Seen in a lung cancer foundation’s chatroom recently:
A: I wish I had a mutation.
B: I’ve got one. If you want it, you can have it.
This is something we don’t talk about in the lung cancer community, at least not out loud: that we might be envious of someone else’s cancer mutation. While personalized medicine is still an ideal rather than a reality, some lung cancer patients find themselves on the frontier of a different approach to medicine, one where each person’s treatment is based on her or his disease’s genetic profile.
in 2003, a medicine called gefitinib was approved by the FDA for treating lung cancer in all patients who had had chemotherapy. After additional research, this approval was rescinded in 2005, because the drug did not extend life over the population of patients as a whole. Doctors noticed, however, that the medication helped a minority of patients a lot, even as it didn’t help other patients at all. When researchers investigated why this was so, they discovered that the patients who responded to gefitinib had an epidermal growth factor receptor mutation in their cancer, or EGFR. The discovery set off a flurry of research into mutations in lung cancer tumors, and the current state of this research looks like this:
Source: “ALK Positive Lung Cancer” presented by Shirish M. Gadgeel, MD, at the Targeted Therapies in Lung Cancer Patient Forum, University of Colorado Cancer Center, August 20, 2016.
These mutations are nearly always somatic, not inherited, existing only in the cancer, and not in the rest of the body. Three of these mutations, EGFR, ALK and ROS1, have at least one FDA approved targeted treatment, and clinical trials are searching for effective treatments for others. In the case of EGFR mutations, the one I know best, there are now three generations of targeted therapies available, one of which treats a new mutation that arises during initial treatment. Mutations upon mutations!
Upsides and downsides, advantages and disadvantages, it’s always a mixed bag in Cancerland if you are stage IV and trying to live with your cancer as a chronic disease. Having a mutation can give you an edge and extend your life by giving you access to targeted medications that are easier on the body than standard chemo, but different people with the same mutation respond differently to treatment. Some may be stable for years on a targeted therapy, while others may develop resistance rapidly. There are no guarantees. I had a shock of realization when I saw these targeted treatments described as “palliative” in an article. They can hold the disease back and improve quality of life, but they do not cure.
Resistance is inevitable when you rely on targeted treatments. It has happened to me. After three months of treatment with erlotinib, my cancer had almost entirely melted away. At six months, however, it proclaimed, “I’m back”, and by ten months, when I changed treatments, it had grown to be larger than it was on diagnosis. I’ve heard of one case of a man who seems to have had a total response to erlotinib that has lasted for 10 years and who chose recently to go off treatment. He is a remarkable exception, and is truly stepping out into unknown and unique territory. It is more usual for patients to get an initial reduction in their cancer followed by stability that lasts until resistance develops and the cancer starts growing again. If you are lucky, there will be a next generation drug you can switch to for another good year or so. If not, you join the rest of the lung cancer patients sitting in the chemo infusion chair.
Just because you have a mutation does not mean that you can find a treatment specific to that mutation. The science of identifying mutations and finding effective treatments is in its relative infancy. A good example is KRAS. As of this writing, no targeted therapy has proven effective in trials, and standard treatment (and prognosis) is the same as for a patient with no targetable mutation. Thus, “Take my mutation. Please.”
Ironically, having a targetable mutation may mean other good treatments are less likely to help you. Immunotherapy is a case in point. This is the hottest development on the lung cancer scene, and two FDA approved drugs are now available for patients who have had chemo. A very recent study demonstrates that one of these drugs, pembrolizumab, is more effective than chemo in newly diagnosed patients, a finding which is going to rapidly change how lung cancer is treated. Meanwhile a third drug has successfully completed trials and is expecting imminent FDA approval. However, subgroup analysis indicates that response rates to immunotherapy in people with the EFGR mutation are lower than they are to crappy second line chemo, and indications are that the ALK and ROS1 folks are in the same situation. For those of us with these mutations, immunotherapy is probably a Hail Mary treatment to try after everything else has stopped working.
I’m now on my third targeted therapy for EGFR mutations. I took erlotinib from August 2014 through June 2015, and developed the resistance mutation T790M during this first line of treatment. I then enrolled in a clinical trial for rociletinib. This drug did an impressive job of shrinking my cancer by 43%, but it was also very toxic. Fortunately I was able to slide on over to osimertinib when I was booted from the trial in February 2016. This EGFR and T790M inhibitor had been FDA approved only three months earlier! I’ve been on it for eight months now, which frankly is longer than I expected to benefit from the drug, because I had already taken a T790M inhibitor for eight months. I’m stable and feeling great. We shall see what we shall see when I have scans in December.
The future I am hoping for is one with many effective treatment options so that it doesn’t matter anymore whether you have a mutation in your cancer, or which one it is. I’m looking forward to the day when all patients with stage IV lung cancer can live a goodly portion of their expected lifespans with good quality of life. Then we won’t be envious of anyone, or at least of each other.
For a comprehensive and detailed discussion of lung cancer mutations and treatments, I recommend the following article, written by Lecia V. Sequist, MD, MPH and Joel W. Neal, MD, PhD.
The history of gefitinib:
On pembrolizumab’s successful trial as a first-line treatment:
On nivolumab vs. docetaxol, with data showing poor response to nivolumab in EGFR patients included in discussion portion:
General presentation by J. Soria, includes slide from Hellman presentation at WCLC 2015 showing poor response to pembrolizumab in EGFR patients (original presentation slides behind paywall) - 48th slide: