Hello, and welcome to today's ISLC Art Committee seminar. So we have a very exciting topic today. We're going to talk about state-of-the-art in combination immunotherapy and radiotherapy for non-small cell lung cancer. So my name is Corinne Fever-Finn. I'm the Chair of the Advanced Radiotherapy Technology Committee of the ISLC, and I work at the Christine Manchester in the UK. I'm also the moderator for today's programme. So I'm going to start with running through some housekeeping notes. So if you would like to download today's slides, you can access them by clicking on the link on the webinar page in this chat. You will also be able to find a video recording of this seminar, and you will get the link within the next few days. It's also great news that we have an article on this topic that has been published in the Journal of Thoracic Oncology, and that is available to the attenders of this webinar. So again, to access this journal, please click on the link in the chat. The link will also be sent to you with the evaluation email after this webinar. You can also claim CME credit, of course. So the camera and the microphone will remain off during this webinar. So if you want to ask questions, you are more than welcome to do so. Please use the Q&A, and I will look at them at the end. We should have 15 to 20 minutes for questions at the end. If you also want a bit of banter, you can do so and use the chat, but I'm not going to look at the chat for questions. We're not going to be using the raise hand function for questions. So we plan to have a panel discussion at the end, and I would encourage you as early as possible to enter your questions during the various presentations. So you're now going to see the speakers' disclosures. And it is now my great pleasure to introduce our first speaker, Dr. Shankar Sivas, who is a radiation oncologist and head of the SABRE service at the Peter Mac Cancer Centre in Melbourne, Australia. He's a funded clinician scientist, and he has designed a large number of clinical trials that I'm sure many of you know about in the context particularly of combining SABRE and immunotherapy, and also in the field of oligometastatic disease. So to you, Shankar. Thank you very much, Corinne. And again, I'd like to thank you, the IASLC, for the opportunity to present to you today. Hopefully this will be an interesting webinar, and we'll also cover a lot of territory here. So, yep, I have control of the screen. So this slide is a bit of a summary of the current era. As we're all aware, we're in the current era of immuno-oncology, and this is a slide just before COVID did hit in the first quarter of 2020, showing the two market leaders of checkpoint blockade inhibitors, both anti-PD-1 agents. And the sales for both of these agents were in excess of $5 billion in the U.S. alone for the first quarter of 2020. So clearly, these kind of agents are not only quite expensive, but they are very prevalent within the use in oncology at present. There is, however, a quite significant need to improve outcomes from checkpoint blockade inhibitors. This is an interesting paper from Vinay Prasad and groups from JAMA Network Open in 2019. It looked at all the patients currently in oncology who are potentially eligible or not eligible for checkpoint blockade inhibitors in patients who had advanced cancers. The majority of patients are in fact not eligible with current indications for checkpoint blockade. However, if we look at the smaller proportion that are benefiting, and that's less than 50% of the patients, those eligible for the checkpoint blockade, only about 12 or 13% of patients actually benefit from these treatments, so in fact have a good outcome from these checkpoint blockade inhibition. Non-small cell lung cancer actually predominates this group, so about 8%, almost 8% of patients who have non-small cell lung cancer are benefiting from these type of checkpoint blockades, so this is an over-represented group with lung cancer who may potentially benefit from checkpoint blockade, but by and large, we really do need to improve as an urgent need to improve outcomes from these agents. So how do we make these effective and revolutionary but rather expensive drugs work better? At the moment, we have a fairly standardized approach. We test drug A with drug B, both delivered through the bloodstream and both limited by the same aspects of trying to actually get penetration within the tumor tissue from the bloodstream and try to test these agents together. However, a potential alternative mechanism would be to look at giving a local modality, and some local modalities have been tested such as surgery or vaccinations, cytolytic tumor vaccines, and these delivered through a different mechanism either direct to the tumor and obviating some of the inherent biological limitations of accessing tumors via the bloodstream. Radiotherapy has been long known to have more than just a direct cell kill effect, but if we know that radiation treatment with potentially the standard type of radiation that we use, which is conventionally fractionated radiotherapy, the predominant form of cell kill is called mitotic catastrophe on the left side of this graph, and this is a form of cell death that is really low inflammatory and low immunogenic. We are understanding, however, with increasing radiation dose and more hypo-fractionated treatments, there are alternative forms of cell kill that are pro-inflammatory and potentially pro-immunogenic, including forms of necrosis and some forms of cellular senescence. Hence, in the era of hyper-fractionated and ablative therapies, we might be finding more outcomes. We know that radiation upregulates tumor cell checkpoints, and these are preclinical studies that have been shown to demonstrate this. So this is a preclinical study showing that by increasing the dose of radiation in x-rays in the top panel there, we can increase the amount of checkpoint blockade protein that is expressed. The mechanism for this is rather through a double-stranded DNA break signaling mechanism, and the non-homologous end-joining repair kind of mechanisms, as well as homologous repair mechanisms, do increase IRF1 expression and PD-L1 expression on the tumor cells. The idea that the addition of anti-PD-L1 and radiotherapy in a murine model has been discovered quite early, back in 2014, and this is just a cell survival curve from a murine model indicating that fractionated radiotherapy, five by two gray, being the red line there, and immunotherapy by itself, anti-PD-L1, the blue line there, have some similar survival characteristics to no treatment in these mouse models. But the addition of this fractionated radiotherapy and anti-PD-L1 really does extend the longevity of these mice in this multi-cancer syngeneic cancer model. So the question arises that maybe a blade of radiotherapy, or at least hyper-fractionated radiotherapy, might be a good fit with immunotherapy. This is an example of different types of effects of the radiation treatment. So we know that radiotherapy causes direct cellular damage and release of tumor-specific antigens, and this results in apoptotic bodies, debris, and damage-associated molecular proteins being released directly at the tumor microenvironment. This can then result in recruitment and activation