In last week’s issue of The Cancer Letter, Raja Flores wrote a guest editorial explaining how he, with his expertise in thoracic surgery, took issue with a nuance in a recent Keytruda commercial.
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In this week’s episode of In the Headlines, Flores spoke with Paul Goldberg, editor and publisher of The Cancer Letter, to explain how his deep dive into the issue led him to discover a broader issue in oncology: How loose terminology among oncologists, however innocuous or inconsequential it might seem, could lead to patient harm.
“When you look at early stage lung cancer, and for this particular commercial, as a surgeon, I’m concerned that if all patients, not 3As or stage 2s, but if stage 1s get neoadjuvant therapy, they may miss their shot at being cured.”
The commercial advertises the utility of preoperative Keytruda for people with “early stage” lung cancer. The commercial is supported by data from a clinical trial and an FDA approval, but the oncology community’s loose terminology when it comes to staging (at least in lung cancer), seems to have led to the commercial targeting all “early stage” patients, when the data supports preoperative Keytruda for patients with stage 2 and 3 disease, not stage 1.
“That’s the important point is that the commercial doesn’t talk about what was in the supplemental forms of that paper that was published in The New England Journal of Medicine,” Flores said. “About one out of every five patients who underwent preoperative therapy, preoperative Keytruda, did not make it to surgery.”
Flores researched the commercial’s history to understand how it got through the endless regulations that govern medical advertising.
“I started doing my homework about this label of ‘early stage.’ And I tried to find out the first time it was used in the KEYNOTE-671 trial, the trial that the commercial is based on,” Flores said. “So, I went to clinicaltrials.org and I went to the first online publication of the trial and it said preoperative therapy for stage 2, stage 3A, and stage 3B. I said, ‘Okay, that doesn’t say early stage.’ Then several months later, in an ASCO abstract, the same authors had down the same title, 2, 3A, 3B. But then, within the abstract, it mentioned for the first time, early stage lung cancer.
“Then I said, ‘Huh, interesting.’ Then when you go to the publication in The New England Journal of Medicine, in the title, it doesn’t say 2, 3A, 3B. It says early stage lung cancer.
“Then I said, ‘How did this get passed by the FDA?’ Then I went to the FDA records and I looked in the FDA records and I could see that when this trial or when these drugs went up for their label, it didn’t have a committee meeting. They felt that the data was compelling enough, and so it passed the FDA.
“So, when you look at all the safeguards that we have in place: FDA, peer-reviewed process, The New England Journal of Medicine, clinical trials office, it completely missed this thing about early stage lung cancer.”
This Keytruda commercial is only one iteration of a broader concern, Flores said.
“I’m in the middle of continuing to investigate this,” Flores said. “And in the end, I’m kind of concerned that we’ve gotten so loose with our oncologic terminology because if you’re speaking to another doctor and you say early stage, they’re going to say, ‘Well, what specific stage are you talking about?’ And then we have a discussion, stage 2, stage 3, etc.
“A lay patient doesn’t have that same, ‘Well, what exactly are you talking about?’ So, when what we know in medicine gets translated to a layperson, there’s a lot of things that can get missed. And I think the safeguards that we have up to protect patients, how we have failed is that we haven’t standardized the terminology.
“It’s actually something that has penetrated the oncologic culture for the past several decades. And I think it’s time to shine a light on it and shift how we talk about it because it’s confusing, at least confusing my patients,” Flores said.
This episode is sponsored by the American Society of Clinical Oncology. Learn more at asco.org/ascoaction.
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This episode was transcribed using transcription services. It has been reviewed by our editorial staff, but the transcript may be imperfect.
The following is a transcript of this week’s In the Headlines, a weekly series on The Cancer Letter Podcast:
Jacquelyn Cobb: This week on The Cancer Letter Podcast…
Raja Flores: And patients nowadays more than ever have access to everything that doctors have access to. They can pull down studies from the New England Journal of Medicine. They can pull up approvals from the FDA just on the internet. So we’re in a different time period now, and I found the commercial to be confusing too many of my patients. So I felt like I should write about it because a big part of that commercial was stressing early stage lung cancer, which for a surgeon, early stage lung cancer is a small lesion without lymph node involvement where you take it out and they’re cured.
