Siddhartha Devarakonda, MD, an Oncologist at Washington University School of Medicine, talks about a new drug that is adding years of life to some lung cancer patients.
Interview conducted by Ivanhoe Broadcast News in August 2021.
How often do you come across lung cancer patients where every option just kind of fails?
DR DEVARAKONDA: Quite often. More often than we would like. The problem is that with lung cancer, like many other cancers, this applies to many solid tumors or non-leukemia cancers, you start off with determining what stage of cancer the patient has. If they have what we call early-stage disease, which is Stage 1 to stage 3, which is cancer confined to the place of birth within the lung, then you try to go in for a cure, through surgery, radiation, chemotherapy plus radiation. But Stage 4 patients are patients who have cancer that has spread throughout their body, right? By the time we already pick it up and identify it we make a diagnosis. So, in these patients, a cure is not possible. So, the goal of our treatment becomes what is it that we can do to prolong life and preserve quality of life? And none of the treatments we have work forever. That would mean a cure, so that doesn’t happen. They control the disease if you’re lucky for many months, sometimes a few years. But more frequently than we would like, the treatments often stop working within a few months. And then we are trying to move on to some other treatment, and since none of these treatments are guaranteed to work, the situation you’re talking about is something that we face quite frequently.
Could this new drug change the landscape on that one?
DR DEVARAKONDA: The best way to put it is it’s more ammunition in our weapon, right? It’s one of those situations where you give your patients chemotherapy. You have immunotherapy. And after that, sometimes your back is against the wall. You don’t have good options. But for a subset of patients who have a very specific genetic change like the KRAS mutation, which you’re referring to, the pill obviously adds an extra line of treatment that we could use. And it’s effective. In patients in whom the pill was successful in controlling the disease it was able to do so for an average of about eleven months, which is I think a meaningful prolongation in their survival.
But that seems not to be the case for Cindy. It seems like it’s lasting longer.
DR DEVARAKONDA: So, these numbers are averages. Averages are good for predicting how the population behaves. It’s hard to take a number and apply it to every patient. It’s not an individualized prediction. So yes, if you have an average of eleven months for which the drug works, in reality you would have half the patients in whom it would quit working before that and half of them would actually go beyond that. And Cindy got extremely lucky.
So, tell me about Cindy. You’ve been with her since the beginning of her diagnosis.
DR DEVARAKONDA: Yeah. I actually first saw Cindy when I was in training myself with one of my mentors here at Washington University. She did well on chemotherapy when she first got it, and then we tried a few other treatments, all of which have meaningfully prolonged survival. Then we hit a point where we were out of treatment options or we were running out of treatment options and this trial just opened. We were one of the first sites in the world to have access to this drug, fortunately, and things just lined up.
What’s the name of the drug?
DR DEVARAKONDA: So, we know it has Amgen 510 because the company that makes the drug is Amgen. That was the proprietary name. That’s what we still call it. But the name for the drug, the marketing name, is Sotorasib.
For Cindy, it was really scary and you’re probably used to this but tumors started popping up everywhere, it seems like.
DR DEVARAKONDA: Right. I mean, we’re used to seeing this, but that doesn’t make it any less scary, even for us. So, we were in a tough situation where the tumor was popping up everywhere and then she had this huge lump that was sitting on her belly. We knew that that was bad. When we started the drug within a couple of weeks, I could no longer find it on exam and we knew that, well, we’re onto something. I guess this drug works.
It was just a few weeks? The timeline was really short that these tumors disappeared.
DR DEVARAKONDA: Yes, and she was getting sick really fast. I’m sure she spoke to you about that. We were requiring a lot of pain medications and within a month we could go off of it. So, it was huge. It was a win-win, because one we’re better able to put the brakes on the cancer once again and number two from a quality-of-life perspective it means a whole lot not to be on pain medications, to kind of have your life back.
Have you seen a drug work that fast?
DR DEVARAKONDA: We have. So there have been quite a few success stories in lung cancer. We’ve had investigational drugs work well. Right now, is the era of immunotherapy where we’re testing immune treatments and these treatments can be quite effective as well. So, the thing is that we need more of these. Some of these drugs that benefit a small subgroup of patients, the hope is that ultimately, we will have treatments like that that would benefit almost everyone we see. The other challenge is that these drugs don’t work forever, and especially for a situation where a cure is not possible. And part of the research is also focused on how do we make these drugs work for longer?
