Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital and Associate Director for Translational Research at Yale Cancer Center in New Haven, Connecticut, talks about a newly FDA approved drug for patients with non-small cell lung cancer.
What were you and your colleagues looking to find out through the ADAURA trial?
Dr. Herbst: Well over 25 years now, we’ve brought targeted therapy to patients with lung cancer, and one of the most important targets is epidermal growth factor receptor. I still recall in the late ’90s during the first trials of drugs called gefitinib and erlotinib, which were EGFR inhibitors, worked well. Over the course of time, EGFR mutations were identified, and we knew that certain patients could be selected for personalized lung cancer therapy who were using all these drugs in the most advanced setting. People who had metastatic disease, or lung cancer that had already spread from the lung to their liver, brain and bone. Then, about four or five years ago a new drug was developed, Osimertinib, which is a third generation EGFR inhibitor. The thing that was special about that drug is that it was more specific, better tolerated, and also had activity in the brain. It was shown to be superior to the earlier generation drugs in randomized trials. So, what my colleagues and I did in the ADAURA trial was we said patients who have early stage lung cancer and get surgery still have as much as a 50 to 70% chance of the cancer coming back. And, chemotherapy, as good as it is, was not able to do that much. It improved the results by about 5%. So the idea was, if someone has lung cancer and it’s being cut out and they have that epidermal growth factor receptor mutation, they can be treated with this drug Osimertinib. The results were exciting results. We had planned the trial for about a 30% improvement and saw a 70 to 80% improvement in patients who did not recur when they got this drug that was well-tolerated and could be given for up to three years. What the ESMO data has shown is that now we’ve looked at the brain as a site of recurrence, and patients who had this were 80% less likely to have a recurrence. For me, having worked in the field for over 20 years and seeing these drugs move from the most advanced setting without any personalization to their most early setting with personalization, gives me a feeling of having more people cured from lung cancer, which is the goal.
Is this one of the best breakthroughs in the recent past?
Dr. Herbst: There was a recent study in the New England Journal of Medicine that looked at lung cancer incidence and death rates over the course of the last 10 to 20 years, and we’re clearly improving. We’ve doubled the survival from lung cancer, and much of that has been due to these targeted agents, or these pills that target the Achilles heel of a tumor that we can identify with all the diagnostic tools we have. The thing about Adora which was interesting and exciting is that now we’ve taken early disease, or disease where there is no visible tumor. So, you leave the surgeon’s operating room and the cancer’s been removed. What you don’t have are those small cells circulating through the body which are going to metastasize. Metastasis is what’s going to cause patients to die and cause them to have a poor quality of life and bad outcome. So, to prevent that with a pill once a day, that’s the future. We now know that there are about eight to 10 different genetic mutations in lung cancer. My group here at the Yale Cancer Center has a spore grant with the National Cancer Institute. We’re looking at other targets now to see if we can bring those to earlier disease.
You were talking about some of these eight to 10 different genetic mutations. I understand, for non-small-cell lung cancer, that there may be something very effective?
Dr. Herbst: Right. I’ve been here at Yale Cancer Center for almost 10 years and immunotherapy for cancer is about 10 to 11 years old. My colleagues have been studying immunotherapy in lung cancer, kidney cancer and melanoma, showing some benefit. One of the first things I worked on when I was here was a drug called MPDL-3280, which we now know as Atezolizumab. We did the first human trials of that drug, which is an inhibitor that targets PDL1 and reactivates the immune system. That trial, which was published in Nature, showed that drug was active in a number of tumor types, including lung cancer. We also had biopsies and took tissue and samples from patients and understood a bit about the mechanism. So, we developed a biomarker and knew that patients with a high level of a certain protein called PDL1 happened to do better when treated with this drug. Fast forward 8 years, that drug was in early phase trials and then moved all the way to phase two and phase three, meaning to the upfront treatment of lung cancer. Who would imagine that you could treat someone with advanced lung cancer disease? We’re using chemotherapy, and at one year, 10 to 15% of patients are alive. What we did is we took the drug Atezolizumab and in a randomized trial compared it to chemotherapy, using a selection for only those patients that had high levels of the immune marker on their tumors. So that would be about 15 to 20% of patients having that marker. In this study recently published, the survival benefit was tremendous. There was a 40% plus improvement in survival in those patients who got the immunotherapy, the Atezolizumab versus the chemotherapy. That means those patients don’t have to get chemotherapy with all the side effects. But chemotherapy would be worth it if it had a great benefit, but in these patients it doesn’t. Instead, you can use the immunotherapy, given intravenously every three weeks, and it improves survival. This is the first PDL1 inhibitor that has now been FDA approved. The approval came a few months ago ahead of this paper, which really speaks to the importance of this in changing clinical practice. The other thing we’ve done in this paper is, there are many different labs in the United States and the world and a number of different bioassays that were being used to measure PDL1. We’ve looked at three or four of them in the paper and compared them, showing that they were relatively equivalent. I believe that’s going to be important for clinicians, such as myself, to know. You get a result, you need to know in the office, how do you treat the patient? Can you use this drug? We’ve been using this drug here at Yale for over nine years and it works where we’re using it in advanced lung cancer, bladder cancer, and a number of other cancers as well.
Is this something they’ll be on long-term and can they go into remission?
Dr. Herbst: We typically treat patients every three weeks until we see progression. In some cases, we can stop after one or two years if patients are doing well. We base it on how well the patient’s doing. The immune system is there for a reason, to fight an infection, or to fight a skin issue… So, patients can develop things like rash and inflammation in different parts of their body. If that becomes too prevalent, you might have to stop. But at this point, that hasn’t been an issue except for about four to 5% of patients that have these severe side effects.
How many patients were involved in this study? And is there anything else you would like to add?
Dr. Herbst: About 500 to 600 patients over 100 centers. What’s amazing is this is the main street of Yale Medical School which has a 200-plus-year-old medical school. And just a block away, Dr. Lieping Chen, one of the people who first discovered this whole immune pathway, is working on new agents. When I went into this field 25 years ago, no one wanted to work in the field. It was difficult for young oncologists like myself. But now we have targeted therapies and immunotherapy. The next step is going to be to personalize that immunotherapy. What does that mean? We’re giving the same immunotherapy to almost all patients. We’re using this one marker. But wouldn’t it be great if we could take a look at someone’s cancer and say, maybe you need two drugs to target the immune system, and these are the two drugs? In these labs around us, we’re working on new targets. Some tumors are driven by different immune factors. We have to identify that and find ways to target that. I’m very optimistic that, in the next couple of years, we’ll have newer agents that can be combined with this first generation of targeted agents and immune agents and even raise the bar further for patients with lung cancer. We always want to do better for patients, offer new options and new hope, and that’s what we’re doing!
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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