Paul Goldberg: You’re listening to The Cancer Letter Podcast. The Cancer Letter is a weekly independent magazine covering oncology since 1973. I’m your host, Paul Goldberg, editor and publisher of The Cancer Letter.
Jacquelyn Cobb: And I’m your host, Jacquelyn Cobb, associate editor of The Cancer Letter. We’ll be bringing you the latest stories, groundbreaking research, and critical conversations shaping oncology.
Paul Goldberg: So, let’s get going.
Welcome to In the Headlines, a weekly podcast of The Cancer Letter. With us today, we have Dr. Raja Flores, who’s the chairman of the Department of Thoracic Surgery and the Steven and Ann Ames Professor in Thoracic Surgery at Mount Sinai. On Aug. 7, in the issue of The Cancer Letter, we published Dr. Flores’s illuminating editorial about the… Well, I guess it’s really about the Merck commercial for Keytruda’s neoadjuvant indication, but it’s really kind of broader than that, which is why we are happy to have Dr. Flores here to talk about the overall overarching, underlying, whichever you wish, issues involved. So Dr. Flores, welcome. And I guess I might just as well jump in and ask you about this television commercial that got a bee in your bonnet. And it’s about the neoadjuvant Keytruda based on the KEYNOTE-671 trial.
Raja Flores: So thank you for having me. I appreciate it. And it’s interesting, I was sitting there watching TV, and actually it was last year when I first saw the commercial was watching the Knick game. And then I see the commercial and it’s about giving Keytruda before surgery for early stage lung cancer. And I didn’t really pay it any mind. Then over the next several months, many patients would come up to me in my office and ask me, patients with stage 1 lung cancer who just needed surgery and nothing more, one centimeter small lung cancers and say, “Hey doc, should I get Keytruda?” I’m like, “No, you don’t need anything. This is curable just on its own.” And that’s when it started occurring to me that they have been seeing this commercial. And then I recently saw a new commercial for Keytruda that came out talking about QLEX where it’s a one-minute subcutaneous injection of Keytruda for those. And again, in the commercial, several times it was stated, several times it was written, early stage lung cancer.
And it just caught my attention because we’re in a time period today where messaging like that is going directly to patients. And patients nowadays more than ever have access to everything that doctors have access to. They can pull down studies from the New England Journal of Medicine. They can pull up approvals from the FDA just on the internet. So we’re in a different time period now. And I found the commercial to be confusing too many of my patients. So I felt like I should write about it because a big part of that commercial was stressing early stage lung cancer, which for a surgeon, early stage lung cancer is a small lesion without lymph node involvement where you take it out and they’re cured.
Jacquelyn Cobb: [ADVERTISEMENT] Is your head spinning from the pace of health policy news? Are you struggling to figure out what it all means for the cancer community? Find the resources you need on ASCO in Action, the online information hub from the American Society of Clinical Oncology and the Association for Clinical Oncology. ASCO in Action has news and analysis on issues like federal research funding, prior authorization and reimbursement, and visitors can find ways to get involved in advocacy efforts. Visit ASCO in Action at asco.org/ascoaction, all one word, today.
Paul Goldberg: I steal my best material from Michael Friedman, who is the former FDA acting commissioner, former head of City of Hope and many other things. And once I called him and said, “How are you, Mike?” Hoping to steal some of his material. And he says, “Well, this weekend I was watching television and there were all these commercials, the dancing diabetics and so forth. And I said to myself, ‘Who is the idiot who allowed all of this direct-to-consumer advertising to happen?'” Then I thought about it, then I was like, “Oh, that was me.” So stealing from Michael. So the question though I have is it’s kind of, I guess, an easy target commercials. But in this case, what was interesting about your story to me was the way you wrote it, which was that it kind of makes you do your job better to explain the nuanced decision that goes into neoadjuvant Keytruda use.
