Chapters Transcript Video Role of Radiation in the Management of Oligo-Progressive Disease Back to Symposium All right. Thank you very much for giving me the opportunity to talk today. OK. I don't have any disclosures. Um So, oligo progression, um metastatic, non small cell lung cancer is a very heterogeneous disease. And its prognosis depends in part to predictive biomarkers, presence of genomic alterations. So this is an evolving story. I have Children that are in elementary school, grade school and so they're learning how to write and this story is still being written. And so it comes to the five ws the who, what, where, when and why of this? So who are these patients? These are patients with any number of metastases? Initially, they respond to systemic therapy and then they have progression of a certain number of metastatic sites. Uh Up to five is utilized in most studies. But uh there's a variety with that and they're not having more widespread dissemination of disease. So what is happening? There is a divergent response to systemic therapy. Some of the lesions are getting smaller, some may be stable, but there's a few that are progressing and where is this happening? And so uh there's um certainly the primary site itself is a common site of progressive disease. Um but and um I'll go sorry for patients treated with immunotherapy monotherapy, lymph nodes, brain longer. Certainly the the three most common, when is this happening? And the when in this uh series of questions for the story, it depends, you know, there's different wins. Uh The incidence of I'll go progressive disease is about 11 to 13% for those patients treated with chemo immunotherapy or immunotherapy. Um those that are on TKIS, the acquired resistance typically happens after a median of 8 to 13 months. So a few wins to consider why? Uh there's multiple, why? So why is this happening? So there's unique mutations, genetic heterogeneity among the metastases that are resulting in progressing sub uh drug resistant sub clones. So why local therapy? The goal is to eradicate resistant sub clones. This will reduce to uh tumor heterogeneity. It's gonna extend the current line of systemic therapy by doing so we'll get more mileage out of the treatment that they're currently on. Additionally, this will hopefully li limit or at least delay um the cost and toxicity that patients have with going on to next line therapy, these resistant sub phones can contribute to systemic receding of new metastases. And so, in theory, local therapy can actually change the natural history of disease by um delaying widespread relapse and improving progression free survival and our overall survival. So why radiation? This is non invasive. There's excellent local control rates approaching 90%. Uh safety profiles are overall uh very acceptable. There's been studies showing cost effectiveness with uh stereotactic radiation and possible abscopal effect whereby using high doses of radiation in the stereotactic setting may actually um cause some sort of change within the immune response of the body and impact tumor cells that weren't even targeted with radiation. Uh Saber SB RT. So stereotactic alo a blade of body radiation or stereotactic body radiation therapy. It's been used for local ablation and upfront all go metastatic lung cancer with excellent results. That's not the focus of the talk, but just to touch briefly. Um This is the Gomez trial. Uh long term follow up was reported in 2019 multi center phase two trial, a randomized 74 patients who had stage four small cell lung cancer, three or fewer metastases, no progression, three months or longer after front line systemic therapy, they either got maintenance or observation um which was the control arm versus consolidative therapy to active sites of disease. So at median follow up of over three years, there was a significant improvement in both overall survival as well as progression free survival. Uh have the numbers there, you could, you know, drive a truck through those lines as well to go with that continued analogy, Saber comment. Uh This is basically comparing for patients that have a controlled primary. Um either again doing standard of care therapy compared to stereotactic radiation. So notably, most of the patients are not lung, uh only about 20% had lung cancer, but about half the lead that were treated um were within the lungs. So this provides us some information but also helped with improving the radiation oncology experience in terms of treating oligo metastatic disease within the thoracic cavity. Um So, again, significant improvement, improvement in progression free survival, overall survival. So 25% difference at five years, very substantial. So, Astro and Estro put forth guidelines last year. Uh you could see the strength recommendation for doing the um local therapy is strong across the board. Unfortunately, the story of Alico progression disease and the treatment with local therapy is again, still evolving. So their recommendation in the oligo progressive setting is conditional. And so there are several retrospective uh trials that report in encouraging results for local therapy and patients with oligo progressive disease during immune checkpoint blockade. I have a summary