of dendritic cells and up-regulation of major histocompatibility of protein 1 for cross-presentation of TAAs. Finally, this results in proliferation, priming, and trafficking of activated CD8 positive T cells back into the tumor site, and these are tumor-specific. Radiation also results in cytokine release that can increase vascular permeability and homing of the cells back into the tumor environment. So all of these are interesting and maybe actually leads to why we have been seeing the abscopal effect of radiation treatment. The abscopal effect refers to off-target effects from radiation, which is Latin for ad being scopus, sorry, away, and scopus being target, and this is a Latin phrase for saying that non-target or off-target effects of localized radiation, so distant tumor sites regressing to a localized form of radiotherapy. However, these have been pretty rare events, really, and this led us to a paper that we wrote suggesting that the abscopal effect could be either Fools Gold or El Dorado, because clinically, with radiation alone, we don't necessarily see many of these effects in the clinic. However, there is a renewed interest with the addition of systemic therapies. This is an example of a patient of my own, which we did see an abscopal response, and these are multiple panels of FDG PET scans as this patient was on a trial. This patient received a single fraction of stereotactic radiotherapy of 26 gray to the right lobe of the lung, the top left panel, number one, and in the middle, shortly afterwards, within two weeks, had a FDG PET scan as part of the process, and she had both a right adrenal metastasis and a painful left lytic humeral metastasis. These lesions, I referred this patient on towards seeing a medical oncologist at this point, and had a backup appointment several months down the track, and was surprised to find out that both the humeral metastasis and the adrenal metastasis were no longer painful, but also had disappeared on FDG PET. This is an example of a patient with stage four metastatic non-small cell lung cancer who had regression of their metastatic disease and lived cancer-free for five years before discharge. However, we may not be all that reliant on single-sided irradiation for abscopal effects, and this is an interesting communication between two groups which are quite strong in this area, which is the Chicago group and the Weill Cornell group, in regards to a study from Jason Luke and Stephen Shemuria looking at multi-sided radiation in non-small cell lung cancer with pembrolizumab, one of the anti-PD-1 agents, and the conclusions from this particular discussion was, given the current lack of clear evidence for abscopal responses of radiation, this group proposed a different mechanism, one which is that radiation really does reduce the tumour volume, which can increase the ratio of proliferating activated T cells within the tumour cells. Secondly, that radiation is likely to have a prophylactic palliation by decreasing the likelihood of metastasis causing harm, and finally by affording immunotherapy agents sufficient time to induce generating its effects. So an alternative point of view, as opposed to single-site irradiation to generate abscopal effects, is that we really just should use radiation treatment to achieve local control, and this is a questionable issue because dosing of radiation is an important aspect, and rather than underdose for immune stimulation, we may need to consider giving an adequate dose for tumour control, and their concept is of debulking most or all sites of disease rather than just one for abscopal effects. Nevertheless, this is just a point of view, and it's something that needs to be tested in future trials. So there's several issues that need to be raised when combining radiation and immunotherapy, and some of these around about the sequencing and optimal dose fractionation and the right target volume to use. Some of the early studies, in fact, were using large single doses of radiation, and this is a study from Sean Park's group looking at melanoma and RCC in a murine model, and the use of either control antibody, anti-PD-1, or SABR plus anti-PD-1 resulted in similar survivals, but prolongation of survival was noted with the tumour size being smaller with a combination of anti-PD-1 and SABR, a single fraction of 15 gray. Shortly after this, there have been several papers looking at controversy in dose fractionation, and these are all quite confusing. There's been a study showing that there's cross-priming of anti-tumour T cells by a single fraction of 15 gray in draining lymph nodes in 2005. The Will Cornell group have been showing that in a specific breast murine TSA model, that three by eight gray fractionation, but not single fractionation, enhances immune response. A separate group used a tubo mouse murine breast model, a different model from the Will Cornell group, showing that single fraction SABR does synergize with anti-PD-1. And also, furthermore, in colorectal cancer, a single fraction of 30 gray and not fractionated 10 by 3 gray increases cytotoxic tumour infiltrating lymphocytes cross-presentation and reduces T regulatory cells. So the issue is when we look at the actual preclinical data, and this is a rather busy slide, but looks at all the different mouse models have been tested with all the different radiation schedules and all the different immune therapies. There are multiple factors at play, not only the site that's been irradiated, but the type of radiation dose and the immune therapy that's being used. And really trying to synergize all this information is quite difficult. Interestingly, more recently, the TREX-1 story has also emerged again from the Will Cornell group, looking at a different mechanism for why checkpoint blockade can be synergistic with radiation. And this is via an interferon gamma pathway. So radiation treatment results in accumulation of cytosolic DNA. And the theory here is on that right hand panel, large doses of radiation, so single fraction of 20 gray induces TREX-1, which then consumes the cytosolic DNA and doesn't allow for synergy with checkpoint blockade. With normal doses or hypofractionated radiation, this does result in accumulation of cytosolic DNA and engagement with the C-gas and sting pathway. And finally, interferon gamma 1 activation of cytotoxic CD8 positive T cells. The timing of RT is also controversial, and it may actually depend on the type of agent being used. This is a murine model, a correlator cancer model, using a single fraction of 20 gray. And this experiment was quite elegant in that it used a checkpoint blockade before and after radiation treatment. So the top left panel, we can see that the tumor is injected into the mouse, and then checkpoint blockade, and then followed by radiation in the first, and then two sequences of radiation, and then anti-CTLA-4. And the best survivals were seen with the use of radiation first, and then anti-CTLA-4, sorry, anti-CTLA-4 first, sorry, it's the wrong one highlighted, and then radiation at day 14. In the other, this same mouse model was used, but then used a, rather than a checkpoint blockade, which is releasing the breaks of the immune system, an anti-Ox40 agent, which is an accelerant for the system. And in this situation, using the exact