-time coverage of the ODAC meeting 22 years ago captured the debates about the puzzling results that FDA and its clinical advisors had to confront without the benefit of knowing the underlying science (The Cancer Letter, Sept. 27, Nov. 8, 2002; May 9, 2003).
Archival materials from that meeting, including the transcript, presentation slides, and other documents, are available on the Cancer History Project and discussed in this issue.
The story of Iressa is also a fascinating case study in accelerated approval, which was granted as advisors and the agency were convinced to take a chance on admittedly weak data, then, under pressure from FDA, the drug was withdrawn by the sponsor after an analogous drug—Genentech’s Tarceva (erlotinib)—demonstrated a survival advantage. Then, in another plot twist, Iressa was brought back on the market after studies conducted in patients selected through a test showed a patient benefit.
Debates in the Kennedy Ballroom
Now, let’s return to that initial ODAC.
In those days, FDA held ODACs at ballrooms of nearby hotels, and the Sept. 24, 2002, was held at Kennedy Ballroom at the Holiday Inn on Georgia Avenue in Silver Spring.
Walking into said Kennedy Ballroom, I was surprised by the number of people who wanted to either testify or witness the proceedings.
It was clear that some of them were patients who had been treated with Iressa.
There was no place for all of them to sit down, so I invited a middle-aged woman and her daughter to sit down in the press section.
We chatted for a few minutes before the meeting began. I assumed the mother was the lung cancer patient. I was wrong. The daughter was.
The mother’s name was Anita Riddle, and the daughter’s name was Adriane. She told me she was 20.
I am a reporter. I don’t root for drugs, but by the time Adriane went up to a mic at the public hearing, I realized that I was rooting for Iressa, this drug that inexplicably made this young woman’s disease disappear.
Recently, when I pulled up the transcript of the meeting, I went straight to Adriane’s testimony:
Good morning and thank you today for this opportunity to speak with you.
When I first learned of this meeting a week ago, my mother and I, we felt it was essential that I come and tell you about my story.
We have come here independently of any sponsorships. Even my doctor, Dr. Natale, didn’t even know I was coming and was surprised to find out I was here.
My name is Adriane Riddle. I am from San Bernardino, California, and I was born in 1982.
I graduated from San Bernardino High School in 2000 and went to San Jose State on a water polo scholarship. I finished out my freshman year, having played the whole season to come home and become very, very sick.
When I came home, I was diagnosed with a tangerine-sized tumor in my right lung and had a complete pneumonectomy on 6-7-2001.
After an MRI and a CAT scan, it showed nine to ten tumors in my brain. It was throughout my lymph nodes and there were nodules in my left lung. I was classified as a stage 4 non-small cell adenocarcinoma.
I have never been around second-hand smoke. I have never picked up a cigarette. I was just this healthy incredible athlete.
After six months of exhausting chemotherapy, I finally had to stop. I couldn’t take it any more. At this time, my tumors appeared to be regressing.
I then found about Iressa from Dr. Natale. He suggested that we try to Iressa expanded-access program. I felt that this trial study showed hope in the midst of very, very few options.
In January 2000, I started Iressa. Since that time, all the remaining brain lesions and nodules in my left lung have ceased to appear. Approval of this drug is very important to me. It has given me a chance to turn 20.
I am no longer a teenager anymore. It has given me a chance to return to college, to just live life, grow.
I urge you to approve this drug because, if someone like me can get lung cancer at age 18, then the future will bring more.
Iressa has helped me fight through this and I feel it was truly the missing link, along with chemotherapy and my surgery. It was a group effort among the options that I decided to take. It has given me a second chance.
Thank you very much for this time. I know you will make the right decision.
For a few weeks before that meeting, I heard FDA-watchers point to AstraZeneca’s expanded access program that the company started after getting encouraging results in phase I and presenting the results at an annual meeting of the American Society of Clinical Oncology.
Working with FDA and the National Organization for Rare Disorders, AstraZeneca enrolled over 18,000 patients worldwide have enrolled into the program. By monitoring supply, the company determined that 40% of patients were continuing the drug beyond 6 months.
Of course, this was a far cry from proof of clinical benefit in a rigorous clinical trial, but it seemed better than nothing.
The case for Iressa
Nothing was slam-dunk in the Iressa application that day.
Initially, the company was going to seek an accelerated approval based on a phase II study of the agent as a third-line treatment for non-small cell lung cancer.
The application was to be supported by data from randomized trials of the agent as a front-line treatment. Soon after getting the drug on the market under an accelerated approval, the company planned to return to FDA and seek approval for the more lucrative front-line indication.
Had things worked out as envisioned, the application for Iressa would have been a no-brainer for FDA. The agency would have likely approved it the way it approved Gleevec, without consulting the ODAC.
In January 2000, I started Iressa. Since that time, all the remaining brain lesions and nodules in my left lung have ceased to appear. Approval of this drug is very important to me. It has given me a chance to turn 20.
