Nanobiotix S.A. (NANO) Earnings Call Transcript & Summary

Good day, and welcome to the Nanobiotix KOL call to discuss the role of NBTXR3 and Immune Oncology in Advancing Head and Neck Cancer. [Operator Instructions] Please be advised that today's conference is being recorded. At this point, I will turn the call over to Craig West, Senior Vice President of Investor Relations of Nanobiotix.

Thank you, Ann. Good afternoon and good morning, and welcome to the Nanobiotix KOL call to discuss the role of NBTXR3 and immune oncology in advancing head and neck cancer. Joining me on the call today are Dr. Colette Shen from the University of North Carolina Lineberger Comprehensive Cancer Care Center; Dr. Ari Rosenberg from the University of Chicago School of Medicine; Dr. Sebastien Paris from Nanobiotix; and moderating today's call will be Dr. Jeffrey Bockman from Lumanity. As a reminder, today's call is being webcast and will be available on our website for replay. I would like to remind you that this call will include forward-looking statements, which may include statements regarding the progress, success and timing of our ongoing and planned clinical trials, collaborations, regulatory filings, dates of presentation and future research and development efforts, among other things. These forward-looking statements are based on current information, assumptions and expectations that are subject to change. They are subject to significant risks and uncertainties that could cause the company's actual results to differ materially from our current expectations. Accordingly, you are cautioned not to place undue reliance on forward-looking statements. Please review the full description of risk factors that can be found in the documents we filed with the AMF in France and SEC in the United States, which are available in the Investor Relations section of our website. In addition, any forward-looking statements made by the company represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, Nanobiotix undertakes no obligation to update them to reflect subsequent events or for future circumstances. With that said, I would like to turn the call over to Dr. Bockman. Please go ahead.

I'd like to welcome you to today's call. Can I have the agenda slide, please? I'd like to welcome you to the call. [ We'll go ] through the agenda, as you see here, and then introduce today's speakers. Kicking things off will be a presentation by Dr. Paris, who take us through how NBTXR3 works, specifically discuss both its local and systemic responses. He will be followed by Dr. Rosenberg, who will discuss head and neck cancer patients, how they present, are treated, what the unmet needs are in the setting. This will then be followed by Dr. Shen's discussion of the 1100 study of NBTXR3 in the setting of recurrent and/or metastatic head and neck squamous cell carcinoma. After the presentations, we will have a panel session to answer questions from our audience and discuss what I'm sure will be many [indiscernible] from the presentations. Next slide, please. And here you can see our speakers for today's call. Again, we have Dr. Colette Shen, who is the principal investigator for the 1100 study, and she is Assistant Professor at the University of North Carolina Lineberger Comprehensive Cancer Care Center. She will be joined by a colleague, Dr. Ari Rosenberg, who is also an investigator for the 1100 study and an Assistant Professor of Medicine at the University of Chicago School of Medicine. They will be joined by Dr. Sebastien Paris, who is Nanobiotix' Director of Translational Research. And I'm Jeff Bockman, Expert Adviser and EVP of Oncology at Lumanity and I'll be the moderator for today. With that, let me turn the call over to today's first presenter, Dr. Sebastien Paris.

