Chapters Transcript Video Locally Advanced Disease: Chemo-RT-IO Studies (No Driver) So I'm gonna uh talk about locally advanced, uh, driver negative non-small cell lung cancer. The title alone tells you how much progress we've made and some of the standards and challenges. These are my disclosures. So, I'm gonna, uh, the overview, I'll talk a little bit about staging to make sure everybody knows where we are, and then the subsets of subsets of stage 3 disease, chemo ads, and immunotherapy. So this is lung cancer staging made ridiculously simple. Um, does this laser do anything? No, it doesn't. Um, as where I've circled that is your typical stage 3 disease. Think of it as those with mediastinal involvement, but it can also include large tumors, tumors invading big pulsating things or other important structures. But, you know, mostly defined by ipsilateral or contralateral mediastinal, uh, involvement. It is incredibly heterogeneous, um. There are all sorts of things. So, for example, a single nodal station that's involved, uh, with a small primary could be surgically managed or managed now with, uh, upfront, uh, chemo, um, chemo immunotherapy followed by resection. But for the most part, this still remains disease with multi-station, ipsilateral or contralateral N2 or N3 disease. Um, and, uh, is treated, uh, primarily, uh, still with, um, uh, definitive, uh, chemotherapy and radiation. And, um, I would say, you know, one thing when it comes to, you know, what's, which modalities are there, the most experimental remains surgery, though clearly in the three A's that are potentially with uh inductible with chemo immunotherapy, they can be there. Since I was asked to talk about non-operative approaches, um, There is, this is really ancient literature. This goes back to ASCO in 1988. Uh, I actually saw the presentation of this data as a fellow, uh, at this cancer leukemia Group B lung Committee. And this showed that chemotherapy, quite archaic, uh, cisplatinum and vinblastin, not vinorelbine, vinblastin for 5 weeks before radiotherapy. And in those days, that was PA and lateral fields, not necessarily computer generated. You took your X-ray, you drew around the tumor with a wax pen, and that was that. And this resulted in a marked improvement in median survival, as well as 5 year survivors. So, you know, sometimes I think we get lost in the fact that we have newer drugs, targeted agents, immunotherapy, but realize that as, you know, long ago as 30 years ago, 40 years ago, Locally advanced, quote, inoperable, non-small cell lung cancer was curable with chemo radiation. Now, this was, you know, a fraction of patients, maybe 15%, but it was real. And then as we over the years developed the use of concurrent treatments, uh, which increased toxicity, most particularly esophagitis, um, we, uh, did increase the rates of cure. So, um, hmm, I've definitely messed with my slides here. Um, so surgery after chemo radiation, uh, no randomized trials have demonstrated benefit. We actually did an intergroup study with this. It was RTOG 9309, the 1993 for the year that this was done, 1993. And, um, the evidence did not show an advantage, but there was a big asterisk with this, which was at the time, a lot of the surgery was done by non-cardiac general surgeons, and a lot of right pneum pneumonectomies were done, and that led to a high mortality. You want to avoid pneumonectomy. It's a big procedure, um, rather than, uh, you know, those with lobectomy did fine. So my basic comment on this is it's not an unreasonable thing to do in the right patient, right circumstance, and right surgeon. So what about questions with chemo radiation? Um, so what's the optimal regimen, uh, for chemotherapy? How long should we continue it, Radiotherapy, the doses of proton versus photon, and of course, immunotherapy. So what's the, uh, chemotherapy regimen? So for a long time, it was a contest between platinum etoposide versus carbotaxol. There have been, uh, systemic literature reviews as well as an analysis of VA data, uh, cut a long story short, both of them show exactly the same thing, that if you wait for the prognostic indicate, you know, prognostic indicators for the patients, such as, you know, why did you get carboplatinin? Well, because you had a renal failure, so a renal insufficiency. But if you wait all of this, there is no difference in outcomes and uh substantially less toxicity with carboplatinum and paclitaxel. Um. So most of the, uh, the current, uh, I consider very standard regimen, low dose carboplatinum paclitaxel. This was used in the RTOG regimens. And this uh curve over here shows your results. This is pre-immunotherapy. You'll notice that it goes out to 5 years. If you look at the blue line, that's a standard 60 gray of radiation. It's very flat over there. And if you sort of draw your line across, it comes in the 20 to 25%. So these are the results pre-immunotherapy, a 5-year cure, inoperable non-small cell lung cancer, RTOG, so United States-Canada study. So the population that we treat, treated in a non-operative fashion with low-dose carboplatin and, Paclitaxel, and standard radiation. You know, so you can take that to the bank as far as what you can expect without immunotherapy. So if you have a patient who's not eligible for the immunotherapy consolidation, it's not like all is lost there. So what about the radiation dose and type? This has been asked a lot, you know, Medical oncologists, radiation oncologists, etc. Everybody thinks that more is better. No, it's not. Uh, did the study in RTOG 60 versus 74, great, no advantage, more toxicity, uh, most likely cardiac. Uh, so that's where it stands. What kind of radiation? Well, protons. Uh, potentially have an advantage because they, uh, there's, they fall off. There's this Bragg effect, and, uh, you don't get as much scatter. The problem is the