Adriane Riddle
Alas, a month before ODAC, AstraZeneca announced that its two randomized trials of Iressa in two-drug regimens used in the frontline treatment of lung cancer showed no advantage to adding Iressa.
Usually, drugs are first approved for later stages of cancer, then advance toward the front line. In the case of Iressa, the chessboard looked different: the agent was check-mated twice in the front line.
Did it matter that the third-line trial tested Iressa as a single agent, while front-line trials tested it in combination with standard chemotherapy? If there has ever been a reason to convene ODAC, this was it.
In a nutshell, AstraZeneca found itself trying to convince ODAC and the agency that the results of its two well-designed phase III studies in the first line treatment of NSCLC were somehow not germane to the application for third-line indication.
This was a difficult argument to make, considering that a positive result would have likely been used to support the application.
Grant Williams, deputy director at the FDA Division of Oncology Drug Products, had this to say:
Whether a 10% response rate in lung cancer is reasonably likely to predict clinical benefit is a good point for discussion.
Clearly, similar response rates in some tumors have correctly predicted subsequent clinical benefit, for instance, the 12% response rate of irinotecan in refractory colon cancer.
However, we also have an unprecedented additional consideration.
We have results from two large randomized studies of excellent design that show no benefit of ZD1839 [Iressa] added to chemotherapy and first-line treatment of non-small cell lung cancer. Ironically, had ZD1839 already received accelerated approval, these studies would have served as the phase IV post-marketing commitment to verify its clinical benefit.
Now that these results have become available prior to a regulatory decision we must weigh the significance of these negative findings on the accelerated approval process.
As the meeting went on, I found myself commenting ODAC procedure to Adriane and her mother.
“Just because the committee members and FDA sound skeptical doesn’t mean the drug is heading toward a ‘No,’” I scribbled on a note pad. “ODAC will surprise you.”
Might it be an EGFR mutation?
Is there any work ongoing to try to define the subset of individuals with cancer who would respond to this drug? Quite honestly, when you just say non-small cell lung cancer, or even adenocarcinoma, you are probably talking about several different diseases that you are treating.
Otis Brawley
As the ODAC discussion went on, I would have bet that Iressa would sink.
Who were the patients benefiting and why was this happening? The committee discussion, especially now that we can read it with 20/20 hindsight, is at the same time humbling and illuminating.
“Is there any work ongoing to try to define the subset of individuals with cancer who would respond to this drug?” asked ODAC member Otis Brawley, at the time an oncologist at Emory Winship Cancer Center. “Quite honestly, when you just say non-small cell lung cancer, or even adenocarcinoma, you are probably talking about several different diseases that you are treating.”
George Blackledge, then clinical vice president of oncology at AstraZeneca, said the company is investigating multiple clues, including a potential role of EGFR:
Yes, I think that you probably are. I think you need to remember that from the findings of trial 39 it is about 40% of the patients who get some benefit. That is, clearly, a very clear 10% who get a response and symptom-related response.
We are looking at trying to identify whether or not there is a specific subset of patients who will respond. I don’t believe that we can do it histologically at the moment. We are looking at EGFR expression. I personally believe it is going to be something more subtle than that.
For example, we are carrying out gene array studies in some of our ongoing trials to try to identify patients more or less likely to respond.
But I think the important thing from the patient’s point of view is that 40% of them are going to gain some benefit from Iressa.
The committee considered a wide range hypotheses about whether the results were a fluke.
One exchange yielded what would now be called a “Pazdur moment,” a point in most ODACs where Richard Pazdur, the FDA “cancer czar,” explains the agency’s interpretation of the regulations and view of the problem at hand.
Pazdur, who came to FDA not quite three years earlier and who at that time was director of the Division of Oncology Drug Products, had this to say:
PAZDUR: I wanted to kind of go over this question before you vote on it, because I think there are several things here that the committee has to understand…
We were rolling around on our merry way here in our division with this 10% response rate and the symptom benefit.
We believed that basically we weren’t going to be taking a look at the symptom-benefit work, per our previous discussion, but we did look at this 10% response rate.
We are looking at trying to identify whether or not there is a specific subset of patients who will respond…We are looking at EGFR expression. I personally believe it is going to be something more subtle than that.
George Blackledge
Then we were kind of floored when the two large studies came into play… We are not asking about a 10% response rate. We approved drugs with a 12, 15% response rate. We already have that history of doing it. That is not the question here. The question is in the context of these two other trials. If we didn’t have these trials, we probably wouldn’t even be here.
We would have already approved the drug on our merry way. We have this data here. We can’t just ignore it. We have to take a look at the whole data package when we look at the approval of the drug.
The question here is not the 10% response rate. It is in the context of these two other trials that are front-line trials.
The observation that this drug does not work with chemotherapy is an observation. It is not an explanation, and I have not heard from the sponsor a viable explanation of why these trials have failed.
