Timothy Burns, MD, PHD, Medical Oncologist specializing in Lung Cancer treatment at UPMC Hillman Cancer Center and the University of Pittsburgh Department of Medicine talks about new targeted therapies in Lung Cancer treatment.
Talk about the difficulty researchers have had in the development of lung cancer treatment.
Dr. Burns: Lung cancer is clearly an area of need. It is the most common killer of both men and women. In fact, it kills almost twice as many women as breast cancer, and kills more men and women than breast cancer, prostate cancer and colorectal cancer combined. When my parents were diagnosed with lung cancer, we were not offering therapy to most patients. But patients started receiving chemotherapy almost three decades ago and now we realize that lung cancer is a collection of different cancers and if we can find the targets for these cancers our patients do a lot better. That has really been the major change in the last 10 years and how long patients live with the disease has really increased. That is due to two things. One is realizing there are targets or genes in the cancers and if we target them it can make a huge difference for our patients by increasing their survival to years in many cases. The other major advance is harnessing our own immune system to attack the tumors. When I started practicing about eight years ago, between now and then things have changed a lot. Most of our patients are diagnosed metastatic and are dying from this disease but the number of patients that are now living two, three, four years is amazing. I even have five and six-year patients that are still alive. So that has really changed. It is an exciting time, and we have a lot of work to do, but we have made a lot of progress. It is very satisfying, but it is very humbling because many of my patients are still not surviving that long.
Why is it that lung cancer is usually caught so late?
Dr. Burns: There are a variety of reasons for that. One is that until recently we have not had a good screening test. The easiest way to cure any cancer is to catch it early and over the last few years, we have adopted CT screening, which compared to other screening tests for cancer is by far the most sensitive. Because it is more sensitive you need to screen less people to save a life than you do a colonoscopy, or mammogram. It is the best screening test we have. The issues we have had is that we have not been screening people and we are still trying to get the knowledge out there that CT screening can save lives. If you can remove a tumor, it is curable. If you cannot remove a tumor, many times it is not curable. So, we are trying to work with our primary care doctors because it is not the oncologists that are doing your mammogram, colonoscopy, or CT screening. It is the population that is being seen by our primary care doctors, who are obviously under a lot of stress with everything else they are dealing with. But it is vitally important.
It used to be that smoking was the only thing that people looked at in terms of lung cancer risk factors. But that is no longer the case.
Dr. Burns: We’ve always known about this. If you take those lung cancer patients who have never smoked, it is about 26,000 patients a year that are diagnosed with never smoking lung cancer. To put that in perspective, it is the sixth most common cancer in the United States if you just took that population out. Unfortunately, we cannot screen for that type of cancer and these cancers are generally driven by the patients’ genes which is usually non-smoking related. In addition, even our patients that have smoking associated lung cancer, we know based on their genes that they have never smoking lung cancer, but they just happened to smoke. So even in some smokers, it is probably more common than that 26,000. Those patients that have never smoking lung cancer, even if they were smokers, will respond to these targeted therapies. So, it is a huge problem. First, we have patients that have a history of smoking that really should be getting CT screening. Then we have another 26,000 or more patients that we have no way currently of detecting their cancers early.
Let us talk a little bit about targeted therapies. Can you tell me what the new drug is and what it is designed to do?