of several of these studies here. Uh What we see is that local therapy can prolong time on 1st and 2nd generation um EGF RT Kis. Um And so, you know, overall this is it's not ideal, it's very diverse. There's a variety of the number of patients um or a number of patients I should say are rather small variety in terms of the number of sites that were allowed uh anywhere between 3 to 6 and also differences in terms of the local therapy that was permitted where some patients got radiation, other surgery, uh and others received ablative treatment. So the first prospective randomized data comes from the curb trial. Uh This is a unicenter phase two trial. Uh This randomized patients to systemic therapy plus or minus SB RT patients either had oligo progressive breast or oligo breast of lung cancer. They allowed up to five lesions, extra cranial disease. People could have had prior radiation but they couldn't, we couldn't reradiate the same site. So this was actually closed to a cruel early. Initially, it was planned for 100 and 60 patients. But it um basically the progression free survival crossed a pre specified efficacy threshold. So it closed with 100 and six patients. Uh of whom 59 had lung cancer, notably, only 11% had driver mutations. So the median follow up of 4.3 years uh for those with lung cancer, uh the median progression free survival was significantly higher if they got stereotactic radiation difference of 10 versus two months. Interestingly, there was no difference in progression freeze revival in breast cancer patients. Uh There was only one grade three pneumonitis after SB RT. So again, supporting that, this is a um not only an effective treatment but one that has good tolerability as well. So the patterns of disease progression was changed by SP RT. And so the green shows the stable disease, the pink, the progression in untreated lesions and then the purple and development of new lesions. And So what you could see is that again, those patients that got SP RT more stable disease. Uh Interestingly, the untreated pres pre existing lesions were less likely to progress. So maybe some abscopal effect there and um development of new lesions was higher. So CT DNA metrics also varied. Um So each one of these lines represents a patient. Uh There was samples taken at baseline and eight weeks post treatment. Multiple speakers before me have commented in terms of CT DNA, in terms of um being reflective of, of disease and um potentially outcome as well. And so for those patients with lung cancer, treated with SP RT, there was no difference in these metrics but those that did receive SP RT, you could actually see a significant decline in terms of CT DNA and uh mutin Allal fraction. Uh The stop trial is a randomized phase two trial. Uh This is, this article is currently in press. Uh it began exclusive to non small cell lung cancer patients. Unfortunately, they couldn't meet a cruel grow. So they opened it up to basically everyone with a non he malignancy. In total, there were 90 patients that were included, they were stratified by type of systemic therapy, then randomized to systemic plus or minus stereotactic radiation. So a follow up of 31 months, there is no difference in progression free survival. Uh Initially, if you look at the media and it looked promising, but uh the lines ended up crossing and there was no difference in uh progression free survival for those that received SB RT or not. Um Certainly for what's a little bit odd, I'll say is that uh or different? Is that from Curb? They actually did see an improvement in terms of for the breast cancer patients. So, opposite of the Curb trial. Um So when they tried to then randomize by those patients that um based on the treatment received as opposed to treatment intent to treat. Uh there was no difference with that either. Uh the protocol adherence was definitely suboptimal. 10% of patients immediately withdrew, 23% who were in the standard of care arm ended up getting um high dose treatment. So the numbers weren't that large to begin with and then you start um with kind of f further diluting it down. Um So leal control was high. Um treatment was again, well tolerated no difference in quality of life. So just to very briefly mention there are multiple studies that are upcoming on. This suppress is one of those looking at up to five extra cranial lesions. This is going to essentially randomized to standard of care versus again, stereotactic RT with um continuation of their current systemic therapy hall trial is a phase 23 trial looking at um patients whether to just continue on their TK I therapy versus stereotactic plus TK I and La Flossie is looking at whether the addition of radiation um or surgery for first line osimertinib can improve progression free survival. So in conclusion, this is an evolving topic. The story is not yet written. We don't have a conclusion for this um this topic yet. Uh the results are encouraging, but we need more data. We need to also clarify the timing of radiation in response to the systemic therapy. I put a couple of specifics for the um different trials there. And certainly multidisciplinary team approach is necessary. So, thank you very much. 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
