Round 1: Immunotherapy vs Alternative Therapy

The debate opens with an insightful review of existing treatment paradigms for metastatic NSCLC. In patient scenarios where pre-existing conditions previously hindered immunotherapy use, panelists discuss which treatment should be used as second-line therapy.

To hear arguments related to adding radiation therapy or switching treatments, see Round 2.

To hear arguments related to for TTFields vs against TTFields, see Round 3. 

Dr Corey Langer: I'm going to start off. We'll have a nice little roundtable discussion. Patient with metastatic non-small cell was previously medically ineligible. Maybe they had a history of RA that some—sitting in the chart someplace. And they were being evaluated for a clinical trial at Jamie's place. And the clinical research manager looked at the chart and said, “This patient has RA. They're disqualified from the study.” And then, patient went on to standard chemo or chemo bev. I don't know if they use that anymore at Memorial. And lo and behold, had progression, maybe 6 months or 8 months later. And then, Jamie said, “I can't find any evidence of the RA.” And then, questions the patient, some primary doctor and outside hospital said, called “osteoarthritis RA.” So, thoughts there? 

Dr Jamie Chaft: Yeah, this was 10:00 AM yesterday. This was 10:00 AM yesterday of the patient blowing through frontline therapy. Sent in rheumatoid factor, and absolutely going to give this patient immunotherapy. I think we could certainly talk about other scenarios, for example, Crohn's disease or autoimmune hepatitis where I might be a little gun shy. But for a patient with RA who's blowing through frontline platinum doublet chemo, I'd have little confidence that alternative chemo is going to do the trick and I would offer immunotherapy. 

Dr Corey Langer: So, you'd be a yes. Eddie?

Dr Edward Garon: Yeah, I think that I agree completely that it's really in many respects a risk-benefit assessment and always is. I think one thing is you do go through the chart. There are times when we'll see patients that have a history of lupus. And you look and obviously there's some people for whom lupus is their major medical issue and drives all sorts of things in their care. But there are also people who got that diagnosis on sort of questionable issues. In those cases I—

Dr Corey Langer: You mean, like a positive ANA, but no real clinical symptoms?

Dr Edward Garon: Yeah, I think that in an era where fibromyalgia is a recognized diagnosis, we tend to see that diagnosis sometimes substituted for cases historically that were given a diagnosis of atypical lupus. But nonetheless, in those cases, there is a clear benefit for adding immunotherapy. And I often will try and add it in the first line. I think that there are many cases where if my choice is sort of a docetaxel-based chemotherapy or trying immunotherapy, even if I withheld it in the first line, that I would consider it. There are still some that you get really nervous about—scleroderma…

Dr Corey Langer: Active scleroderma.

Dr Edward Garon: …with lung involvement. The question is, have we tried it in all of these scenarios? The answer is probably yes, we've tried it. Sometimes it goes okay, but sometimes it goes very badly. And I think that particularly for some of these where you have greater concern, my plan has always been to actually just develop a plan with the patient beforehand that I don't want a situation where you have somebody with scleroderma with lung involvement that ends up getting immunotherapy that's on the ventilator for months, because this is the sort of thing you should have discussed beforehand. And that if this goes badly, almost certainly it's going to go badly. 

Dr Corey Langer: So, even though you're a no, you would basically say if you're going to do it, make sure the patient knows flat out all the potential risks. That they're signing a very validated ICS that details these risks. 

Dr Edward Garon: Yeah, and obviously it's an interesting thing. We don't, for our N-of-1 experiments, we don't have people sign an informed consent. We just have them, we just do it. 

Dr Corey Langer: We have all our patients sign an informed consent. 

Dr Edward Garon: We do have a consent for chemo, but it's a pretty generic form. And the consent for someone with scleroderma lung disease who's going on immunotherapy…
 
Dr Corey Langer: I'll add that to the consent. 

Dr Edward Garon: Yeah, and we've had cases as well where, with solid organ transplants, where this comes up as well. And these are hard. I've definitely had cases where I've been involved in with a kidney. The kidney's the one that's a little bit unique because obviously there are other replacement approaches. But, all of a sudden, they get sort of rejection. And everybody's running around, I'm on the inpatient service, everybody’s wondering what to do. “Let's start high-dose steroids. What other medicines should we start?” And I'm, like, well, this is something ideally we would have a plan beforehand. Is this patient willing to go on dialysis? Are they willing to end the immunotherapy if they know that they're going to lose the kidney? I think these are complex discussions. 

Dr Corey Langer: So, two questions. Number one, does the PD-L1 level influence your decision? And then, we'll start with that. And then, number two will be the different scenarios, the different “contraindications” to IO. So, for the “yes” position, Jamie. 

Dr Jamie Chaft: I think any tumor that's PD-L1 positive for TMB high—you're talking to two TMB believers here. I know you don't believe in it. But PD-L1 positive TMB high. It's that PD-L1 negative I'll throw to Eddie for the no argument. 

