“Pineapple, my dad has advanced lung cancer, is resistant to first-line treatment, and has no genetic mutations, and his doctor recommended the latest PD-1 inhibitor-based immune drug. I’ve heard it works really well, but is it too early to use it? Has anyone suggested trying another therapy and switching to an immune drug when all else fails?”
Immune drugs have undoubtedly been a revolution and have given hope to many patients with advanced disease.
But the question is often asked: Should immune drugs be used early, or should they be the last straw?
This is a question that used to be hard to answer, but as we follow patients for longer and have more data, the answer is clear:
“When available, immunotherapy should not be left until the end, it’s better to use it early!”
(Image from Station Cool Helo)
Why do you say that?
First, the principle of immune drug onset supports early use.
Compared to targeted therapies or chemotherapy, immunotherapy is fundamentally different. Instead of directly targeting cancer cells, it mobilizes immune cells in the body that recognize tumors and relies on them to kill and control the cancer.
An additional feature of immunotherapy is the trailing effect, which means that patients can survive for a long time after it takes effect, turning cancer into a chronic disease. What’s even more amazing is that patients don’t even need to use the drugs for life, and many patients don’t come back after a period of time, even when they stop using them, which is very different from targeted drugs.
This is because the immune system has another characteristic: the ability to remember. While removing cancer cells, some of the immune cells develop a memory of these bad guys, which is important for killing the remaining cancer cells, preventing recurrence, and achieving long-term survival.
So, whether it’s short-term killing of cancer cells or long-term control of tumor recurrence, the necessary condition for immune drugs to work is a healthy immune system.
When is the immune system at its healthiest?
The earlier the healthier, of course.
Many anti-cancer treatments, especially high-dose chemotherapy, have a suppressive effect on the immune system, which is part of killing a thousand enemies and damaging eight hundred. The immune cells of many patients are in a poor state by the end of treatment and are difficult to be activated by immune drugs, so the effect is not good.
Of course, the above is all theoretical, but what are the real data? The first thing you need to do is to use immune drugs early.
Don’t worry, here’s some more “real world” data.
Second, the big data show that patients who start with immunotherapy may have longer overall survival.
In 2017 JAMA ONC had a classic article that looked at big data from 25 clinical trials in non-small cell lung cancer with more than 20,000 patients and found that patients who participated in immunotherapy and targeted therapies had very different survival curves.
What does this graph mean? Does it mean that targeted drugs do not extend life at all?
No. Many patients in clinical trials “cross-over,” meaning they try drugs from another group when they are resistant to drugs in their own group, for example, patients assigned to the chemotherapy group who fail may also use targeted drugs from the trial. This is mainly for patient protection, so that patients assigned to the control group may also be on the new drug.
In the targeted therapy section above –
- Trial group (blue): targeted drugs first, then other drugs after failure;
- Control group (orange): other drugs first, then targeted drugs after failure.
The graph shows that the survival curves for the two groups of targeted therapy are very similar, which suggests that whether the targeted drug is used first or second has about the same effect on survival.
But immunologic drugs are a completely different story.
As you can see, the immunotherapy trial group (immune drugs first, then other drugs after failure) had a significantly higher overall survival than the control group (other drugs first, then immune drugs after failure), and the overall risk of death for patients was reduced by more than 30%.
This demonstrates that immunologic drugs are very different from targeted drugs, and there is a difference in the effect of using them first or later. Survival is better with immune drugs early.
Third, the better the physical status of the patient, the better the immunotherapy effect.
The common clinical system for evaluating patient health status is called ECOG PS (ECOG Physical Status Scale), and the smaller the score, the better the physical status.
Score 0 – perfectly normal mobility, no difference in mobility from before the onset of the disease.Score 1 – Ability to walk freely and perform light physical activities, including general housework or office work, but not heavier physical activities.Score 2 – Able to walk freely and care for themselves, but have lost the ability to work and get up and move around for at least half of the day.
Score 3 – Only partially able to care for themselves, bedridden or wheelchair bound for more than half of the day.
Score 4 – bedridden and unable to care for himself/herself.
5 points – Death
Many clinical trials have found that patients who are well have better outcomes with immune drugs. For example, in 2016, the results of the O-drug clinical trial (code name CheckMate153) presented at the World Lung Cancer Congress showed that patients with PS 0 or PS 1 benefited much better from immunotherapy than patients with PS 2.
In general, the more advanced patients are, the worse their health status becomes, especially with drugs such as chemotherapy. patients on 3rd line therapy are usually in much worse shape than on 1st or 2nd line therapy.
These data also support the idea of using immune drugs early and not waiting until the end, when you are so poorly that you want to come back from the dead.
More so, some patients simply don’t have the opportunity to try other drugs by the end of the day. This is especially important for rapidly progressing cancer types. For example, statistics show that 75% of Chinese patients with intermediate to advanced squamous lung cancer will receive formal 1st-line therapy, but only 28% will have access to 2nd-line therapy, and less than 5% will have access to 3rd-line therapy.
In conclusion, both theory and clinical trial data support earlier use of immune drugs. Our Chinese habitual thinking of being frugal and saving the good stuff for last is not always the right choice, so please still believe in science and statistics.
