Lung cancer treatment is clearly the story of the week coming out of the annual meeting of the American Association for Cancer Research in Chicago. And although media coverage of this emerging information about the role of immunotherapy in lung cancer has been extensive, there is—as always—more to the story, especially if you look closely at the numbers and in particular if you are a non-smoker with lung cancer.
One study stands out among the others in which immunotherapy along with chemotherapy significantly improved survival for patients with certain forms of lung cancer when compared to chemotherapy alone. Not only was that study reported at the Chicago meeting, it was also published simultaneously in the prestigious New England Journal of Medicine, offering us considerable detail into how the study was performed and the results.
The research was one of the next logical steps in understanding how to best use immunotherapy in lung cancer. In this case, the drug used in the study was pembrolizumab, one of the three immunotherapy medicines currently available on the market which have shown value in the treatment of patients with advanced lung cancer.
Previously, pembrolizumab has been approved for the treatment of patients with advanced lung cancer as a first line agent, meaning at the time the cancer has been shown to spread beyond the lung. However, it’s been limited to patients whose lung cancer tissue specimen had evidence of a certain marker called PD-L1 which, in some situations, predicts a better chance of responding to immunotherapy. Unfortunately, that marker is found in a minority of the lung cancer patients who are potential candidates for treatment with pembrolizumab.
In this new clinical trial, lung cancer patients with non-small cell lung cancer (NSCLC) who didn’t have squamous cell cancer and/or other biologic signals in their cancer tissue that suggested they would probably respond much better to certain targeted therapies were candidates for the study. They also had no prior treatment for their metastatic disease. If eligible for the trial, the participants were then randomly assigned to receive either standard treatment with two chemotherapy drugs (platinum-based drugs such as carboplatin or cisplatin along with pemetrexed) with or without the immunotherapy drug, which in this trial was pembrolizumab. The main outcomes of the study were how long it took for the disease to progress, and overall survival of the patients who participated in the study.
Two out of three patients were placed in the group that received chemotherapy and pembrolizumab, while 1/3 of the patients received just the chemotherapy. Although the patients’ cancers were tested to see their level of immune markers in their tissue, they could still receive the immunotherapy even if they had a low level of those markers, which would have predicted less of a response to the immunotherapy drug. That’s an important distinction from what is done currently in the United States, where higher levels of this particular immune marker are necessary before receiving pembrolizumab as a first-line treatment of metastatic lung cancer.
616 patients were part of the study, and 607 were actually treated. There are a lot of details about the results of the trial that are too complex to go into depth here. The most important fact is probably that almost 70% of the patients treated with the combination of immunotherapy and chemotherapy were alive at one year, compared to almost 50% of the patients in the chemotherapy-alone arm at the same time. That’s a very significant difference.
Perhaps as important a piece of information is that over half the patients who received the combination therapy were still alive when the study was analyzed while half of the patients who received chemotherapy alone had died by 11.3 months. In different terms, the chances of someone dying was about 50% less if they received the immunotherapy treatment in addition to the standard chemotherapy. That is—in a word—a remarkable difference.
To put this into perspective, I asked my colleagues at the American Cancer Society to research the typical survival in the United States for patients who present with the same lung cancer types as studied in this trial. The sad reality is that nationwide 30% of patients survive one year, 15% at two years and 4.5% at 5 years. That helps explain why this study is getting so much attention with 70% of those receiving immunotherapy/chemotherapy alive at one year.
Another observation was that the results were not quite as good in patients receiving immunotherapy who had lower levels of the immune marker, they were still significantly better than chemo alone. Remember: these are patients who under our current rules today in the United States would not be eligible to receive immunotherapy as a first line treatment, yet in this study they did better if they received the additional immunotherapy.
So now we get into some of the other information that hasn’t received a lot of publicity:
First, what struck me when I read the report in the New England Journal was that one group of patients who received the combination therapy did exceptionally well: those patients with lung cancer who had never smoked. Their odds of dying if they received the combination therapy compared to chemotherapy was a stunning 0.23, or 77% less. Again, that is remarkable.