Raja Flores: And that’s the important point is that the commercial doesn’t talk about what was in the supplemental forms of that paper that was published in New England Journal of Medicine. About one out of every five patients who underwent preoperative therapy, preoperative Keytruda, did not make it to surgery. So when you talk about early stage lung cancer, as a surgeon, you want to make sure you can cure that patient. And then when you look at the patients that were enrolled in the trial, they were stage 2, stage 3A, and stage 3B. And really in thoracic surgery and in many other cancers, 3A, 3B is not considered early stage, it’s late stage. So it’s a little confusing. Then I started doing my homework about this label of early stage. And I tried to find out the first time it was used in the KEYNOTE-671 trial, the trial that the commercial is based on.
So, I went to clinicaltrials.org and I went to the first online publication of the trial and it said preoperative therapy for stage 2, stage 3A, and stage 3B. I said, “Okay, that doesn’t say early stage.” Then several months later in an ASCO abstract, the same authors had down the same title, 2, 3A, 3B. But then within the abstract, it mentioned for the first time, early stage lung cancer. Then I said, “Huh, interesting.” Then when you go to the publication in The New England Journal of Medicine, in the title, it doesn’t say 2, 3A, 3B. It says early stage lung cancer. Then I said, “How did this get passed by the FDA?” Then I went to the FDA records and I looked in the FDA records and I could see that when this trial or when these drugs went up for their label, it didn’t have a committee meeting. They felt that the data was compelling enough, and so it passed the FDA.
So, when you look at all the safeguards that we have in place, FDA, peer-reviewed process, The New England Journal of Medicine, clinical trials office, it completely missed this thing about early stage lung cancer. Then I said, “Well, what about other cancers?” Because when you look at early stage lung cancer, and for this particular commercial, as a surgeon, I’m concerned that if all patients, not 3As or stage 2s, but if stage 1s get neoadjuvant therapy, they may miss their shot at being cured. So I said, “Where did this early stage come from?” And then I looked at some other cancers. I looked at breast. I looked at colon. I looked at melanoma. And surprisingly to me, those other cancers will also include stage 3A as early stage. When you look at breast, there’s a trial that came out in Nature Medicine last year that labeled as early stage this trial, which included inflammatory breast cancer with negative lymph nodes.
So I was like, “Whoa.” And then I looked at colon cancer and stage 3A colon cancer sometimes wrapped into it. So I’m in the middle of continuing to investigate this. And in the end, I’m kind of concerned that we’ve gotten so loose with our oncologic terminology because if you’re speaking to another doctor and you say early stage, they’re going to say, “Well, what specific stage are you talking about?” And then we have a discussion, stage 2, stage 3, et cetera. A lay patient doesn’t have that same, “Well, what exactly are you talking about?” So when what we know in medicine gets translated to a layperson, there’s a lot of things that can get missed. And I think the safeguards that we have up to protect patients, how we have failed is that we haven’t standardized the terminology.
When you look at melanoma, they’re very specific. Stage 1, stage 2 is early. Stage 3A melanoma, they say that’s locally advanced. But then you got stage 3B lung cancer in the KEYNOTE-671 trial where it’s being labeled as early stage, we know that’s advanced lung cancer.
Paul Goldberg: Yeah. No, I think we have an opportunity here to coin the phrase like grade inflation. Would this be called stage deflation?
Raja Flores: You know, that’s a good point. I like that name and I think it captures what’s happening. But it’s interesting when I dive deeper, I saw the breast thing getting conflated in the ’90s. I saw the colon cancer thing being conflated in the ’80s. So someone may right away want to point a finger to pharma and say, “Well, pharma’s doing this.” But it’s actually something that has penetrated the oncologic culture for the past several decades. And I think it’s time to shine a light on it and shift how we talk about it because it’s confusing, at least confusing my patients.
Paul Goldberg: Yeah. I wonder if we should. This is another historic moment. Would you consider writing a story about this?
Raja Flores: Oh, absolutely. Absolutely. I’m going to do a little more homework, but absolutely, I’d love to.
Paul Goldberg: Yeah, because what this says is why is this happening is not addressed here yet. We know what is happening, but why? Can we talk about potential wise? Because you’re saying it’s not pharma, so that leaves only academic oncologists. So are they the culprit?
