Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity (Science Immunology 09 Aug 2019)
Overview by Dr. Dan Cadigan, EGFR Resisters member.
This is an exciting study regarding a novel medication approach to treating EGFR positive cancer with tyrosine kinase inhibitors (TKIs). It looks at the concept of “hypofractionation” versus “hyperfractionation.” Several mouse cancer models were used in the study. In addition, the hypofractionated TKI was also studied in conjunction with use with an anti-PD-L1 antibody (immunotherapy). The study showed that the hypofractionated EGFR TKI had improved effectiveness in triggering anti-tumor cell responses and in preventing relapse, and that the combination with the anti-PD-L1 antibody further improved anti-tumor responses and reduced relapse.
Hypofractionation involves giving larger amounts of medication, that is, a larger dose, less often rather than giving smaller doses on a daily basis. As an example, if a regimen normally involves taking 1 pill daily, this is the hyperfractionation regimen. Hypofractionation would involve possibly taking 5 pills once a week or 10 pills every 2 weeks as a single dose.
Although TKIs for EGFR have been felt to work through direct blocking of cancer growth signals, the authors mention that recent studies show that the treatment might also enhance recognition of the tumor cells and breakdown of tumor cells by natural killer cells and T-cells within the patient’s body from their own immune system.
The authors showed that giving a higher medication dose less often was more effective in preventing relapse then standard dosing, and they showed that the patient’s own immune system played a role in this as well. They felt that their study supported the use of immunotherapy to boost the immune response to be given along with the EGFR tyrosine kinase inhibitor.
The study primarily looked at afatanib (Gilotrif), but also gefitinib (Iressa) and osimertinib
(Tagrisso).The authors found that the hypofractionated (higher dose less often given) regimen reduced tumor burden and also the rate of relapse. They showed that this blocked a pathway more effectively that results in cell death and suppresses cell proliferation.
The study also assessed side effects from the hypofractionated/higher dose regimen by evaluating the mice for weight loss and ocular damage. Less side effects were noted in the mice treated with the hypofractionated dose regimen.
The authors then attempt to explain how such short courses of treatment can limit relapse. They state this could not be due to direct killing of the cells alone, so they proposed that the hypofractionated regimen may trigger the host immune system to control tumor relapse. They measured numerous immune cell types 72 hours after treatment and noted that the levels of these were markedly increased with the hypofractionated regimen but not the hyperfractionated standard treatment. They stated, “these data indicate that HypoTKI is more potent than HyperTKI with respect to inducing an anti-tumor micro-environment that limits tumor growth and relapse.” To confirm this, they then performed experiments in mice with immunodeficiency and noted that although the hypofractionated regimen resulted in initial rapid tumor regression, all tumors relapsed immediately after treatment in these mice, thereby showing that the treatment requires the host immune system to be working and suggesting that an immune response does play a role. They did extensive measurements regarding various aspects of the immune response to confirm their findings.In their studies using a combination with PD-L1 inhibitors, they hypothesized that proper use of a hypofractionated TKI regimen might overcome the resistance of anti-PD-L1 immunotherapy. which is frequently seen in EGFR-mutated patients and which have limited the benefit of such medications in these patients. They found that the response was dependent upon the timing of the immunotherapy. When the therapies were initiated at the same time, tumor regression was improved and relapse rates were lower.
In their summary discussion, the authors felt that the combination of immunotherapy with hypofractionated TKI treatment could control advanced large tumors and limit tumor relapse. They suggested that immunotherapy could be considered as first-line treatment concurrently with a TKI for an EGFR patient. They did mention that another clinical trial presently is showing that the maximal tolerated doses of afatinib can be increased up to 150-200 mg daily, which is about 5 times higher than the normal standard dose at present. They stated that this dose in the clinical trial was given once daily for 3 days and then repeated every 14 days in a 28-day cycle. They suggested their own regimen of twice weekly, in which case the doses could be even higher, and the toxicity would be manageable. Their hope was that the high-dose would kill tumor cells and delay the development of drug resistance. They felt an additional benefit of the combination was that the hypofractionated TKI regimen can trigger specific T-cell responses not seen with PD-L1 blockade alone.
In my opinion, this study presents fairly outstanding data to suggest that higher dose regimens given less often than usual of EGFR TKIs, without PD-L1 immunotherapy medications or with these medications started at the same time, could have potential to enable new mechanisms of allowing the patient’s own immune system to help control tumor growth and improve rates of tumor regression and relapse. This is a rather extensive paper with well documented scientific technique and findings with an exceptional study design. This is a potentially exciting concept which they propose could be studied with other medications for other lung cancer mutations. Read the entire article.
My cancer journey began with this one seemingly benign symptom. In the winter of 2017, at the age of 44, I developed a lingering cough that waxed and waned over a period of about six months. Everyone attributed this mysterious cough to frequent viral infections —after all, I am the mother of two young children. Not that unusual, right?