A word of serious caution, however, about assuming this is a “real” number: this is a subgroup in a much larger study. There were only 73 non-smokers who received the combination therapy, so there is a real chance this is not the same number that would show up if a more formal study was done that focused solely on never smokers with lung cancer. But it is enough of an observation to take note of it. And in the past, this is the group that has had a higher likelihood of benefitting from other targeted therapies so immunotherapy might not be the first choice for some of these folks. Still, this represents an intriguing new potential approach that should be evaluated carefully and may raise the question of whether targeted therapies or this new approach to the treatment of lung cancer is appropriate first line care. That may take another study to determine.
There is another wrinkle in the research report: 41% of the patients assigned to the chemotherapy-only arm received immunotherapy once it became evident their disease was progressing on chemo alone. Another fairly large number of patients who decided to stop taking their assigned treatment decided to continue immunotherapy beyond their participation in the trial.
What is this important? Again, we are always supposed to be very cautious about making statements regarding clinical trials that were not measured as part of the initial design of the trial. However, there is a question that should be asked: if the group of patients who decided to take immunotherapy after they failed chemo had not done so, would the survival differences have been even greater than we have seen here? I am not suggesting that their receiving immunotherapy was not appropriate, merely that we should be aware such “crossover” treatment did in fact occur and may have influenced the results in unknown and perhaps unanticipated ways.
And then there is the question of why this immunotherapy/chemotherapy combo worked so well in the first place. Why did chemotherapy—a treatment that can in fact help patients live longer however is not necessarily a stellar treatment for lung cancer with few long-term survivors–make such a difference when combined with immunotherapy?
There is a clue to the answer in the NEJM paper, where the authors suggest traditional chemotherapy may have its own immune-related effects brought on by destruction of tumor cells, impacting white blood cells (in a good way, as opposed to just decreasing white cell counts and increasing the risk of infection) or altering the numbers of various immune cells in the body in a way that increases the number of white cells needed to mount an immune response to the cancer, thus augmenting the known positive effects of the immunotherapy drugs themselves.
And finally, there is the observation from the data that some of the patients have done much better than expected. There is still a need to continue following these patients for a longer time, however there are 89 folks in the group of the immunotherapy treated patients who are alive 15 months or more after starting their participation in this study. And looking at that entire immunotherapy/chemotherapy group—as noted earlier—well over half the patients remain alive at fifteen months and beyond. It remains possible that there may be some patients who have an unexpected but very welcome long-term survival as a result of this new approach to treatment. We have seen that happen in malignant melanoma, another cancer that until recently had no effective treatment and it is possible we may see the same circumstance happen here as well.
How do I interpret all this information?
I have gone through eras of lung cancer treatment during my career. Decades ago we realized we didn’t have much in the way of effective treatment for metastatic lung cancer. There was even a time when a study was done to prove that giving chemotherapy vs. simply providing supportive care made a difference. Chemotherapy prevailed, however you can begin to understand how little we had to offer in the past.
We have gone through studies to find out how many drugs in combination were best for the treatment of lung cancer, and for the most part settled on two drugs as best—vs. three or four. We have done studies to learn which drugs work best in combination. We have learned that for a handful of patients, there are remarkable responses to targeted therapies, however even those become ineffective after too short a time for most folks.
Now we are moving forward in the era of immunotherapy, trying to figure out which approach to treatment works best. It appears possible that immunotherapy in combination with chemotherapy may be a significant improvement, however we still must balance the impressive outcomes of this study relative to other effective therapies such as targeted medicines which can produce impressive results in some patients.
All of this together offers a glimpse of the challenging road ahead, trying to dissect out the messages to determine which treatment is best for which patient under what circumstances. That is an immense task.
And we should never forget that not everyone benefitted from the new treatment described in this research study. We still have a long way to go. However, for now we can afford a moment of optimism that perhaps—just perhaps—we have moved one step further down that road with the results of this study and offer more hope to patients afflicted with a life-threatening cancer.