If they would like to get up now and give it, I would like to hear it. George?
BLACKLEDGE: Well, Dr. Pazdur, I can hypothesize as well as anyone else.
It is very clear that whatever effects you are seeing with doublet chemotherapy, you cannot, it appears, add to.
That appears to be the case, whether it is another chemotherapy agent or whether it is a novel agent of this kind.
I don’t have the explanation yet, and I don’t think anyone else does. All I can say is that it does seem to be an emerging pattern for both chemotherapy agents added as a triplet and also for novel agents added as a triplet.
Whilst I don’t think we can ignore the data, I do think that it looks an extraordinarily different situation from where we have clearly seen agents, noncytotoxic agents, giving real benefit as monotherapy in various different situations when they haven’t shown any additional benefit in combination.
I think that, whilst you must take these data into effect, use as a monotherapy for clinical benefit and for response which leads to clinical benefit is a very, very different situation.
PAZDUR: One of the problems that I see with that answer, George, when you take a look at this drug when it is favorable to your situation, you may look at it as a chemotherapy drug. When it is not favorable to your situation, you take a look at it as a special agent here, which is somewhat perplexing to me.
Ultimately, the committee agreed with the chair, Donna Przepiorka, a malignant hematology and transplantation expert at the University of Tennessee.
Said Przepiorka:
I think it is very clear there is clinical benefit in the single-arm study, but I think the questions being asked in the randomized studies are completely different questions.
Although we don’t know why, I am not sure we actually know that the inhibition of the kinase is actually the mechanism of action that this drug uses because there doesn’t seem to be any correlation with EGFR expression.
I don’t know that anybody right now could actually answer your question about why the combination does not work because I don’t think we have enough information available.
ODAC recommends approval
That day, ODAC voted 11-3 that Iressa’s response rate constituted sufficient grounds for an accelerated approval.
Next to me in the press section, Anita and Adriane Riddle were elated.
For a moment, I shared their delight at seeing ODAC recognize that something about that drug was compelling enough to warrant suspending disbelief. The vote recognized that something was out there, some crucial piece of information that perhaps would ultimately declare itself.
Indeed, the story didn’t end there.
A confirmatory randomized trial powered to detect survival came up negative, causing great disappointment and cessation of further clinical investigations by NCI-funded clinical trials cooperative groups (The Cancer Letter, Jan. 7, Jan. 21, April 22, 2005).
Meanwhile, the data for a similar agent, Genentech’s Tarceva (erlotinib), was positive for extending survival, and the drug was approved for second-line indication in November 2004. This two-month survival advantage (6.7 months for Tarceva vs 4.7 for placebo) was visible even without limiting the population to patients with specifying the population.
As a result, in 2005, FDA placed Iressa in a limited access program (The Cancer Letter, June 24, 2005). The drug was to be available only to patients who were at the time responding to the therapy or had responded to it in the past. All others were to be switched to Tarceva.
Although we don’t know why, I am not sure we actually know that the inhibition of the kinase is actually the mechanism of action that this drug uses because there doesn’t seem to be any correlation with EGFR expression.
Donna Przepiorka
It’s unclear why, in trials conducted in an unselected population, Tarceva showed a survival advantage while Iressa failed to do so. Some hypothesize that Iressa would have performed better if it had been administered at a higher dose, but this, of course, will never be known.
The science that would ultimately explain response to Iressa and Tarceva started to emerge in the midst of the Iressa controversy (The Cancer Letter, May 6, 2005).
Methodology for determining response to the drug is covered by U.S. patent #7294468, which has the priority date of March 31, 2004, and a publication date of Nov. 13, 2007. The technology was invented at Dana-Farber Cancer Institute and Massachusetts General Hospital.
Though the Iressa was almost completely withdrawn in the U.S., it remained on the market in about 70 countries.
In Europe, the drug’s indication was expanded to all lines of therapy of metastatic or locally advanced NSCLC with activating mutations in 2009 (The Cancer Letter, July 31, 2009). The European approval of Iressa was based on two non-inferiority trials.
- One trial, called INTEREST, compared Iressa with Taxotere (docetaxel) as second-line treatment for NSCLC.
- The other, IPASS, compared Iressa with carboplatin and paclitaxel as a front-line therapy in a cohort enriched with groups that are known to respond to this class of drugs: Asians, non-smokers, and patients with adenocarcinoma. Also, 79% of patients enrolled were women, another group believed likely to have a better response to Iressa.
In 2015, the science finally caught up with Iressa, and the drug was brought back on the US market, this time with a companion diagnostic (The Cancer Letter, July 17, Aug. 7, 2015).
After pulling up the transcript of the Sept. 24, 2002, ODAC recently, I googled Adriane’s name, hoping that the response she had to Iressa had continued, and that she is alive, well, and eager to talk about the drug that made her disease go away.
I learned instead that Adriane had died eight months after that ODAC meeting and a year before scientists pinpointed why her tumors had regressed.
