Chapters Transcript Video Metastatic Disease: Oligo Met, Oligo Progressive, Oligo Whatever So thank you for the opportunity to give me, uh, for giving me the opportunity to talk here. Uh, so just to start. OK, don't have any financial disclosures. All right. So for that outline, we're going to be going through some definitions, some recent trials that have helped with shaping, uh, care of our oligometastatic patients. And I'm going to focus mainly on oligoprogressive disease, uh, in particular, the curb trial and the stop trial, uh, also some ongoing and upcoming studies. So Oligo metastatic disease was originally thought of back in the 90s, thinking that it was along this continuum. So we have patients who have localized disease where we can provide curative treatment, and then on the other end of the spectrum, patients that have diffuse or polymetastatic disease. So along the spectrum, the thought is that there's an opportunity for these patients with limited volume disease to provide aggressive treatment and hopefully render them curable. Since that initial time, there's been this blossoming of definitions and subtypes for oligo, everything. So, again, the oligometastatic synchronous, meaning that at the time of initial presentation, there's, again, limited number of disease sites, uh, that are metastatic, whether this be 135, kind of depends on the study. Generally, all 5 or fewer though. Um, metachronous oligometastatic would be someone who received their initial curative treatment and then developed, um, again, limited volume metastatic disease. For those patients who are metastatic at initial diagnosis, but then receive their initial systemic therapy or initial, uh, treatment upfront, there may be a mixed response where they have oligo resistance, so some of the lesions are not appropriately responding. Um, perhaps there's a response, but a few of those sites are still being a little bit more rogue than the others. So I'll go persistent, and then those that are oligo progressive. So this may occur either in during their time on systemic therapy or treatment breaks. And so, Uh, Doctor Kumar already ran through multiple studies looking at synchronous oligometastatic disease. We had a few slam dunks at the beginning, and then, uh, the NRGLU 002 kind of muddied the waters. So it's still a bit unclear. And so, for oligoprogressive disease, it's an ongoing story. So who, what, where, when and why of this. And so these are patients again that have developed limited metastatic disease, uh, after initially responding to their systemic therapy. There's divergent responses to systemic therapy. So, some of these cancer cells have gone rogue. They're not responding the way that we want them to. The sites of oligoprogression vary, but a lot of times within the lymph nodes, brain, lung, adrenal glands, so on. And so in terms of the timing of this, while the cumulative incidence at 2 years is about 11 to 13% for patients treated with chemo IO or IO monotherapy, and time for acquired resistance to TKIs is a median of 8 to 13 months. So, this is happening because there's unique mutations or there's heterogeneity among these mets that's resulting in some of these drug resistant subclones. So why would we consider local therapy? Well, we want to eradicate those. We want to get rid of those rogue players here. We could hopefully reduce tumor heterogeneity, extend the current line of systemic therapy, thereby also introducing hopefully, lower cost, lower toxicity for our patients as well by allowing them to get their current line of treatment. Um, doing local therapy, hopefully will change the history of disease progression by delaying widespread relapse and also improving survival outcomes. So radiation, uh, certainly, as Doctor Kumarhar discussed, when we think about local therapy, surgery and radiation are Often, um, allowed on clinical trials. Thought about radiation though, is it's non-invasive, excellent local control rates, uh, safe toxicity profiles, cost-effective. There's a question of a scoopal effect, and, um, we've had great results in the upfront setting. So the Curb trial, this was a randomized phase two trial, and there were some retrospective and smaller studies that had very promising results, but, uh, this basically randomized patients to either systemic therapy with or without SBRT. Uh, patients were allowed to have olio-progressive. Breast or lung cancer, up to 5 lesions. So patients who got prior radiation, they were eligible, but you couldn't retreat the same sites. This closed early due to prelim and terminalysis, and, um, ultimately just over 100 patients followed for just over 4 years. So the medium progression free survival was better in those patients that received