Round 1: The Optimal Approach for Patients With Diffuse Progression on IO

The debate begins with diffuse progression on immunotherapy. The panelists explore whether to change treatment or add TTFields therapy, with discussion focused on benefit, toxicity, and quality of life.

To hear arguments related to managing oligoprogression, see Round 2.

To hear arguments related to sequencing in the real-world setting, see Round 3.

Beth Sandy: So let's start with Round 1. There will be 3 rounds of debates. In the first round, we're going to talk about the optimal approach for patients with diffuse progression on IO. This would be rapid progression on front-line immunotherapy, chemo plus immunotherapy. So rapid diffuse progression on front-line immunotherapy. 

So the question here is, for patients with diffuse or rapid progression that’s not amenable to local therapy, because that'll be a different debate. So, not amenable to any local therapy. Should you continue the immunotherapy and add Tumor Treating Fields, or would you switch the systemic therapy entirely?  

So, Dr Chun, I’m going to turn it over to you first, and you go ahead and debate your side.

Dr Stephen Chun: So, I'm a radiation oncologist, and I just want to make that disclaimer up front that I'm not a real doctor. I have no internal medicine training. In fact, I did a surgical internship. Yet, I have prescribed Tumor Treating Fields many times for both this setting and for oligoprogression. But just for diffuse progression, outside of a clinical trial, I treat many patients who come in from rural locations because I practice in a community-based satellite center, which is actually where the majority of patients are treated for cancer in this country. It's actually a minority of patients who are treated in an academic tertiary care center, where you have a robust clinical trial portfolio. Many of my patients cannot get to a main campus where they have sophisticated INDs with pharmacokinetics, pharmacodynamics. 

And, outside of a clinical trial, the second-line treatment for metastatic non-small cell would be docetaxel. And while perhaps the subset of patients in the LUNAR Trial treated with docetaxel, the benefit was not as significant or pronounced as patients who received immune therapy. There seems to be some signal of a hazard ratio, indicating at least some of the patients had some indication of benefit. 

And I think in this situation, rapid progression after first-line therapy, there's no actionable mutation, I just think it’s all hands on deck; very little is going to work, and even if there's some glimmer of hope from something like Tumor Treating Fields, I feel like, why not? We're talking about something, no systemic side effects. There at most is a 5%, maybe 7% rate of bad dermatologic toxicity. And hey, I'm a radiation oncologist, so I deal with bad dermatologic toxicity every day. So that doesn't really scare me. And to me, so what? You develop a grade 3 dermatitis from the applicators, take it off, right? So again, being someone who's not a real doctor, I will say that this is probably the easiest thing I've written a prescription for. You don't have to take vital signs. You don't have to do any labs. You have them– They put it on themselves, and they take it off themselves with some training. And really the only requirement is following, as we should be following them, every 3 months with imaging.  

And so, I have offered this even for rapid progression, looking at LUNAR Trial patients who progressed like this, were allowed to be treated in conjunction either with immune therapy or docetaxel, because we just have very little left at that point to offer a patient.

Beth Sandy: Dr Chun, before we move on, you said, “So what for grade 3 skin toxicity?”  

Now the good thing is, in the LUNAR Trial, that was actually really uncommon. The majority was grade 1 or 2, but grade 3 would be bad; that would require hospitalization. So, hopefully they wouldn't, but it was less than 10% in the LUNAR Trial, so that at least was good. The majority was grade 1 or 2, but have you had any experience with a grade 3 skin toxicity with it?

Dr Stephen Chun: Yeah, I will say, I personally haven't, but Grade 3 skin is not necessarily hospitalization. It's just full-thickness ulceration of the skin. I'm very used to the grading because we grade radiation dermatitis in the same way.  

Grade 1 is something where it's just irritated. No medication.  

Grade 2 is where you have to apply steroids or some kind of antihistamine, et cetera. Grade 3 is basically full-thickness ulceration of the skin.  

Grade 4, it's spontaneous bleeding and possibly hospitalization.  

Grade 5 is, of course, a fatal complication.  

There were no fatal complications related to Tumor Treating Fields in any clinical trial, whether for brain, or lung, or anything else that I am aware of. I can't think of any second- or third-line treatment that you can say that you've never had a patient die from– Even the most benign targeted therapy, there have been fatal side effects.  

I have never, ever, heard of that from alternating electric fields, certainly not from an intervention that has a hazard ratio across all comers in the 0.8 range and for patients with immunotherapy in the 0.6 range.