Dr. Burns: With lung cancer, about a third of patients are going to have a molecularly targeted alteration and we find that through genetic testing. Most are on FDA approved drugs which are pills and the response rates are about 70% or 80%. Patients can live years today in the metastatic setting. In addition, there are other drugs coming along and it may get to the point where almost half of our patients are going to have targetable alterations in their tumor. So, lung cancer has been where most of the work on targeted therapy is happening because we have found we can target most of these genes. In Linda’s case, she has a mutation in one of the most common oncogenic drivers we find and it is targetable. It is called EGFR. We have known about this mutation since 2005. Once we found this mutation it was the first targeted gene in lung cancer, and it led to the approval of early drugs that targeted the EGFR protein. Over the years, we have gotten much better drugs and we have figured out how to make the effects lasts longer. A drug called osimertinib or tagrisso was approved several years ago in the metastatic setting. Right now, that is our standard of first line of care when newly diagnosed metastatic patients have an EGFR mutation. These patients can expect a response rate of 70% to 80% and they can be on these drugs for years. Even with the older generation drugs, I still have patients that have been on these drugs for years. After that, there are other targeted drugs we can give them prior to chemotherapy. In the early stages, when the tumors are diagnosed and can be resected or taken out by surgery, the traditional therapy is chemotherapy, even if they have an EGFR mutation. There have been trials looking at using a targeted therapy in addition to chemotherapy or instead of chemotherapy and to date it is not clear whether we are curing more patients by giving them this drug. So recently at the ASCO Annual Meeting in 2020 results of the ADAURA trial were presented. What was exciting is they took patients like Linda with stage three, and gave them adjuvant therapy which they normally get, and then randomize them to get three years of this drug osimertinib versus not. This trial was so positive, the Independent Data Monitoring Committee stopped the trial because it was not ethical to continue a placebo arm. That rarely ever happens. So, this was not expected because obviously when you are looking in the resected setting, and you are looking for a cure, you must follow people out for five years. They stopped the trial early because what they saw were numbers that they generally do not see. Overall, you saw about an 80% reduction in the chance of your cancer coming back. In Linda’s case, she has a stage three, so it was more. It was essentially an 88% reduction in the chance of her cancer coming back. The other key is, if you are going to give someone a drug for three years, you want to make sure it works and it is tolerable. One of the big advances with osimertinib, or tagrisso, is that it is much more tolerable. The side effects are much less, and patients can tolerate three years of treatment. It can become a daily treatment, which is how it is given in the metastatic setting. So, this is quite exciting because I think the patients do a lot better, especially with later stage disease which becomes more aggressive. We still need a lot of work on your average patient with stage two lung cancer that has a 50% survival and your average stage three patient, where we must surgically remove the tumor and they get adjuvant therapy, and it is about 30%. So, for EGFR mutant NSCLC patients this is really a game changer and that is why we are extremely excited about this.
When she is at stage three and taking this drug, what does that mean for her?
Dr. Burns: What it means is this is her best chance of trying to cure this disease and never have it come back. We have had discussions about this because they stopped the trial early, and we do not have the follow up yet. That is not the trial’s fault, the Independent Data Monitoring Committee found that it was unethical to continue this trial because of the remarkable findings with this drug. We will continue to watch for the updated survival data, but I think a lot of us believe this is going to be the most game-changing thing we have seen this year and maybe in a couple of years on lung cancer. This is really Linda’s best chance to prevent this from coming back and being cured.
You mentioned it would not be ethical to continue the trial with the placebo arm. Is that because they saw that it was such clear evidence and they wanted to give it to everyone?
Dr. Burns: Every large trial has an Independent Data Monitoring Committee that is independent of anyone that works with the trial. Their job is to make sure the drug is not causing harm and if it is not going to benefit someone, they will stop the trial early. Alternatively, when a drug does so well it is not ethical to deny people a drug that can improve their survival so they can stop the trial for that as well. I can only think of a handful of times in the last decade in cancer treatment research when that has happened and this is one of them. It is the Independent Data Monitoring Committee that decided that we cannot continue with this trial and randomize people.
When was this FDA-approved?
Dr. Burns: This is still technically under review by the FDA, which is remarkable. Of note, the FDA recently announced in October that it was granting this drug a priority review designation which means they must make a decision within six months. We have had nine FDA approvals in lung cancer this year and I will say there are several that are practice-changing and many that are not. This is yet to be one, although insurance companies are covering this. It is going to be on our national guidelines, the NCCN guidelines. So, the formal FDA approval has not yet happened, but this drug has been FDA-approved for several years in lung cancer in the metastatic setting.
Under this drug, survival rates had gone from what to what?