Raja Flores: Well, I don’t know if it’s not pharma. I don’t know if it’s medical oncologist. Some of these studies are funded by pharma. So it’s a combination of everybody involved in cancer medicine, including surgeons. And I don’t think there’s any maliciousness in it, but I think it points to some blind spots. And even though we have FDA, peer-reviewed, all these safeguards in place, this has still fallen through the cracks. And I haven’t seen anyone address it. And I think we have an opportunity here to shine a light on something that is confusing patients. Because when you look at, let’s say, the International Early Stage Lung Cancer Project, it’s focused on stage 1, catching patients at stage 1 lung cancer where it is curable without chemo, without radiation. And when you look at KEYNOTE-671, 3B is under that umbrella of early stage lung cancer. Now, I think they’re confusing resectable with early stage.
We know that you can have an advanced cancer and it may still be resectable, but that is not early stage. So I think we have to fine tune how we speak about things in our world of medical oncology because now patients have access to it. And matter of fact, I just got a call from a patient who saw their results before I did on Epic. So nowadays patients have access to things hot off the press. And I think we owe it to them to clarify what we mean by early stage. And we need to standardize it because early stage for melanoma is different than early stage right now for lung cancer or breast cancer. And I think we need to standardize how we talk about this, keeping in mind it’s not just cancer doctors talking to each other anymore. It is patients who have tapped into the sources that we use.
Paul Goldberg: Yeah. Actually, you mentioned I-ELCAP. There, it’s actually not even stage 1 if I remember correctly. Correct me if I’m wrong, but we’re talking about nodules, we’re talking about schmutz, we’re talking about dirt. And so basically it’s a question of what do you do with a nodule of this size versus a nodule of another size. It’s not really early stage disease, it’s dirt. And then I remember actually having a conversation with Claudia Henschke about it when she was objecting to randomized trials to NLSD. And she said, “Well, the only way you can randomize ethically is if you look at people with a certain size nodule versus another size nodule and you operate on some and not others, and then you can randomize, otherwise unethical.” Later she became a champion of NLSD, but that’s another matter. And boy, are we off the subject? We’re off the subject to the point where… But let me just put on my rose. Am I wrong, by the way?
Raja Flores: About-
Paul Goldberg: The I-ELCAP bit.
Raja Flores: Oh, I think for lung cancer, catching it early is the key. If you catch it early, then that’s when it’s curable without chemo, without radiation, without immunotherapy. But the problem, if we’re going to sidetrack with screening, everyone brings up overdiagnosis. I will tell you there’s no such thing as overdiagnosis, only overtreatment. You don’t want to go to a surgeon who has a quick trigger finger. You want to make sure it’s a surgeon that’s going to evaluate it, watch it when it needs to be watched. What you don’t need is overtreatment.
Paul Goldberg: Right. Right. Right. So actually getting back to the neoadjuvant question, and I’m just going to… I put on my rose-colored glasses and gee, maybe it’s a good thing because if you take a stage 2 disease, shrink it down, give it to you to cut the rest out, and boom, you’ve got potentially a very effective cure, a treatment rather, or maybe even a cure. So maybe that’s what’s driving this push, this stage deflation.
Raja Flores: Intuitively, it would make sense. Does this drug work? Oh, if it works, give it to somebody at an earlier stage and then cut it out and maybe you’ll have a better cure rate. But that doesn’t always work out. And when one in five patients, when you look at the KEYNOTE-671, never make it to curative surgery, you’re not just evaluating a drug. You’re evaluating a process of giving something ahead of time. And are you going to be able to get the curative surgery afterwards? And what we know from the LACE meta-analysis, which is why we don’t treat stage 1A lung cancer with chemo, is that that group of patients did worse with treatment. So you don’t treat it. At some point, there is a, what do you call it? Reduced benefit.
At some point, there’s a tipping point where you get overtreatment, which has a detrimental effect on the patient. Point of diminishing returns. That’s what I was trying to come up with. And that may be what we’re dealing with at a certain point. For advanced stage, we know we do this and we’ve seen benefit. As you’re getting to the intermediates, the stage 2s, at some point you may get to a point of diminishing returns where it could actually hurt instead of help. But I find it fascinating when I looked back, when you’re put on an investigative journalist hat, you’re looking for the smoking gun. And I’m not finding that. What I’m finding is that this loosely thrown around language, early stage this or that, has been going on for years, for decades actually. But it has been kept within the medical community. Now that patients have access to that information and now that drug companies have direct to consumer advertising, we have to take that into account so that our patients are better informed.