So, can you explain a little bit how this drug works? It attacks a specific gene?
DR DEVARAKONDA: A good way to think about cancer, especially the type of cancer that we’re talking about, lung adenocarcinoma, is that it’s like turning the light bulb on. You have a switch. The switch here that I’m referring to is actually a chemical that’s stuck in the on position. So here the light is this cancer cell multiplying. So, it’s one of those situations where you have a change in the DNA or a mutation, which you can refer to as a chemical switch. It’s stuck in the on position. So, the cell just cannot stop from multiplying. It keeps on multiplying. That’s essentially what cancer is. You have a lot of those chemical switches. For some of these, you can actually design a pill that jams the switch. So that type of switch that Cindy has is what the drug blocks. And we refer to this as the KRAS gene. It’s actually the most commonly messed up switch or mutated switch in lung cancer.
Perfect. So you’ve given Cindy back her quality of life. I mean, here’s this woman that jumps out of planes and rides motorcycles across the country. I mean that has to feel good even if you don’t know how long this quality of life will continue, to be able to give her back the ability to go on mission trips to Alaska.
DR DEVARAKONDA: It’s fabulous what successful treatments can do. It’s very humbling to watch patients do well. It’s equally defeating to sometimes watch some of our other patients struggle. But that’s the spirit of oncology, right? We’ve all got to go someday. The point is can we preserve quality of life to the extent possible.
Perfect. Was Cindy a smoker?
DR DEVARAKONDA: She quit smoking. She did smoke in the past.
You’re also working on something about lung cancer in nonsmokers. Is that very common?
DR DEVARAKONDA: So that’s a very good question. The biggest risk factor, it turns out, for getting lung cancer is having lungs. Previously at least all the research, lung cancer was largely considered to be a disease in cigarette smokers, and it still is. About 90 percent of the lung cancers we see are predominantly in former smokers or people who continue to smoke. So, the biggest way you can cut down your risk of getting lung cancer is to not smoke or to quit smoking if you are already a smoker. So that that goes without saying. Having said that, about 10 percent of the people we see are patients who have never touched a cigarette in their entire life. So, the one question that continues to haunt us in the field is why do these people get lung cancer? Is there any way in which you can pick this up early? Right? Like for instance for breast cancer you can do mammograms. In people who are nonsmokers, they can get C.T. scans on an annual basis for a few years to see if any nodules pop up in their lung that are at risk for lung cancer. For colon cancer, you do colonoscopies. Maybe, the thought process is that if you understand why nonsmokers get lung cancer you could probably come up with the test of the future. Having said that, we’ve done some large studies, our group included, to try and get to the bottom of why do never smokers get it? To this state, despite these large research efforts, I don’t think we have a good handle on why people get it. It does not seem to be genetically predisposed, and there does not seem to be a clear environmental risk factor. There are some studies that suggest radon to be a risk factor in never smoker lung cancers, maybe exposure to cooking fumes, passive smoke, but a lot of this data is indirect, and we don’t have a direct causal relationship. Getting back to the point that we were talking about, it’s important, especially for lung cancer oncologists, to keep this in mind, too, when they see patients with nonsmoker lung cancer because the switches that I’m talking about that turn on for which you can have a pill, it’s very common to have those switches in non-smoker lung cancers. So clinically that’s an important factor to keep in mind.
Is secondhand smoke any part of this as well?
DR DEVARAKONDA: Once again it could be. It’s hard to do these kinds of studies especially if you’re trying to determine smoking is a much more direct risk factor. You can talk to somebody and say how long have you been smoking for? How much do you smoke? You can get some kind of a direct answer. The problem with passive smoke is we’ve all been exposed to passive smoke at some level. Then I’m sure the risk is a lot higher if somebody has a household member that smokes. How much of that really translates into a risk for never smoker lung cancer is kind of unknown because some of these patients are fairly young. They’re in their 30s sometimes when they get never smoker lung cancer. So, it’s a little hard to…
You’re talking about the lungs. I read someplace that said that if you are a smoker, you change your DNA.