physics doesn't work so well in the lung because it moves around in three dimensions and there's air-filled spaces, etc. So there actually has been a phase 2 randomized study. Uh, this, uh, was sort of the trifecta of results, which it showed that there was increased toxicity. Not as much efficacy and increased costs. Now, it was done by two institutions, a large one in Texas that remain nameless, uh, and a Boston institution. So take it with a grain of salt. Um, but no evidence to support that. Uh, the outcomes, you know, these are pretty close on the lines there, so no advantage. Well, what was the big change? So the big advantage was uh immunotherapy, the addition of durvalumab. Now understand it's a black box coming into this. Everybody had their chemo radiation of whatever it was. Some of it was sequential, some of it was concurrent, no controls on the amount of radiation, the dose of radiation, the chemotherapy used, etc. and then randomized to Derva versus no derva. And what this showed was a very clear advantage for the use of immunotherapy here. Uh, and, you know, pretty substantial, and it's actually strikingly limited degree of toxicity, particularly pneumonitis, which was a pleasant surprise to the data safe. Monitoring board. I was a member. I am a member of these data safety monitoring boards with AZ. And uh we looked at this, uh, and like month after month, and I can tell you this went on for years. It was like, where's the toxicity? So this is very well tolerated, um, and uh quite reasonable. But, you know, it's immunotherapy. And then toxicities show up when they do and are unpredictable. Uh, but that's clearly it. So, these are the issues with the study, you know, quality control on the radiation, chemo radiation was not standardized. And the entry was halfway, uh, down the race. Now, um, we'll get to the Pacific 2, which started the race at the starting line. But a couple of things. So, you know, one thing that, um, there were subset analysis upon subset analysis with this. One of them is, oh, you got to start within 2 weeks, those patients do better. Well, The interesting thing is, why would somebody start within 2 weeks in this? Well, that's because they had less toxicity. Well, why do they have less toxicity? They had a smaller tumor, maybe a smaller field. Well, smaller tumor, smaller field, less nodal involvement, etc. means that they have a better prognosis to start with. Another shocking feature of this was that healthier patients with less tumor did better. Surprise. OK, so, but this was good. I, I forget where, what high profile journal this was published in. But again, when you look at these subset analysis, not just with this, but all of them, look at it also was not planned, the data were incomplete, etc. So Let's get to, uh, we can skip the cyst versus, OK, that's the timing, the cyst versus carbo, they had better, uh, you know, renal function, you know, so all of these things are, are very, uh, clear. So where do we go from here? So we wanna, you know, can we treat patients based on genomics? What about concurrent with chemo rats? It's like, it's great. Let's bring it in earlier, what could possibly go wrong, and immunotherapy combinations. So this is a derva consolidation with driver, uh, genomic alterations. And it looked good for KRRAS, not for other things. Again, as we're learning, you know, the EGFR mutated, probably the other mutated tumors with the exception of KRRAS, um, just don't respond well to immunotherapy. So it may be a way that we can help out with this. So Pacific 2 was we brought immunotherapy earlier, same total amount of immunotherapy, but brought to be concurrent with the chemo radiation. And this was done largely in the RTOG. So it was a much more carefully assessed group of patients. It was the chemotherapy was defined, the radiation was defined and quality controlled. And of course, it would be better, but nope, it was the same. Um, and interestingly enough, this same issue of bringing radi of bringing immunotherapy concurrently with multi-fraction sustained, uh, radiation is now proven not to be a great strategy in a large number of trials, most recently also in small cell, uh, but also in head and neck and other things, probably because of, uh, toxicity, uh, to lymphocytes. So, not a good idea. This remains sequential, not concurrent. And, um, One of the things that came out, uh, from this, uh, let's see, subgroup, we can forget that, moving right along here. So again, overall survival, overall response, absolutely no difference. Um, trying other drugs, uh, terragoliab, you know, another, uh, immunotherapy, no difference from this one. So, so far, we haven't improved anything on that. Thought I took those slides out. Um, so, in conclusion here, uh, stage 3 disease, potentially curable with definitive chemo rads. The optimal radiation dose is 6D gray. IMRT preferred over 3D. That was a, uh, an analysis that was prospective in the RTOG trial, and no role for protons at this time. The optimal chemotherapy regimen probably is the low dose carbotaxol in Pacific too. There was a subgroup analysis, again, take it with a grain of salt of platinum pemetrexate, which did not do as well as carbotaxol. And Durva definitely improves PFS and OS. But you know, you want to start it, you know, as soon as you can, but don't feel crazy. You don't go crazy if it's not within that first two weeks. Must be sequential, not concurrent. Um, and, uh, if for one reason or another, such as the patient has an active autoimmune disease, all is not lost, they still may do well with, uh, chemotherapy. So, uh, thank you very much. And I think I'm a little ahead of schedule. Created by Related Presenters Martin Edelman, MD Department of Hematology/Oncology Chair, Department of Hematology/Oncology, Professor, Department of Hematology/Oncology View full profile