Paul Goldberg: It’s really a fascinating way of looking at it. So basically reanalyze what we know through… Well, can you do it with 671, with Keytruda-671?
Raja Flores: Well, with 671, I found the exact point where early stage was inserted and it slowly got inserted. So the initial trial, no mention of early stage. They were very specific. Stage 2, stage 3A, stage 3B. Then this ASCO abstract, the title was the same, but then it said early stage lung cancer. Then you get to the publication. Now the title of the publication is different than the NIH trial. Now it says early stage lung cancer perioperative pembrolizumab. So the title shifted. Now, as a doctor, there’s nothing different. It’s the same trials, same patients, et cetera. But now with early stage in there, that passes the FDA, gets put on the label, and now it goes into a commercial, and now a patient sees early stage.
Our first reaction, I’ll point a finger at the drug companies, but this has been going on for a long time. Like I said, in the ’90s, you would conflate early stage breast cancer with stage 3A, colon cancer in the ’80s, stage 3A getting called early. So at some point in the medical community, we have lessened our… We haven’t continued with a rigorous terminology to encompass everything. And from cancer to cancer, early is considered different. Like I said from melanoma, 3A is not considered early in melanoma. So I think we need to focus on getting a standardized way of looking at this to translate it to the general public. What really is early stage? Because like I said, it is confusing the hell out of my patients.
Paul Goldberg: Is there patient harm as far as you can see on this?
Raja Flores: I have seen a couple of patients with stage 1 lung cancers who were treated in the community with chemo-immunotherapy before seeing me, and then they come to see me for surgery. And if that patient never makes it to me and doesn’t get surgery, they’re losing a shot at cure. So I do think there is potential harm that can happen to patients. I’ve seen it with my own eyes. But I do think we need to step back and analyze why this ambiguity and terminology has evolved and then try and correct it.
Paul Goldberg: Just by being more specific.
Raja Flores: Yes.
Paul Goldberg: Yeah. Yeah. So the patient harm would be undertreatment.
Raja Flores: Or overtreatment.
Paul Goldberg: Right. That’s right. My next question. The example you gave was undertreatment potentially. And overtreatment we didn’t talk about. Have you ever seen that?
Raja Flores: Yeah. So, that’s the biggest thing. When you look at the cure rate for lung cancer for a stage 1 lung cancer, let’s say a one centimeter between 80% and 90%. So they’re not all being cured. So everybody, or at least the medical oncologists are always trying to think, how do we optimize that? Maybe immunotherapy, chemo-immunotherapy could optimize that, but it’s a double-edged sword because if that patient doesn’t go to surgery for one reason or another, whether it’s adverse effects, decrease in performance status, then that patient has lost an opportunity to get that 80% to 90% cure rate.
Now, does the benefit of chemo-immunotherapy, given ahead of time, is that more of a benefit than not going to surgery? No. The balance is very tipped towards surgery. So I think it’s very important to understand as we go from later stages where I think the data is very compelling, 3A, 3B, give the chemo-immunotherapy, and then they do well, you can attack it with surgery then. As we start getting down into the stage 1 area, which is investigative, we’ve got to be a little careful.
Paul Goldberg: Well, it’s interesting because 671 is a win. So you can go and look at the subsets.
Raja Flores: Well, that’s the problem is that the subsets are stage 2, stage 3A, and stage 3B. And I’ve been asking Merck for the longest time. I want the TNM subcategories because within those subcategories, the outcome can vary from 10% to 30%. It’s difficult to get those TNM subcategories. But the danger when you use early stage and they’re just including stage 2 and there’s no stage 1s, you can’t evaluate it in the stage 1s because they weren’t enrolled in the trial. But that’s how most people know early stage, stage 1.
Paul Goldberg: Okay. Okay. This was really fascinating. How has your practice changed since KEYNOTE-671?