DR DEVARAKONDA: That is correct. When you say your DNA, in a broad sense you are correct. So, there’s two types of, when you said DNA and DNA changes, there’s two things you have to keep in mind. One is the kind of DNA we are born with. So, we all get half of our DNA from our mom, half from our dad, to be very purist about it, a little bit more from the mom because your mitochondria, that’s entirely from your mom. It’s a part within your cell. So also, you have DNA from your mom and dad. Sometimes if there is a mistake or a mutation in that DNA, every cell in your body is going to have that mistake. If that mistake is in one of those parts of DNA that increases your risk for cancer, people pop up with cancers at a very early age. An example of that situation is what we call the BRCA mutation which puts women at risk for developing breast cancer or a variant cancer, some men for prostate cancer very early in their life. Then there’s a second kind of DNA change that happens. This is something that we acquire through the course of our life. Each time a cell in your body multiplies, some mistakes in the DNA happen. It’s just the price we pay for being alive. That mistake, if they happen to fall in the wrong gene the wrong part of your DNA, that could increase your risk for cancer. Having said that, if you expose yourself to carcinogens or chemicals or any environmental factor that increases the mistake rate of the DNA, for instance, you spend lots of time in the sun, there’s ultraviolet rays in the sun. The skin cells can get their DNA damaged. So, these mistakes that normally happen, you can increase the rate of mistakes quite a bit. Normally when cells multiply, there’s less than one mistake that happens because your cells are so good at correcting and proofreading them. When somebody exposes themselves to these carcinogens, for instance like UV light that I spoke about or when somebody picks up a cigarette and smokes, all that smoke that goes into the lung probably puts a few thousand mutations within the cell. Now you’re increasing the probability of one of these mistakes hitting a cancer-causing gene, which is why smokers are at much higher risk for getting cancers.
Do these 10 percent of people who have never smoked before – do you find that they’re younger?
DR DEVARAKONDA: They usually are. Even older people can get it, but on average these tend to be a little bit more predominant in the younger group, and surprisingly in women. More so, there’s also a little bit of an ethnic predisposition or geographic predisposition here that we see. It’s a little bit more common in the eastern part of the world. Why? We still don’t know the answer to that.
And age group?
DR DEVARAKONDA: Once again, I’ve seen all age groups with never smoker lung cancer. I’ve seen people in their 20s and also people in their 90s get never smoker lung cancer. The usual is a middle-aged woman, not smoking, Asian ethnicity, that’s often the type of population that we see this cancer in.
So, the big takeaways from your latest study?
DR DEVARAKONDA: The big takeaway is hard: never smokers can get lung cancer. The risk factors are still kind of unknown. We still don’t really understand. This is an area that needs a lot of study, and I think research of this nature also destigmatizes lung cancer because many people, when they hear the word lung cancer, often the responsibility is put on the patient, almost as if they deserve it and nobody does. It’s a lifestyle choice that you made. That’s not necessarily the case. I think the other important thing to keep in mind is that not all lung cancer is the same. There are some lung cancers where you have these chemical switches that turn on that you can block with pills. So, the treatment options are going to be very different for these patients as opposed to those who do not have those chemical alterations or mutations.
Perfect. Anything else?
DR DEVARAKONDA: No. I would say the biggest thing that people can do to cut down their risk of lung cancer is to not smoke and to not pick up a cigarette. If you’re already a smoker, it’s not too late. Quit smoking.
Can you really reverse the damage? Let’s say you’ve smoked since you were 17 years old and now, you’re 60.
DR DEVARAKONDA: I don’t know how much of it you can reverse, because sometimes the scars that are there are there. Still, I think you can substantially cut down your risk because the body is actually quite good in fighting off cancers. We have an immune system that surveys everything. I guess if it did not have a functioning immune system, we would all end up with cancer much earlier in our life or even get a nasty infection. Then the other thing is that nature has honed us over millions of years. We have these mechanisms that actually are able to proofread and correct any damages that happen in the DNA. You quit smoking, you stop overwhelming them and you let the cells do what they do best which is stay alive.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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