Beth Sandy: Thank you; that's really helpful to know. So, it did seem like the majority were pretty easily managed, Grade 1 or 2 in those patients.

Dr Stephen Chun: Right, and radiation oncology, I'm very used to managing that.  

Beth Sandy: All right, so Dr Patel, do you want to, from your end, and there are slides after this one with the LUNAR and REVEL data if you want to reference them.  

Dr Eshan Patel: Yeah, so I think a very loaded question, and I agree, it’s such an unmet need; we do not have good options for those patients. But I think I would like to break this question into different approaches.  

I think first is, should you continue immunotherapy or not, right? And then, whatever you do with the Tumor Treating Field added on or not is a second option.  

But I think continuation of immunotherapy for patients who have diffuse progression, as a medical oncologist, I think will be very challenging with somebody who has diffuse liver mets or diffuse bone mets. And we have seen on many trials and it has proven that, even with the continuation of immunotherapy plus addition of ramucirumab, for example, per Pragmatica trial, did not show any survival benefit, right? And there were other trials that have shown that even adding continuation of immunotherapy plus adding something on top of a different backbone, and it still did not show much of the benefit. So, I think when patients had diffuse progression, liver mets or bone mets, multiple bone mets, brain mets, I think those patients are definitely developing a clone and resistance from the immunotherapy. So I, as a medical oncologist, I don't think I will be able to continue immunotherapy. I think there is not enough data on it.  

And I have seen even in real-life scenarios where patients were chemo-averse, they did not want more chemo, and they're like, “Okay, I want to continue immunotherapy, I don't want anything else, I'm barely symptomatic.” Even at that point, insurance was giving us the hard stop. Like, “Why are you continuing immunotherapy, right? The patient is progressing; there is no data on it.” So, I think I would prefer them to switch to some other systemic therapy. 

Now, what therapy do you switch to? I think the only therapy that has shown some survival benefit, a very modest survival benefit, was ramucirumab plus docetaxel based on the REVEL data. And I think the survival was 1.4 months, very modest. And it did, came with a lot of toxicity. Those patients in the combination arm had much higher hypertension, bleeding, arterial thrombosis, right? So it did came with the toxicity. Those patients are already frail to begin with. So it's not for everyone, I think it's reserved more for patients who are a little bit younger, fit patients. And so  

I will definitely switch them to some form of systemic therapy.  

Now, what will you do in terms of Tumor Treating Fields? So that was not an option, but I think that should be an option; switch to a different systemic therapy plus/minus consider Tumor Treating Field. I think that option should have been up there. But I think that will be another option I think people, or I myself, will consider.  

Now, will I do docetaxel plus ramucirumab plus Tumor Treating Field? Unlikely. I think that will add a lot to toxicity. But can you do docetaxel plus Tumor Treating Field to those patients? Maybe, it's debatable, and I think that's our third question, and I will answer that at that time. 

But I think, in my humble opinion, I think those patients who have diffuse progression, resistant to immunotherapy, and I think it should be switched to a systemic therapy.

Beth Sandy: Let's look at the LUNAR Trial data, if you advance to the next slide on yours. Do you want to comment, because your side of the argument is like, “No, I wouldn't do it,” where Dr Chun is saying, “Yes, I would add the Tumor Treating Fields.” 

Now obviously, in this study, patients didn’t, the majority of them didn't receive immunotherapy in the front-line. I think it was right around 30% had immunotherapy in the front-line setting with chemotherapy. So, the majority didn't. So how do you interpret this data given that?

Dr Eshan Patel: I think, A) you made a good point that the majority of patients did not have immunotherapy. This was all based on second-line, right? In a real-life setting now, that does not happen, right? Most of our patients, everybody gets immunotherapy upfront. That’s one.  

Second is, in the LUNAR trial, 50% of patients, we do not know the PD-L1 status, right? So we are not sure if a lot of the data is significant, if their PD-L1 status were different, right? So, I think that's another question. We are not sure about that portion. Also, what's driving that benefit? 

And I think the third thing I will make, differences in the LUNAR Trial, we do not know when diffuse mets, how many patients had that kind of aggressive biology? We do not have biomarker-driven data yet. And we do not also know liver mets patients, I think it was 15% on each arm, right? So, when we say diffuse mets, what are those high-risk patients? Diffuse mets, liver mets, bone mets, TP53 co-mutation… What are those patients? What's happening to them, right? So those kind of analysis, I think, is not available to us.  

Beth Sandy: Yeah, I think there’s a lot of nuance that goes into it.