same model, the use of anti-Ox40 was most effective given after the radiation treatment. So clearly sequencing is an important aspect. And perhaps the most interesting study that's looked at abscopal effects was not the checkpoint blockade at all, but in a study that was looking at 41 patients with mixed histology cohorts, but using an agent that doesn't typically cause abscopal effects on its own, which is GM-CSF. Patients were recruited who were either stable or progressing on their initial lines of systemic therapy up to two to three, and then were given radiation to one site of disease, followed by GM-CSF, and radiation to another site. And the measured abscopal responses were in the order of 33%. And so the use of radiotherapy to multiple sites within multiple different tumor-associated androgens was really an interesting approach in this kind of study without the use of a classic immunotherapy agent. We talked briefly about a tumor site and a study from MD Anderson, Chek Tang, and colleagues. We're looking at tumor location in addition to several other aspects of the tumor. We're looking at tumor location in addition to several other aspects, including dose and sequencing. But this particular study found that in different advanced solid malignancies, that the use of radiation to the liver appeared to be more immunogenic and induce more infiltrating cytotoxic T cells than radiotherapy to the lung. So not only is dose fractionation an issue, tumour site and the type of agent and sequencing are all issues that need to be fully elucidated in the combination of checkpoint blockade and radiation. And very recently a study from Ariel Marascano and group and colleagues were looking at the use of the type of radiation, whether it covers lymph nodes or not, draining lymph nodes, and its impact on the anti-tumour effect. So on panel A and C at the top, they did a quick study from injecting a dye, which was able to localise the draining lymph node. And then on the bottom left is a schema for this murine model, which is injection of MC38 over cells and then use of radiotherapy at day 11, around three cycles of immune checkpoint monoclonal antibodies that were injected at day 10, 12 and 14. And panel C shows that radiotherapy to the tumour alone results in increased infiltrating T cells and longer survival than irradiation of the draining lymph node. And this is accentuated on the far right with the use of anti-CTLA4 checkpoint blockade inhibition. So radiotherapy to the tumour alone with anti-CTLA4 had the longest survival in this group as compared to radiation of the lymph nodes with a combination of anti-CTLA4 or just the drug itself. So I'm just going to close on some of the toxicities of combining sabre and immunotherapy, because this is an area that we're all interested in at the moment. And one of the studies that is currently running that's hopefully going to be very informative in the space is the TOAST Prospective Registry. So this is a study that's been run out of Switzerland from Stephanie Kurtz and Matthias Gutenberg's group. And looking at multiple countries, we are also participating in this at the Penicillin Cancer Centre. And so far, there is 483 patients who've been prospectively collected with either the use of combination sabre with targeted therapies or immune checkpoint inhibition. And the total grade three acute toxicities with these combinations of both sabre and targeted agents or immunotherapy is 12%. And it doesn't appear to be much in the way of added benefit with either pausing the systemic therapy or giving a break within the systemic therapies. And with a rate of 12%, you could arguably say that these kind of radiation and immune checkpoint blockade or targeted therapy toxicity rates from high grade toxicity is additive rather than synergistic. But that's a topic worthy of discussion. From a thoracic perspective, we're obviously interested in pneumonitis as a particular issue. And this is data represented at Lung Cancer Congress last year in 2019. Sorry, 2019 in Barcelona, seems like a lifetime ago. Although this is for renal cell carcinoma, this is an oligometastatic study of which we did multiple radiation to primary targets. So this is a single fraction of 20 grade to each oligometastasis and when unable to do so, 30 grade in three grade fractions. And this is followed by six months or eight cycles of adjuvant pembrolizumab starting between five and seven days after SABRE. So of the 21 patients who had pulmonary metastasis, we had 43 targets. And the majority of patients had a single lung metastasis, but there were multiple patients who had multiple lung metastases, the majority of whom were receiving a single fraction of 20 grade SABRE followed by immunotherapy. And the response data is interesting, just interesting to note that the majority of patients had demonstrable response with a CRPR rate of 44% in this group and disease control of 70% in this group. However, probably more interesting is that three of the patients stopped with grade three pneumonitis and this is after three, six and seven cycles of immunotherapy. And the worst grade of immune related adverse events was grade three in these patients. So about 20% of these patients had some of these grade three events. And those patients who had the pneumonitis had one, two and one lung oligomet respectively. So it wasn't the total number of mets, we had up to five lung metastases. So it didn't seem to be necessarily related to that, but there were no grade four or grade five adverse events. And even a quarter of these patients reported no adverse events of this treatment at all. So grade three pneumonitis rate of 15% is definitely higher than what we'd expect with either SABRE or Pembrolizumab alone. The question is whether this issue is synergistic or in my opinion, potentially additive. So in summary, the combination of radiotherapy and immunotherapy has strong preclinical rationale. There's multiple studies with murine models and also in vitro studies that have looked at the combination radiotherapy immunotherapy and radiation itself does induce immune responses. Abscopal effects with radiation therapy alone are rare. We are increasingly seeing them in the stereotactic era. However, it is still a rare event and cannot be relied upon. We think that synergy with radiotherapy and immuno-oncology to enhance abscopal responses are likely to be the way forward. The question is whether toxicities are additive rather than synergistic. And the unanswered question that in my opinion, the timing of SABRE around systemic therapy, whether we pause if it's before or after the treatment, the ideal dose fractionation schedule to be using, the optimal agent for combination and the optimal target site for radiation if we have multiple organs to pick from. And whether single site radiation or maximal site reduction is the best approach. And there's still clinical data that's emerging. Dr. Taylor will be continuing from this point, but I'd just like to highlight, we're hopefully going to have some data of our own clinical trial through Australia and New Zealand, which is a randomized phase two study of the addition of single site radiotherapy to nivolumab in advanced non-small cell lung cancer. This study was aiming to recruit 120 patients. Unfortunately, it