So next slide, please. So I will start today's presentation by a quick overview of NBTXR3 or what we call R3, a first-in-class radioenhancer. R3 is made of hafnium oxide nanoparticles and thanks to high electron density, hafnium is an excellent energy absorber. R3 is inert without ionizing radiation, but activated when irradiated. Its negative surface charge and its nanometer scale facilitate entry of R3 into tumor cells. When injected into a tumor, which is done one time before starting radiotherapy, R3 allows for a higher level of energy from radiotherapy to be absorbed and transferred to the tumor. R3 has been shown to be safe and effective in soft tissue sarcoma, and we believe that its mechanism of action is universal and active in all tumor types tested. Next slide. As mentioned, R3 is able to increase energy absorption in any solid tumor after injection. This has 2 effects: First, it amplifies cancer cell restriction in the R3 injected tumor, improving its local control. But data suggests that R3 is also able to trigger a systemic effect, which seems to affect non-injected tumors outside of the field of irradiation. We believe this is -- this effect is mediated by the patient's immune system. Next slide. Next slide, please. Yes, thank you. As you can see here, we are and have tested R3 in several solid tumor types. We have successfully demonstrated the benefit of R3 activated by radiotherapy compared to radiotherapy alone in patients with local advanced soft tissue sarcoma. So far, hundreds of patients were treated showing safety, feasibility of this approach and consistent tumor response. In addition, R3 not only appears to be tumor-agnostic, but also can be combined with other therapies like checkpoint inhibitors or chemotherapy. In fact, we believe that any patient who is going to receive radiotherapy is likely a candidate to a [ bacterial ] therapy enhanced by R3. Next slide, please. As you can see from our clinic trial pipeline, there is still a lot of work to do. We are working closely with J&J to develop 3 arms primarily focused on head and neck and lung cancers. However, you can see at the bottom part of this slide, there are also many opportunities for expansion into other indications. Next slide, please. So as I said before, there are 2 mechanisms by which R3 acts, direct cell-killing and priming the immune system, and I'm going to describe that effect in depth right now. Next slide, please. So this slide summarizes all the different steps followed by R3 from intratumoral injection and internalization by the cell through radioenhancement to cell destruction. Thanks to its unique mode of action, R3 can induce multiple biological responses. Next slide, please. Among the steps, certain biological responses like, this is [ my on-brand canalization ] observed only with R3s -- plus R3 in our models as well as amplified image and certainly other biological effects. Ultimately lead to increased cell deaths and can be associated with the physical and pleiotropic mechanisms of action of R3. Next slide, please. What is also very interesting with R3 is that beyond its capacity to amplify cell deaths, the biological responses produced can also participate in activating the antitumor immune response. This is the case, for example, of the improved formation of [ micronuclei ] and just seeing the production of interferon beta known to be a potent activator of the immune system. This is also the case for the increase in the amount of peptides presented on the [ cell ] surface by MHC-I complex, the increase of the [ energics in this ] and a greater release of antigens facilitating the activation of the adaptive immune response. Next slide. To illustrate the directed enhancements of R3, you can see on the left some of the efficacy experiments performed on 15 different cancer cell lines, showing that the addition of R3 activated by radiotherapy amplify cell deaths compared to radiotherapy alone. These enhancements of cell deaths results in a better local control of the tumor in vivo, as can be seen on the right in some of the 11 models tested. Next slide, please. On this slide, you can now see some of the preclinical results illustrating impact of R3 on different biological pathways, such as DNA damages, activation of cGAS/STING pathway leading to secretion of interferon beta, the immunogenic cell deaths, which here represented the real localization of [ caretaking ] to cell surface membrane or the modulation of the immunopeptidome required by CD8 T cells to identify specifically destroyed tumor cells. All these pathways participate in the priming of the immune response. Next slide, please. The priming of the immune response by R3 is well illustrated by this study. Immunocompetent mice bear a tumor on each flank. Only 1 tumor received treatment, the other remained untreated. On the left, we can see that at the level of the treated tumor, R3 plus radiotherapy, and you see it's a slight benefit compared to radiotherapy. But if you look at the untreated tumors, only the mice in the R3 plus RT group saw the growth of their tumor significantly slowed down while [ RT ] had no effect. This better local control of tumors, of course, significantly increases the survival of mice. As we can see on the right part, this effect is linked to better CD8 infiltration in both tumors, only in mice for -- from the RT plus R3 group. We can see here that only the mode of action of R3 and the quantity of cell deaths are able of inducing an immune response strong enough to produce a systemic effect, while RT alone cannot. Next slide, please. This ability of RT [ activity ] R3 to produce antitumor response made possible to overcome anti-PD-1 resistance. In the study presented here, [ site ] resistance to anti-PD-1 were implanted on each flank of immunocompetent mice. As previously, only 1 tumor received treatment with RT and R3, the other did not. Mice also received anti-PD-1 treatment. You can see on the -- at the bottom in the green curve that the combination of RT plus R3 and anti-PD-1 provides better control of both tumors compared to RT plus anti-PD-1 in blue. This better local control of tumor significantly increases the survival of mice and drastically reduces the formation of lung metastasis. Next slide, please. Other combinations of checkpoint inhibitors have given similar results, strong priming of the adaptive antitumor response overcoming resistance and offering both local and systemic control and decrease of spontaneous lung metastasis. Next slide, please. Another very interesting point regarding the combination of R3 plus RT with CPI, with checkpoints inhibitors, is the ability to produce a long-lasting memory response, similar to what can be obtained after vaccination. In this study, mice in the R3 plus RT and a combination of CPI group, saw both tumors completely disappear. After several weeks with [ our sense ] of relapse this mice where we challenge with the new injection of tumor sets, no mice developed a tumor, unlike the naive control group, where all mice developed a tumor. Next slide, please. And finally, here, we showed a translation of what I just detailed before for this particular patient with a single injection of R3 before the patient's course of radiotherapy, they achieved both local control at the site of injection and irradiation but also a full complete response at the distal side of the disease that did not receive R3 nor radiotherapy. And these results were seen in patients with anti-PD-1 resistant. So you will hear more about these kinds of reasons in the next 2 presentations. And with that, let me turn the call over to Dr. Ari Rosenberg.