stereotactic radiation for the lung cancer patients. This was negative for breast cancer, but for lung, it was positive. Uh, this was well tolerated with only one grade 3 pneumonitis. And we saw that the radiation actually altered the patterns of disease progression. And so, for those patients that received radiation, they were less likely to have progression in sites that they started with. So, uh, there was this, uh, differential, uh, response that was happening. When they looked at CTDNA metrics, there was also a correlate. So basically, each one of those lines represents a patient. And for those patients treated with SBRT, um, when you looked at baseline versus eight-week time frame, there was a significantly, um, there was a significant difference in improvement for those patients that were treated with stereotactic treatment with radiotherapy. So again, we're altering their treatment course. The stop trial. Uh, also looked at up to 5 lesions. It began exclusive to lung cancer, but unfortunately, needed, they needed to open it up to all non-heme malignancies, uh, just in order to get accrual numbers. They did have to have an initial response to therapy, uh, prior to their development of oligop-progressive disease. These patients were randomized to systemic therapy, um, plus or minus the stereotactic RT. Uh, palliative radiation was allowed for those that got the standard of care arm. And this trial showed that there was no difference in progression-free survival. So, there was, um, median survival, 8 versus 4 months, but not statistically, uh, significant. And in this case, there was no difference when they looked at subgroup analysis specifically for lung patients, but this time there was for breast. So, uh, we have discordant results here. Uh, there may be more, um, heterogeneity of patients, heterogeneity of tumors in the stop trial. Um, and so, again, no difference in overall survival either. So it's a little confusing though, when you look at this, the adherence wasn't great. Yeah, 10% of patients who withdrew immediately, um, almost a quarter of patients who ended up getting high dose or ablative therapy. So they gave recommendations for, uh, palliative dosings, but, uh, certainly, there were quite a few patients that ended up getting higher doses than that. And so then that's going to end up, um, basically diluting some of the effectiveness that we could have seen for the stereotactic patients. So when they tried to look at subclassification, uh, based on treatment received and not intend to treat, there was a trend, but it wasn't statistically significant either. Uh, the lesional control was better, so 71% versus, uh, 39% for those that received stereotactic treatment. Again, treatment was well tolerated. There was no difference in terms of the quality of life. There are multiple upcoming studies. Uh, Doctor Kumar had mentioned some of these, the SARin trial, uh, the SAR Comet 3 and 10 are extensions of the initial SAE trial that she had presented earlier. And so again, kind of stretching and kind of changing what we're thinking from oligometastas and the SARcomma 10 trial even up to 10 METs. For oligop-progressive disease, we have the HALT trial. This is looking at, uh, essentially treating patients with continued TKI therapy, plus or minus SBRT. The SUPRES, um, and SCLC trial is looking at either continuing or changing systemic therapy versus continued systemic therapy with stereotactic treatment, and then the CurRB 2 trial as well. So in conclusion, this is an evolving topic. The story is still reaching its conclusion. It's continuing to change as more information comes out. Uh, there were multiple phase two trials that were positive, but the large scale study in the IOR did not demonstrate a progressive free survival benefit. And, um, At least in the synchronous oligometastatic setting. And so we need additional data. Time on drug may be a meaningful endpoint for those with oligo-progressive disease, better selection of patients, and this means understanding the metastatic mechanisms and the disease trajectory. We know that the patient prognosis is going to be different depending on where their METs are. So bone-only METs are going to do a lot better than those that have lung and brain METs. And so trying to help with, um, getting a more homogeneous patient population could help with, um, showing us benefit as well. And then clarification regarding the timing of systemic therapy, radiation, and always a multidisciplinary approach is necessary. So thank you for your time. Created by Related Presenters Randi Cohen, MD, MS Director of Radiation Oncology, Fox Chase Cancer Center – East Norriton,Associate Professor, Department of Radiation Oncology, Fox Chase Cancer Center