Raja Flores: More patients are getting chemo-immunotherapy. More patients with advanced cancers are going to surgery and getting resected. About 20% to 25% will have a complete response, and that’s phenomenal. I wish we could get more. Now, is that complete response that we see in some of those patients something that we can translate to stage 1s and improve our already great outcomes of 80% to 90% cure rate? That needs to be done under clinical trials. Right now, you can’t do that in regular practice. Though I am seeing some patients with stage 1s being treated in that manner, and that concerns me. And I don’t know if that is from this confusion of what’s early stage. It’s not the norm, but I do see it here and there. Yeah.
Paul Goldberg: That drift is something we should really investigate. It’s also kind of interesting because it’s kind of on that edge between journalism and medical research to look at that. And I understand you’re a journalist, a certified journalist.
Raja Flores: So my midlife crisis, I went to journalism school and I recently graduated from Columbia. But before journalism school, I did go and I got another master’s in biostatistics. So when I look at the data, I can’t ignore the statistics involved. And I got to say, you can see through a lot of conclusions that are not based on the data, that they’re preconceived conclusions. Like Mark Twain said, there are lies, damned lies, and statistics. So my biostatistical background helped me see through a lot of the science. But the journalistic side of me realized that certain narratives can take form depending on the words that you use. And early stage cancer is one of them. And I found it fascinating and I’m going to keep doing some investigation into it to find out the root of it, why it took hold, and why now it’s leading to confusion that maybe we need to backtrack and start being more specific on how we label things.
Paul Goldberg: That could be a really interesting series of stories. And boy, would we love to publish them.
Raja Flores: Yeah. I can’t wait to continue with my investigative work into that area.
Paul Goldberg: Yeah. Yeah. And since you are thinking of the next act, becoming a journalist, should I consider becoming a surgeon?
Raja Flores: Well, I got to say, I am a surgeon first and foremost. I will be a surgeon till the day I die. But I do think it’s part of my duty. If I see something, I have to say something. And going to journalism school actually just helped me realize how important the words you use to convey a message, they have to be very specific or else they can convey the wrong message. So I’ve have newfound respect for journalism and truth, and that’s what I’m going to keep searching for. But my number one role is surgeon. If I can’t operate, just let me die.
Paul Goldberg: Wow.
Raja Flores: I have my scrubs on right now.
Paul Goldberg: Right, right, right, right, right. So I have my un-ironed, button-down shirt, which is a journalist uniform. Yeah, so is there anything we missed? Anything we didn’t talk about?
Raja Flores: No, I think I love this platform because it is a platform that will get to medical doctors. It’s a platform that I think is more useful when you have a medical background. And what I’m trying to portray here, I think it’s difficult for the average person without a medical background to absorb. And I’m hoping that by presenting things in this platform that we can together figure out a better way to do this where patients will not be confused and then they’re able to make better decisions based on the information they have. Because right now they don’t have all that they need to make a proper decision. They rely on us. Many times patients will say, “Hey, doc, just do whatever you want.” But then I get patients who are really investigating things with ChatGPT and the internet, et cetera, and they are trying to figure out what suits them.
And that’s my job as a surgeon, as a doctor, is to help them figure out what’s best for them. Because what’s best for Mrs. Jones may not be the same thing of what’s best for Mr. Smith. They’re just two completely different people. And like we learn in medical school, you need to treat the patient, not just the disease, not just stage 2, stage 3. You need to treat Ms. Jones or Ms. Smith.
Paul Goldberg: Well, it sounds like you needed to do a lot of explaining before KEYNOTE-671 and the commercial for neoadjuvant Keytruda. And you still have to do a lot of explaining. And I guess, your patients are fortunate to have you do this with such enthusiasm and such precision. Thank you so much.
Raja Flores: Thank you for having me.
Jacquelyn Cobb: Thank you for joining us on The Cancer Letter Podcast, where we explore the stories shaping the future of oncology. For more in-depth reporting and analysis, visit us at cancerletter.com. With over 200 site license subscriptions, you may already have access through your workplace. If you found this episode valuable, don’t forget to subscribe, rate, and share. Together, we’ll keep the conversation going.
Paul Goldberg: Until next time, stay informed, stay engaged, and thank you for listening.