closed early. We should have some data in the next month or so. And with that, I'd like to say thank you very much for your attention and hand over back to our chair. Thank you very much Shanker for an excellent talk. So we'll take the questions at the end. So it's now my great pleasure to introduce Dr. Willemijn Fellin. So she's a pneumonologist from the National Cancer Institute in Amsterdam. And she's been working there since 2014. She recently finished a PhD focusing on exploring and modulating the microenvironment in non-small cell lung cancer. And she will be now working on the combination of advanced immunotherapy trials in non-small cell lung cancer, particularly in combination with radiotherapy. So we're looking forward to your talk Willemijn. Thank you so much for this introduction and thank you all for inviting me to introduce you on some of the data. Can I have the next slides? Thank you. First I want to talk a little bit of the current facts and the clinical situation in advanced non-small cell lung cancer as this is important to fully understand how radiotherapy and immunotherapy combinations can have a future in treatment of patients. We know from recent trials that the overall response rate of checkpoint inhibition monotherapy is around 20 percent, which is great but still means that we have a long way to go. We have seen long and durable responses in these patients and from the early phase one trials we know that this treatment is able to improve five-year overall survival rates. The response rate do depend on PD-L1 expression on tumor cells but even the tumors that show no PD-L1 expression at all still have a nine percent chance of responding to NTP1 or NTPDL1 checkpoint inhibition, which is of course very interesting finding. We see that patients with tumors with high PD-L1 expression of over 50 percent of tumor cells have a higher response rate of around 45 percent. Still impressive and for that reason they did a first-line trial where they in this specific subgroup of patients with high PD-L1 expression and in first line they compared pembrolizumab, the PD-L1 inhibitor, versus a platinum-based chemotherapy and they showed in the checkpoint 24 study that monotherapy pembrolizumab showed better responses and is for this specific subgroup now the number of choice of treatment. They also did another keynote in squamous and in non-squamous where they combined platinum-based chemo together with NTPD1 treatment. They did this in all comers so irrespective of PD-L1 expression and they found that the combination treatment proves to be better for patient outcomes without adding any significant toxicity, which is very interesting. So PD-L1 treatment is now standard of care in first line advanced non-small cell lung cancer, well actually all patients, some with or some without chemotherapy. This is all about the patients who do not have a non-smoker or an amputational driver, but for the ones who don't immunotherapy is now an important first-line treatment option. Next slide please. Can I have the next? Yeah, thank you. We also tried to add NTC-34 treatment to first-line or beyond and this has led to significantly more toxicity that has to be set about that treatment, but we did see some responses and this might be a solution for a solution for patients that have tumors with low or negative PD-L1 expression and they do not tolerate or do not want to receive any chemotherapy. This might be an option because these patients have a higher response rate, this specific group, but still primary and secondary resistance to immunotherapy develops and so there is still a very high need to optimize the treatment of non-small cell lung cancer patients and like Dr. Shiva has already shown us before, these scopal responses that could be induced by radiotherapy together with immune therapy might be a way forward for specific patients. Next slide. I want to first talk a little bit further about a little bit more about the safety issue this might this combination might have and especially in our lung cancer patients which are a little bit more prone to developing pneumonitis or pulmonary toxicity. This could be very an important issue as we know that immunotherapy has a chance of developing immune responses and immune adverse events and we also know that radiotherapy might induce inflammation, so a case like this where pneumonitis has happened might occur more often. Next slide. Many retrospective small series have been evaluated on the combination in regards to safety. Most of those retrospective series say that there are no real concern in regards to safety and an interesting subgroup analysis from the keynote 001 trial, phase one trial with Nivolumab where they compared the patient that had received a small dose of immunotherapy to the patient that had received extracranial radiotherapy previously to entering the trial versus the patient who had never received any radiotherapy. First of all, they didn't see any real differences between pulmonary toxicity in both groups. Numerical was a little bit higher in the patients that had received radiotherapy but grade three was similar and they did find an interesting thing that the group with radiotherapy had an improved PFS and also an improved overall survival. But again, this is retrospective, of course, so it has to be taken with caution. Luke and colleagues performed and published in 2018 a prospective safety study where they treated 73 patients with a combination of pembrolizumab and SBRT on two to four tumor lesions. They did have some grade three toxicities where they did see some pneumonitis in a couple of patients, colitis and hepatitis, and then at least in one patient the pneumonitis was correlated to long SBRT but not in all and overall they regarded it as a safe combination. As I mentioned before, anti-CTLA-4 treatment has a little bit higher chance of giving toxic toxicities. The group of Formenti in New York did a combination of fractionated radiotherapy, two different regimes, and they combined this with CTLA-4 inhibition and didn't see any additive adverse events. It was comparable to what you would expect on monotherapy and also an interesting finding in their translational research that they did see T-cell activation in all patients that received this treatment, but the responders showed a specific upregulation in radiotherapy related genes, so they suggested that there are signs in this combination as well of an episcopal effect. Next slide, please. I do want to point out two concerns, however. A very recent publication in the Annals of Oncology by the group of Sheverdian, they did a retrospective analysis of a specific patient group, namely the patients that had a history of immune-related adverse events on immune checkpoint inhibition, and they looked into the group of those patients if they received thoracic radiotherapy after having developed an IRIA, and they found that these patients not only seem to be prone to immune-related toxicities, but if you radiate them afterwards, they have a higher chance of developing a pneumonitis, and this was associated with the height of the mean lung dose, but even saw that at a relatively low dose of a little bit over five gray, development of pneumonitis was higher than they would expect, and the authors suggest