Dr Edward Garon: Yeah, and I think that, again, all of these things are risk-benefit. So, if you have someone whose TMB, tumor mutation burden, is in the third percentile and they have PD-L1 less than 1%, your likelihood in your mind that they're going to have a profound benefit from immunotherapy is very low. It's going to be very difficult if that's a solid organ transplant patient to say, okay, we're going to roll the dice on this because we expect so little from immunotherapy. Where it becomes more difficult is in the setting of a bad toxicity, potential toxicity, and biomarkers that are more suggestive of likelihood to benefit. 

Dr Corey Langer: So, if I recall correctly—and this is going back almost 10 years when IOs first came on the scene—pembro’s approval second line after chemo is restricted to PD-L1 positive, not to all comers. Because the study was just done in 1 positive. Atezo’s approval, I think was in the OAK trial, was agnostic to PD-L1. And the same held true for nivo in 017057 squamous and non-squamous. So, would you have—you couldn't give pembro if you wanted in the PD-L1 negative. 

Dr Jamie Chaft: I prescribed nivo yesterday for this reason with PD-L1 unknown. 

Dr Corey Langer: Let's go through specific scenarios. Somebody's both first and second line. Heart transplant? 

Dr Jamie Chaft: No. 

Dr Corey Langer: Eddie. No? 

Dr Edward Garon: No, but it does become difficult. 

Dr Corey Langer: Notice they're reversing their position. 

Dr Jamie Chaft: I told the organizers to switch us. 

Dr Edward Garon: So, the issue is—so this came up. I had a patient and he actually lived away. So, in the end, it was going to be somebody else's decision. But it wasn't heart. It was liver. Progressed on chemotherapy, PD-L1 90%, history of liver transplant.

Dr Corey Langer: There wasn't major options, yeah. 

Dr Edward Garon: The likelihood that he's going to die of liver failure is probably upwards of 50% If you give him a PD-1 inhibitor. The likelihood of him dying of cancer if you don't is near 100%. But over a short period of time. 

Dr Jamie Chaft: But this is second line. You have other chemos. 

Dr Edward Garon: Yeah, it's true. And it depends a little bit on whether you think you're going to have another option, another opportunity. 

Dr Corey Langer: You alluded to it earlier, but renal transplant. Jamie? 

Dr Jamie Chaft: As Eddie said, if they're willing to go on hemodialysis… 

Dr Corey Langer: So, you would predicate— 

Dr Jamie Chaft: …and alter their lifestyle tremendously, then yes. 

Dr Corey Langer: Eddie? 

Dr Edward Garon: Same. 

Dr Corey Langer: Same. So, I had a patient when these drugs were first coming out. Obviously, that patient couldn't go on a clinical trial. But it was already FDA approved. And when he presented with the prospect of potentially losing his kidney and having to go on dialysis, that was a hard no for him. Even though he knew that—they got docetaxel and it didn't work. Crohn's 20 years ago, or at least the label’s on the chart. It's inactive. He's on no immuno agents. 

Dr Jamie Chaft: For me, no. We're switching roles again. Not in second line. Overlap between Crohn's and autoimmune hepatitis is real. 

Dr Corey Langer: So, you wouldn't do it. 

Dr Jamie Chaft: Not in second line. 

Dr Corey Langer: Not second line. 

Dr Jamie Chaft: And if you have a chance at third, I'd save it. 

Dr Corey Langer: So, third line, maybe. Eddie? 

Dr Edward Garon: I think it would depend on biomarkers. 

Dr Corey Langer: Okay. I think we talked about the pseudo rheumatoid arthritis or lupus versus active scleroderma. HIV—controlled, no viral load on decent drugs. Again, all of these folks were excluded from the original trial. 

Dr Jamie Chaft: They were more permissively included in… 

Dr Corey Langer: Later studies.

Dr Jamie Chaft: …more recent studies. So, yes. 

Dr Corey Langer: So, you would say yes?

Dr Edward Garon: Yeah, I think that we would probably give these frontline in that setting. And, as was alluded to, even our IRB, our ethics committee, basically has pushed back very hard on just blanket exclusion of HIV. 

Dr Corey Langer: Last one before we go to oligoprogression or the role of radiation, potentially. Not autoimmune hepatitis, but a viral hepatitis that's now in remission. 

Dr Jamie Chaft: No problems. I mean, these drugs are used in hepatocellular carcinoma. 

Dr Corey Langer: So, much more permissive. And you agree with that, Eddie. And I agree with that as well. And again, for the most part, with the exceptions that Jamie's alluded to, virtually all of these patients were excluded from the clinical trials. We actually went through our numbers at Penn. And that comes to about 30% of the patients we see for one reason or another. There's some—one of these would've been a major exclusion.