I consulted with a doctor who assured me that it was just a cold or allergies. I was prescribed over-the-counter medications and sent on my way. The cough did seem to go away at times, but it always came back. Even multiple courses of antibiotics didn’t keep it at bay for long. Still, I felt pretty good, overall. I had no other symptoms. And because the cough sometimes vanished, I didn’t suspect a serious health problem. I certainly didn’t suspect that there was a tumor lurking in my lung, waiting to wreak havoc on my life. Given my never-smoker status and relatively young age, lung cancer never crossed my mind.
But there was that one nagging symptom. One day I was providing anesthesia during surgery for one of my ear, nose, and throat colleagues. We spent the entire day working together in the operating room. Apparently, I coughed most of the day because my colleague asked about the cough. How long had I had it? Did I have any other symptoms?He ordered a chest x-ray on the spot. That was the day that changed my life forever. Like so many other cancer survivors, in a matter of moments, my life was divided into “Before and After.” It was the end of one life and the beginning of another.
The chest x-ray revealed a mass in my left lung. My colleague and I were both concerned. But at the same time, we were both confident that this mass wasn’t life-threatening. We were both doctors, after all. We knew that the odds were stacked against this mass being lung cancer. I mean, I was only 44 years old! There were other more likely diagnoses, weren’t there? I was healthy and active, I had just returned from a family ski trip… surely, I couldn’t have lung cancer! We agreed that it was most likely an infection that would clear with a course of antibiotics. He ordered a CAT scan immediately. The diagnosis?Metastatic EGFR-sensitizing non-small cell lung adenocarcinoma. Stage IV.
I’m a doctor. I knew what this diagnosis meant. I understood that, realistically, chronic disease and lifelong treatment would be the best-case scenario. I knew that I needed to find a doctor who was willing to do absolutely everything possible to prolong my survival and to treat this disease as aggressively as possible. And I needed to find him fast. I needed to be here for many years. I needed to raise my young children.
After six months of treatment with Tagrisso, all of my scans showed a significant reduction in tumor volume and activity. This, coupled with my otherwise good health, allowed me to take the next step: surgery to remove the residual lung tumor altogether.
Living with a terminal lung cancer diagnosis profoundly changes your life. It puts everything into perspective the way little else can. Did I mourn? Oh, yes. I swept through every possible stage of grief (shock, denial, guilt, anger, bargaining, and depression). Then I started working through my feelings. I’ve accepted my diagnosis now. And you know what? I’m actually hopeful about my future. I don’t take anything for granted. I’m alive.
The silver lining is that living with terminal lung cancer has forced me to stop and enjoy each moment and be grateful for every day that I’m here on earth with my husband and children. I’ve gotten better at living in the present. I am vividly aware of the joy in the little things. I’m more aware of everything around me. I focus on day-to-day living and living each day to its fullest. I spend more time with my family, especially my young children. I have significantly downsized my life and everything in it. I live a more simple and pure life, a life with less stuff and more joy.
My children Charlotte, age 9, and Jack, age 6, and my amazing husband Matt, are what keep me strong. I am fighting for as much time with them as possible. They are my world. But there are challenges. It is very difficult living your life with the knowledge that you have a terminal illness. And it’s difficult for your loved ones, as well. Trying to educate family and friends, while also staying strong for them on a daily basis can be hard at times. It definitely takes an emotional toll. And, of course, those of us living with terminal cancer must learn to coexist with that ever-present fear of progression.
Once I had exhausted all the stages of grief, I realized I had two choices: I could surrender and allow myself to keep spiraling down into a deep, dark hole of depression and hopelessness, or I could take positive, proactive steps that could hopefully make a difference for everyone who will suffer and die from this disease. I decided to make the unknown amount of time I have left as meaningful as possible. I’m hoping that sharing my story will help others who receive this devastating diagnosis feel that they are not alone.
If we want to be able to manage cancer the way we manage other unfortunate health conditions — as a chronic, treatable disease — I must do my part. I will continue to spread the word and help to educate the public about lung cancer and its misconceptions. As a doctor, and now a patient, it is my belief in science and modern medicine that gives me hope. I remain optimistic that the hard work of brilliant scientists and medical researchers will lead to the discovery of effective, long-lasting treatments that will allow all of us to live our lives for many years to come.
We recently asked for your support in a research project that aimed to understand symptoms related to treatment for EGFR-positive lung cancer and their impacts on everyday life. There was a huge amount of interest in the study, with so many of you willing to take part in a telephone interview and share your experiences so we just wanted to say THANK YOU! Your input has been invaluable.
Even for those of you who called and recruitment was already full, or we found a small detail that made you ineligible, we want you to know that this information also helped to better inform the researchers about the real world experience for EGFR positive lung cancer patients, and these issues are being discussed and considered as the next phase of the study is being planned. For example, the next study will have improved eligibility criteria to ensure more patients can participate.
The information learned from this pilot study has been very helpful in shaping future studies, and also showed us areas where we could make some improvements. The results of the pilot study have been accepted in an abstract for presentation at World Conference on Lung Cancer (WCLC) 2019, and will be promoted to raise awareness about the meaningful treatment experiences from the patient perspective. So, we want you to know that your efforts to support research and specifically to take part in this study are already bearing fruit and are so much appreciated!
Thank you!