from this retrospective series that you have to be aware that in this specific subgroup of patients, you might reduce the mean lung dose a little bit if you want to treat those patients with thoracic radiotherapy. And a second concern that I would like to point out is that this is especially seen in melanoma patients, but we see it more and more in non-small cell lung cancer patients as well, that in series we've seen that these patients who develop brain metastasis and they get upfront radiation and then are treated with immune checkpoint emission, a doubling of the incidence of radiation necrosis develops, and I think that from these experiences, I do think that we need to be very cautious that if we see patients that have brain metastasis, maybe asymptomatic, and when patients have a high chance of response to immune checkpoint inhibition, I think you should carefully evaluate whether you should give upfront radiotherapy or maybe you should for this specific patient group may try and let do the immune therapy, do the work on the brain metastasis as well, as we know that they can have responses on brain metastasis on immune checkpoints alone. So I do think that these are two specific concerns that we need to look forward, look into to the clinic to be careful with that. The next slide, please. Next slide. Yeah, Thank you. Then over to the efficacy. This is one of the patients that we treated in the PEMBRO-RT trial that I want to show you the results. This was a trial that we performed in the Netherlands, and where you can see on the left side in the red circle was one of the pulmonary metastases in the left lower lobe, which we treated with radiotherapy, and on the upper slide, you can see in four years, which was two years after we stopped the peperodysumab because of ongoing response, this patient still has an ongoing response not only in irradiated lesions, but also in all the other lesions, and this patient is still in very good health. Next slide. The trial that I talked about is the PEMBRO-RT trial where we randomized 74 patients in total between receiving peperodysumab alone versus SBRT, or 3 times 8 gray. I'm not a radiotherapist, so some people pointed out to me that maybe 3 times 8 gray shouldn't be referred to as SBRT. If people here listening to my talk think so, then I apologize for that. But we treated them with 3 times 8 gray on a single tumor lesion, and then they received PEMBRO-RT within seven days of the last radiation dose. This was in second line and further, so patients were already treated with platinum-based chemotherapy before and had developed progression. We did serial biopsies in these patients before treatment and on treatment to do some translational work afterwards. These patients weren't allowed to have had radiotherapy within six months as to not influence the outcomes, maybe. We started this trial in 2015 where we didn't have access to PD-L1 staining at that time, so we chose to do a stratification by smoking status instead of PD-L1, which would be something we would do now, but we went for smoking status. Next slide, please. Here are the results of the trial. They were published in 2019 in Young Oncology, and here you can see that in blue, you see the line of the experimental arm of the patients that received SBRT and then received the PEMBRO-Lizumab, and they did perform better in regards to PFS as well as in overall survival. These differences weren't statistically significant, but this phase two trial, however, does show a sign that patients might benefit from this combination treatment. We had a little bit of a disbalance between PD-L1, height of PD-L1 expression. We had higher PD-L1 patients, a little bit more higher PD-L1 patients in the experimental arm, so this might have influenced the data a little bit afterward, but we made subgroup analysis looking into different PD-L1 subgroups, and we did find a signal that, especially the PD-L1 negative subgroup, patients seemed to benefit more of the addition of radiotherapy because these were small numbers or significantly different. Next slide. We also, of course, looked into toxicities. These are the toxicities related to the PEMBRO-Lizumab, and these were similar in both arms, and this treatment was very well performed by the patient. We had one patient that had received SBRT on a retroperitoneal lesion in close relation to the kidney and subsequently developed a nephritis on PEMBRO-Lizumab, so this was a toxicity that I believe is really related to the combination and to the radiotherapy specifically on that lesion. With pneumonitis, we had a lot of thoracic radiotherapy in this trial, and pneumonitis numbers are really low, even higher in the control arm. In regards to toxicities, we concluded that this was really safe to perform and that there was a sign that this might benefit at least some patients. Next slide. Then we joined forces with a group of Jim Welch at MD Anderson Cancer Center. They did a similar trial like the PEMBRO-RT. They made two cohorts, however. They had one radiotherapy cohort where they had 15 fractions up to 45 gray, and that cohort had its own control group, and they had a second cohort where they gave four fractions up to 50 gray with their own control group. This was not a randomized choice, the radiotherapy regimen, but these were seen fit by the physician which radiation dose the patients could receive. That makes comparison between arms a little bit difficult, but if you pull all the data and you pull all the control arms, you can do a nice comparison together with the patient that we treated in the PEMBRO-RT. We did see a better balance in characteristics, in baseline characteristics, especially in regards to the PD-L1 stages, which was now well balanced between both groups. Next slide. These are the results of this pooled analysis that was in Lancet Respiratory Medicine last year. Here, we do see significant benefits of the combination of radiotherapy with immune therapy. They had a significantly better PFS, as well as an overall survival. Of course, it was a retrospective, or at least we pulled the data, so this has to be taken with a little bit of caution, but I do believe that there is an even stronger sign here that, in efficacy, this might help patients having benefits on immunotherapy. This is still not strong enough to make this a standard of care, unfortunately, so there is still a lot of work that needs to be done. Next slide, please. One of the things that we did look into in this pooled analysis was a comparison of the radiotherapy regimens, and I already explained to you, because these patients were randomized, that this is upmost hypothesis-generating, and there cannot be really hard conclusions drawn from this, but we did see that the patients that received the 15-fraction radiotherapy regimen, they did not seem to have an advantage compared to the PEMRL alone, and we thought that maybe because lymphocytes are very sensitive to radiotherapy, we postulated that maybe the higher and the bigger field that was radiated might be detrimental to the abscopal effect, and we did see, you can see that on the right side of the screen, the lower box plot, where you can see that the difference between before and after the radiotherapy in lymphocyte count, the blood of the patients is lowered