New Concepts: Multimodal Approaches to Advanced NSCLC - Episode 12
Suresh Senan, MRCP, FRCR, PhD: In locally advanced non—small cell lung cancer, we are actively investigating the context of how the improvements were observed in the PACIFIC trial. We know that the building block approach works and immunotherapy after immune checkpoint inhibitors after that works. We know that the PD-L1 expression before commencing any treatment doesn’t make a difference. What we would like to know is, what is it after completing the induction chemoradiotherapy? Could that identify good and bad factors?
A second point is that not all patients with locally advanced non—small cell lung cancer are fit for concurrent chemoradiotherapy, which then raises the question, are there other strategies which could improve the immunogenic profile of the tumor? For example, a certain dose of chemotherapy or certain combinations of chemotherapy and radiotherapy. If sequential chemoradiotherapy led to the same immunogenic microenvironment after completion as concurrent, then that opens the way to applying immunotherapy in those patients as well.
We don’t have a trial directly answering that question, but it would be good to know in translational research whether we are warming the tumor up and creating a hot microenvironment in that way. And the same applies to patients who perhaps are unfit for chemotherapy. Are there radiation schemes that can then create a hot tumor microenvironment—locally advanced therapy which then opens the door, the therapeutic window, to apply immunotherapy? So, what the tumor is doing is in a fascinating area of research. What happens to the tumor? And one of the ways to study is using an imaging marker PET label to PD-L1 inhibitors, for example. And we have to characterize it better. I suspect that the immunogram, or immune profile, of a tumor before treatment after chemoradiotherapy, and during, may be the most exciting area of research to then help us identify the timing of standard strategies and perhaps also the combination immune strategies, which could apply after completion of standard chemoradiotherapy. So, this is knowledge of why we succeeded in PACIFIC in getting great results and also new therapeutic options with our patients. I think the translational research is going to be extremely important to build on to take us to the next level.
Given the recent breakthroughs in locally advanced non—small cell lung cancer, I see a number of changes coming on. The first is that the dose of radiation has now settled, in the radiation guidelines and in the studies. The second point is that patients are going to get immunotherapy, and we want them to start immunotherapy early so radiation techniques that limit the number of amount of damage, sparing the heart, esophagus, will then take a prominent role. So, more modern radiotherapy techniques to limit the amount of collateral damage.
The third change, at least in our practice is, if there’s a very effective treatment available, we make the push to start treatment immediately. Because in the past, especially in Europe, we didn’t have the capacity. We often started the radiotherapy after the first cycle of chemotherapy, or the second, which means patients had a gap of between 3 and 6 weeks before getting the concurrent treatment. But concurrent treatment is the immuno-activating building block. We do not want to delay it. So, at least in our center, they’re moving to immediate concurrent chemoradiotherapy stopping so that they get the next proven treatment as quickly as possible.
Transcript Edited for Clarity