Transcript:Jeffrey Weber, MD, PhD: Interestingly, the data from early studies on pseudoprogression have led us to treat often beyond progression, with both immunotherapy and targeted therapy. So, Reinhard, do you treat beyond progression even with targeted therapy? It’s a different scenario, but…

Reinhard Dummer, MD: Yes, it’s a different scenario. So, if I have a mild progression and good control of major metastatic sites, I often discuss these cases together with my radio-oncologist—because radio-oncologists, nowadays, can help us a lot. If there are metastases, they can more or less irradiate everything, not restricted to the brain with stereotactic irradiations, but also liver or lymph nodes. And I don’t know whether this will translate to impact on overall survival, but it gives a lot of confidence if you see that a patient is doing fine, and there are 1 or 2 lesions that are not behaving the right way, and then you can just wipe them out by stereotactic irradiation, and keep the patient in a close-to-complete remission. Therefore, I do this.

Jeffrey Weber, MD, PhD: This is urban legend number 6, that you can have someone on targeted therapy, have progression in an isolated area, radiate it, and maintain disease control, and not need to switch.

Caroline Robert, MD, PhD: I agree.

Dirk Schadendorf, MD: I completely agree.

Axel Hauschild, MD: This is done routinely, and all the clinical trials show that 25% of the patients are treated beyond progression. This was a case with single-agent BRAF inhibitors when they were approved, but it’s the same now with the BRAF plus MEK inhibition. And, I think, this makes perfect sense. And, don’t forget, there are so many patients who have just the progression in the brain. They are irradiated with stereotactic surgery, typically. They have a nice response, though, in the extracranial organs. And so, why should we stop the treatment, so we continue…

Jeffrey Weber, MD, PhD: There’s a contradiction here. We were just talking a little while ago about the fact that you should give a burst of BRAF/MEK, and then, at the point when you think they’re becoming resistant, switch to immunotherapy. Now you’re saying, when you think they’re becoming resistant, you should radiate it and keep going? So, I’m just confused, which is the best path?

Reinhard Dummer, MD: But, Jeff, what we have learned, resistance is very heterogeneous from site-to-site. And we have these data now. If you can investigate several molecular mechanisms of resistance in 1 patient and investigate 5 metastases, the chances are very high that every metastasis has a different mechanism. So, this means you have a subclonal development of the disease. And by just cutting one branch of the evolutionary tree of this tumor, you might do a good thing. We cannot prove it, but there is also a scientific rationale behind that.

Caroline Robert, MD, PhD: Also, when you asked the question about treating beyond progression BRAF, MEK or immunotherapy, it’s a different objective when you have a patient who is obviously progressing, and they’re on one or the other therapy. I think on one side, with targeted agents, when there is obvious progression, sometimes you are afraid to stop if you don’t have any other treatment that you can give, because you are afraid that if you stop, it’s getting worse. With immunotherapy, you treat beyond progression very often because you hope that you will see a response coming sometimes.

Dirk Schadendorf, MD: So, that you’re not confused with pseudoprogression, as in our previous discussion, if the patient is doing well, if their ECOG is not changing, possibly even a biomarker like LDH is dropping, you see, and your radiologist tells you, it is possibly not true progression. You just keep on going, treating this patient.

Caroline Robert, MD, PhD: Yes. On one side you are afraid of worse, and in the other side, you hope for better.

Jeffrey Weber, MD, PhD: Well, also, I guess, we would agree there are differing mechanisms here. Some of the pseudoprogression may be just an inflammatory response around the tumor without actual progression, which is why the word ‘pseudo’ is used. It sounds like with BRAF-MEK it really is progression, but I love the way that Reinhard put it: the tree got chopped down, but one new branch came, chop off that branch, the tree is still gone and you still have a remission. But, again, don’t isolated branching abnormalities prognosticate in the future for a true resistance? Dirk?

Dirk Schadendorf, MD: Yes. But, several of these patients, whom we have treated with targeted therapy beyond progression, had a very long benefit from the treatment. These are usually patients who are benefiting from this treatment 1 or 2 years before this limited progression appeared. So, I think, here it’s clear that Reinhard’s concept of chopping down one tree, one part of a tree, is possibly a solution. Nevertheless, I think this was done in the clinical trials because we had no other option. And this was also done in clinical practice because the options we had at that point were limited. I think, now, I completely agree. Could that be a perfect starting point, you know, eliminating this limited progression, and then switching to checkpoint blockade? Could that be the best decision point controlling the disease otherwise? Again, as we have discussed previously, I think it would be important to test that in a clinical study.

Transcript Edited for Clarity