in the 45 gray, 15 fractions, which was not different before and after in the other two groups, so this might maybe be why this group of forms did not show a strong abscopal effect. This is something that needs to be taken into account regarding the many questions that Dr. Shiva has already mentioned at the end of his talk, which we still need to answer, and these are little specks of data that might help a little bit with that. The next slide, please. I do want to mention something about the oligometastatic non-small cell lung cancer. This is, of course, a really interesting subgroup. Local ablative therapy for these patients is beneficial, and Baumel published in 2019 a trial where they did a single-arm phase two study, where they had oligometastatic non-small cell lung cancer treated with adjuvant pembrolizumab after the locally ablative therapy, and they established that this was relatively safe to do. 11% of pneumonitis is a little bit higher than you would expect normally, but they did have a very impressive PFS of 19 months versus historical control. The role of pembrolizumab in this oligometastatic disease is really interesting, and it needs to be explored further. Next slide shows a very important trial, the PACIFIC trial. This concerns patients that have locally advanced unresectable non-small cell lung cancer, and standard of care of these patients has always, and since a long time, been chemoradiation therapy. This has been for many years. Now, finally, we have a trial which really shows a benefit for this specific patient subgroup. What they did was patients who had a response, did not show any disease progression after the chemoradiation treatment, they received one year of adjuvant durvalumab, a PD-L1 inhibitor, versus placebo, and they saw that the durvalumab subgroup had a better overall survival and a better PFS compared to the placebo group. Now, this has become the new standard of care for these locally advanced unresectable non-small cell lung cancer patients. They didn't see that much added toxicity. At first, we were a little bit afraid of pneumonitis for this specific patient group, but the grade 3 to 4 was comparable between both arms, so that was good to see. What I find really interesting in this setting is that we don't really know whether this is the effect of an abscopal effect, where the radiotherapy and the immunotherapy really work synergistically. This is difficult to tell. Maybe it's just because we give the immunotherapy before we have established stage 4, and that is the reason why these patients perform better. How impressive it is, it still leaves a lot of questions in regard to how to optimize for these patients, the combination of radiotherapy and immunotherapy. Other trials are ongoing in stage 3 disease at the moment. I want to mention the NICOLA study. They have given already some safety data. In this study, nivolumab is given concurrently with chemoradiation and has been deemed safe up until now. Efficacy data is awaited. I'm not sure whether this is going to show any benefit over the benefit that Pacifica has already shown. Given it concurrently, it might be one way to go forward. Next slide. Then I want to show you this trial. This is a trial that we're currently performing at the NKI, where I work. This has a different approach. This also concerns patients with locally advanced that are treated with chemoradiation, but here we're trying to treat these patients with neoadjuvant immunotherapy. As mentioned before from some preclinical data, maybe anti-CTL4 antibodies should be given before the radiotherapy. This trial combines the PD-L1 inhibitor dervalumab with the CTL4 antibody tremolimumab in two courses before giving those patients chemoradiation. Afterwards, they still get their one year of dervalumab. We're currently working on the feasibility phase. Cohort 1A was a success and we're currently working on cohort, including patients for cohort 2A. These patients, they get a restaging after neoadjuvant immunotherapy before they get the concurrent chemoradiation. I'm really excited in finding out whether this approach might even further improve benefit for these patients and if we can find signs of scopal effects by doing it this way. Next slide, please. This will be my last slide because I want to share with you some future perspectives. First of all, in the advanced states, I've shown you some data of SBRT or radiotherapy with immune therapy, monotherapy. I think a lot of work needs to be performed. We're working on a lot of translational research in the PEMBRA-RT trial to further explain the biological principle of the scopal effects and try to investigate which patients benefit from this combination. Also, diagnostic trials comparing the timing and the different radiotherapy regimens need to be developed to further explore the optimal way to do scopal effects. It might be interesting, we have seen some case reports where patients developed resistance to immune checkpoint inhibition and those patients were able with a combination of radiotherapy and retreatment of immunotherapy could receive novel responses. This is something that would be very interesting to look into in the future as well. As mentioned in earlier stages, the combination is also being explored. Trials are giving adjuvant immune therapy after SBRT and other trials are currently ongoing of adding immunotherapy to chemoradiation, a concurrent application of checkpoint inhibition with concurrent radiations are ongoing. Another trial we're currently performing at the NKI is really more of a diagnostic trial where we compare patients that go for surgery, which have stage one, and we give the neoadjuvant pembrolizumab versus SBRT versus pembrolizumab together with SBRT. We're not only looking to the effects of the tumor pre and post, but we'll also be looking at the effects of the draining lymph nodes. Hopefully, all of these efforts are going to help us further understand the scopal effects and help us designing trials how to further improve patient outcomes with this combination treatment. Thanks a lot, Willemijn, for this very nice talk. We now have a bit of time for some questions. We may, if some of you can stay, go over slightly. We've had quite a number of questions, which I'm going to group between toxicity, efficacy, scopal effect, and a number of questions on brain metastasis, which I think is very interesting. The first question is about the tumor volume impact on pneumonitis rates from studies such as the LUKE study and the PALMA study. What is your view? Perhaps, Shankar, do you want to take that question? Yeah, absolutely. Thanks. That was from David Rabin. I think the question on tumor volume is a reasonable one. I think the more lung that is irradiated, the more likelihood of getting pneumonitis. Radiation fuels independently. Larger volumes have a larger toxicity rate. I think it's an additive effect with the likelihood of high-grade toxicity and checkpoint blockade. I do think tumour volume will have an effect on both on toxicity rates. Yeah, and I think it's a real shame that we don't have any data on tumour volume from a specific study. That's one of the sort of important data that is unfortunately missing. And then we've had also a question about the timing of the immunotherapy and