Dr. Burns: There was an 88% reduction in the chance of your disease coming back. That is with about three years of follow-up. I think we need longer follow-up. But, if you look at the overall population, and you look at stage three about 80% are still alive. This is quite a dramatic difference. To put this in perspective, the standard of care for all our patients is chemotherapy. The benefit of chemotherapy after you have had your tumor removed ranges from about five percent to ten percent. That means out of one hundred people, we will save five to ten lives that would not have been saved without chemotherapy. Since we don’t know who is not going to be cured and who really benefits, we give chemotherapy to everybody. This is the first targeted early stage therapy where your chance of benefitting is quite high because you have this gene. It is really going to open this up for those other oncogenic drivers. Again, in the metastatic setting, this is the most common one and we see about 17% of our patients. But there are twice as many patients that have other oncogenic drivers. So, the question is, can we start targeting these other genes in the adjuvant setting, and will it have the same benefit?
Do you mind telling me about your patient, Linda?
Dr. Burns: Linda is a remarkable woman, and grandmother. She is retired now and quite active. This was really found by accident because she has never smoked. There is no reason for her to get the CT. She underwent surgery and was surprised to see how big the tumor was and that she had some positive lymph nodes. She wanted to be as aggressive as possible, so she went through chemotherapy, which was our standard of care and then this new drug became available and we discussed it. In fact, there were earlier trials with older EGFR targeting drugs and we discussed her joining one of those trials but the side effects of some of the drugs made it a less reasonable thing to do. She is someone who has really been engaged in her care and really trying to do everything she can to be around for her family.
You mentioned at the beginning that both of your parents were diagnosed with lung cancer and you lost both?
Dr. Burns: I lost my father when I was 7 and I lost my mother when I was 16. My father had a resected disease and then it came back. This was in the early ’80s, so there wasn’t really much offered to these patients. Then my mother had cancer in the early ’90s and was just offered radiation which helped for a few months and did improve her quality of life. But, I think of where we’ve come, and I can almost guarantee they would have lived longer today because, as we strive to cure our patients what we’re doing in some cases is extending their life because that time is very valuable. You know, my whole family and myself would have loved to have my mother and father around longer. So right now, we are trying to help our patients live longer and cure more of them.
Did that shape your career choice?
Dr. Burns: It was a big part of it and it was a big part of not only my decision to become a doctor, but also to do lab research, because I think we are making advances in lung cancer. Obviously, clinical trials are especially important, and I run those as well. But to get where we want to go it is going to take lab research, coming up with new drugs, and figuring out why certain drugs do not work. So, the driving force is – we must do better. I mean, this is the most common killer of both men and women in terms of cancer, and we have got to do more. Everyone knows someone who has this, and it is a disease with a stigma associated with it because it is smoking-related. We need more advocacy for this disease because everyone knows someone with this.
Anything I did not ask you that you want people to know?
Dr. Burns: The only thing is to restate that we’ve made a lot of progress in lung cancer, but I’m still humbled by the number of patients we can’t help or those whose lives we extend and then they pass away. We really need more effort to fund the research, not only in the clinic but in the lab and that is going to get us where want to go. We have come so far, but we have so far to go. We have made progress, but we are only beginning.
Is your lab currently investigating any new drugs or are you involved in any trials?
Dr. Burns: Yes, we are running trials on a patient’s progress on these first therapies. What is the next therapy for other ones, like KRAS which is the most common oncogenic driver? So, 40,000 patients a year have KRAS mutant lung cancer. There are no treatments that are FDA approved. There is one that is quite exciting, but it targets only one of the KRAS mutations, which is in 40% of these patients. Sixteen thousand patients a year can benefit from this drug. We are running some of those trials in the clinic. In the lab, I am doing two things. One is trying to develop new drugs that can work on these oncogene-driven lung cancers. The other is to take drugs that are in the clinic and bring them back to the lab. Where the industry plays a huge role, but academics can make a difference, we can take the drugs, figure out who they work for and when they stop working then figure out what would be the best combination. Half of my lab focuses on drugs that are in phase one or phase two and figuring out why they work and do not work. The other half is figuring out what are the important targets in in lung cancer and can we develop a new drug for that. So, we do both of those and it is important to always be working in the lab, because if we wait for stuff to show up in the clinic, it may never get there.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Cyndy Patton
412-415-6085
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