radiotherapy, which is really important in terms of avoiding the overlapping in toxicity. So in terms of a sequencing, and if we think about the routine setting, what would you advise, for example, in someone who's got stage four disease, is receiving a palliative course of radiotherapies on an immune checkpoint inhibitor, would you stop the treatment in advance? So perhaps Willemijn, what do you do at the NKI? Yeah, if we have a patient that is already treated with the immunotherapy, and they develop a progressive disease where immunotherapy, I think that, you know, we just continue with the immunotherapy, the half-life of these agents is extremely long, over a month. So stopping it is probably not that necessary. And I think that the current data shows that this is relatively safe to apply together. So as regard to safety, I wouldn't have too much trouble. Yeah, and if at all possible, I think, you know, continue recruiting patients to clinical trials where that is recorded, and there are studies in the oligometastatic setting, for example, where there is an option of continuing or stopping the drug, and I think we'll learn a lot from that. Okay, now, some questions more around efficacy. So a question from Gerald Walls in Belfast. Are there any concerns that lymphopenia secondary to radical radiotherapy doses could impact on efficacy of the iboviage of a concomitant immunotherapy? So again, Willemijn, do you want to take that one? Yeah, yeah, I do think that this is, of course, a very important and a very interesting question. And this is exactly what we tried to look into in our pooled analysis. And we did find some signs that lymphopenia might produce a problem in the episcopal effect. So I really do think that this is something that we really need to look into even further. And the stage three disease patients where a relatively large area is radiated would probably help us giving answers to these questions. Thank you. Do you want to add anything to that, Shankar? Yeah, I think I might actually pull this in with a question from Gava Plavich. I'm sorry if I've murdered this surname, but who's also asking about whether low dose radiotherapy, which is actually whole body radiotherapy can affect cause of lymphopenia. This is a really complex question, because there was a preclinical model I showed from Marascano's group that looked at draining lymph node irradiation being detrimental. Yet the best data we have is basically Pacific, which is looking at involved mediastinal lymph nodes and the addition of immunotherapy afterwards. So it is a complex thing regarding the tumour volume, the inclusion of radiation of uninvolved lymph nodes. I'm sure that's a bad thing, because that will prevent the expansion of adapted T cells, cytosolic T cells, and reintroduction within the systemic circulation. So uninvolved lymph node radiation is probably a bad thing. We know that lymphocyte neutrophil count is an indecent core prognostic feature. So even before the immunotherapy era, lymphopenia was an issue. And I think that in the ideal situation, if we can irradiate the primary only in an advanced disease, but if we're talking about locally advanced disease, I think we have to cover all the lymph nodes as we would normally do. Yes, well, actually, I was going to raise that as a sort of a bit of a provocative question. You know, this idea of perhaps only treating part of a disease, the primary, not treating the lymph nodes, is that going to become a reality or is it still a fantasy? I think it's a very important clinical question. So we're trying to open a study like this through the TOGA Thoracic Oncology Group of Australasia, which is looking at primary radiation of the tumour in advanced lung cancer, non-small cell lung cancer, called prime lung. I think that's a really interesting question, but it's experimental, of course. And with lymphopenia, the idea of whole body irradiation, the presumption is that some of these low dose radiation whole body is going to eradicate some of this exhausted T cell profile phenotype that we see from within the microenvironment, allowing expansion of adapted T cells to re-enter into the microenvironment. So, you know, there's a whole bunch of things that's really complex here that we don't fully understand. Yes, the message is do not try this in your clinic that is not really ready for prime time as yet. Now, a very important question from a colleague of mine, Dr. Ahmed Salem, about the hypoxic microenvironment. And is that a barrier in terms of the efficacy of immunotherapy and radiotherapy? And is there a merit to combine in trials immunotherapy, hypoxia modification and radiotherapy? And how can we investigate that? Do you want to take that one, Shankar? Yeah, I think hypoxia is a real issue. And I think particularly if we're looking at a drug that's trying to enter into a hypoxic tumour microenvironment via the bloodstream, it is a major issue. So this is something that needs to be overcome. Radiation is great at a local effect, but in advanced lung cancer, we really can't do this for multiple targets effectively at this point in time. I'm not aware of any trials. I'm not sure, Lamar, if you're aware of any trials and combining hypoxia modification agents, but be interested to see them. No, I don't know any of these trials are currently ongoing. In the Netherlands, we did a trial with radiotherapy and O, which was negative, unfortunately. So, but I'm not aware of anything that is looking into this at the moment. OK, so now I'd like to move on. We're just going to use a few more minutes, if that's OK with the audience, because we have some really interesting questions. We'll be able to address everything, but an enormous problem in patients with lung cancer and a lot of questions about immunotherapy in these patients. So a question from Nora Sundal asking, if we consider withholding radiotherapy for these patients, even though they generally were excluded in the trials investigating checkpoint inhibitors in case of brain metastasis. So what's your practice? Willemijn, what's your practice at the NKI? This is exactly, this is a very hot topic at our institute as well. And I think that this is something that we really discuss in a case by case basis, whether these patients, it depends on so many items. Are they symptomatic? I mean, if they are symptomatic, I would prefer giving to radiate the patients. But then a second problem, of course, is that they often get high doses of steroids afterwards, which might be detrimental for the effect of immunotherapy. We're not sure, but it might be so. So if we don't see an opportunity to withhold radiotherapy because we think that we could give the immunotherapy a chance, then we would be willing to do that, actually. We are trying to withhold it if we think it is safe. And we have seen some very good responses in brain meds. So we know that this can be done. But of course, case by case basis, you do not want to have your patient develop symptomatic brain meds while you're already on systemic treatment. And Shankar, do you want to add to that? A hundred percent agree. I think the clinical priority is the patient. So if they're symptomatic brain meds, deal with them first. If it's asymptomatic and small, then the questions that come up are the extracranial burden of disease. If it's high and low volume brain metastases, certainly start with a systemic therapy first. But it is a case by case situation. And you talked about the potential issue. I think it was Willem and you talked about the potential issue of combining radiotherapy to the brain and IO. I mean, do we know much about the differential between whole-brain radiotherapy and SRS in these patients who are also receiving immunotherapy? I don't know that data specific whether that matters, but I do think that especially my institute, we don't very often use whole-brain radiotherapy anymore. It's all gamma knife and stereotactic radiotherapy. And I do believe that chances on radiation necrosis is way higher with that approach. So even though chances are higher of radiation necrosis, we do tend to choose over stereotactic radiation, over whole-brain radiotherapy, even in this setting. Okay. And then again, with regards to efficacy, so we both talked about the different dose fractionation regime that are used and what is optimal. And there's still many, many questions about that. And Dave Rabin has been raising this issue of what should we treat. He's saying we should stay away from ENI, which I think most of us are doing now. But he's raising the issue of using hypo-fractionation in stage three disease versus six weeks of chemo radiotherapy to avoid immunosuppression. And that's very topical, obviously, in the era of the COVID. Is that something that you would consider in your practice, using more hypo-fractionated treatments or such as the regimes we use in the UK, 55 brain, 20 fractions or other? Shankar, do you want to take that one? For me, I think that we don't have all of the answers in terms of dose fractionation as yet. So I think the underlying principle is treat the patient as you would normally treat them. And so if that means in the COVID era, hyper-fractionated treatments, I think that's fine. I don't know that a single fraction of 20 gray is worse than eight by three, and I don't know that eight by three is better than a very large fractionation schedule, say 50 and five. We don't have these answers yet. So I think we treat the lesion in question and the patient in question on the merits, and then use the addition of the systemic therapy in that context. That's my personal opinion. Okay. Thanks for that. And then there's a question specifically for Willem and on So you describe a higher benefit to the addition of SVRT in patients with PL1 negative tumours. Could this be explained by the imbalance in PL1 expression between the experimental and controlled groups? Or do you think this could be of clinical importance? And could you explain in the latter case this effect? Yeah, that's an interesting question. I don't think, if when you look in the subgroup of the PL1 negative patients, we compare the effects of SVRT at the experimental arm versus the control arm in the whole group of PL1 negative patients. So this was not caused by the imbalance. The conclusion that we draw from that specific subgroup analysis was that maybe radiotherapy was able to make a non-inflammed tumour an inflamed tumour and therefore raising the response chances of immunotherapy. That was our hypothesis from that subgroup analysis in the PEMBR-RT trial. In the pooled analysis, however, we couldn't find a specific effect in the PL1 negative subgroup. So based on the additional analysis we did, I'm still not really sure if our previous conclusion about the subgroup analysis in PL1 negative tumours was true. So I do think that we need to do a lot more work to really know if we have something for this negative subgroup. I'm not sure at the moment. Okay, thank you. Tamuna Chachava is asking whether we have any data on combination of immune checkpoint and anti-angiogenics with radiotherapy. Any of you know about that? Not yet. No, I think this is an open question. It's interesting because I think radiation has an anti-angiogenic effect anyway. So I'm not entirely sure if it's just going to be additive toxicity without necessarily benefit. But I'm interested. Willemijn, what do you think? Sorry, I'm a little bit unsure. Which question are we discussing? Anti-angiogenics plus immunotherapy plus radiotherapy. Do we know of any data on that? The answer is probably no. Exactly. Okay, and then just I'm conscious of time, so we're going to close in a minute, but with regards to abscopal effects, there's a question from Anna Maria Cattino about do we think that adding radiotherapy during immunotherapy for advanced lung cancer could lead to an abscopal effect? Does the timing matter? So I guess in the routine setting, is that something that you would advocate given the experience that you described from the trials? Personally, not yet. I think this should really be confined to clinical trials at present. So when I'm asked to just irradiate a lesion and see what happens, I don't often say yes. But if there is a lesion that looks like it will be causing harm in the future, so early prophylaxis that might benefit from radiation, that makes a lot of sense to me. And you carry on with the immune checkpoint inhibitor? Correct. And as Dr Tillum was mentioning, these checkpoint blockades have months half-life. So if someone's oligo-progressing, I don't bother stopping. And if we have a situation with an upfront indication, then irradiate a dominant lesion and then commence a systemic therapy is a good combination I think. Okay, that's great. So just to finish this really interesting Q&A session, just to ask you very briefly, to both of you, if you had to put your money on a strategy in terms of immunotherapy, radiotherapy combination, what would that be? So Willem, do you want to tell me what you think? Well, what I would be really interested to do as a next step after that we did the PEMBRA-RT trial, I mean, of course, I want to know more about the translational business, but that is still ongoing. So for me, a next step would be whether we could reinvigorate responses on immune therapy after progression on first-line treatments with this combination, and then maybe add TTLA-4 with a retreatment of PD-1 in combination with radiotherapy. I think that that would be the next step for me to explore whether that could be possible. Okay, great. And then Shankar? For me, I think it's the kitchen sink approach. So multi-site irradiation, multi-organ if possible, and before and after the first cycle of immunotherapy. So really to cover all bases, I think the questions are too complex to answer necessarily quickly on their own, so do the whole thing. Okay, that's wonderful. Thank you so much. So I think I'm sure it is time for you to either get on with your day or have your evening dinner, depending on where you are. So I'd like to thank both Philippine and Shankar for wonderful presentations and for the ASLC for putting this together. So keep an eye on your emails, you will be receiving CME information and program evaluation. And thank you all for your participation and speak to you all soon, hopefully one day face-to-face, and importantly, stay safe. Bye-bye. Bye-bye. Thank you so much.

immunotherapy

radiotherapy

non-small cell lung cancer

combination therapy

abscopal effect

dose fractionation

sequencing

toxicity

brain metastases

anti-angiogenics

research