Thanks, Sebastien, and thanks, everyone, for joining. Over the next several minutes, I'll discuss head and neck cancer, particularly recurrent/metastatic disease, and the current standard of care treatment approaches for this disease with particular focus on challenges and opportunities. Next slide. Here are my disclosures. Next slide. So I'll start with a patient case. This is a patient of mine, a 68-year-old woman who developed a recurrent head and neck cancer. She was initially diagnosed back in 2016 when she was diagnosed with a locoregionally advanced supraglottic cancer that was staged as a T3N3 tumor. She received, at that time, induction chemotherapy followed by definitive concurrent chemoradiation and after which also underwent a salvage neck dissection, a surgery, which demonstrated a pathologic complete response at that time. She did well for a number of years, but unfortunately, when I met her in 2020 she had developed an enlarging right-sided neck mass, with biopsy demonstrating, at that time, recurrent squamous cell carcinoma and PD-L1 testing, the biomarker that we use for immunotherapy was completely negative. Her combined positive score was 0. You can appreciate in some of these PET scan images here that this was very extensive locoregionally recurrent disease, including invasion of the supraclavicular space. And as I'm sure you can imagine, this has -- not only was a very painful tumor at the time that she presented, but had major impacts also on swallowing and on function and, of course, as you can imagine, on quality of life. And so the question becomes in this particular setting, what is the best treatment approach. It was determined by our surgeons that this was nonamenable to salvage surgery, given the extent of disease. And so immunotherapy with chemotherapy would be the standard palliative treatment approach in this treatment setting, although with PD-L1-negative disease, the opportunity for PD-1 alone or the addition of that to standard approach remains quite reserved. Next slide. So we actually enrolled this patient on the 1100 study, which involved injection of her right-sided recurrent tumor with NBTXR3. And you can actually appreciate the post-injection imaging on the top there and the CT scan, where you see in the area of the very large tumor the radio-opaque nanoparticles that we can actually see on the CT scan. This was followed by SBRT radiation as well as immunotherapy. And on her follow-up scan, which as you can see on the bottom slide, you can appreciate now that while you can still see the clear nanoparticles quite apparent on that CT scan, it actually looks even more clear than on the top slide after the initial injection because we see regression of the tumor around the nanoparticle. As you can imagine, with regression of her tumor, this also resulted in improvement in her pain and number of her symptoms and fortunately, for her, she completed 2 years of immunotherapy without disease progression. And again, with PD-L1-negative disease, this would be quite unusual and unexpected with pembrolizumab alone. Next slide. So when we think about locoregionally advanced disease, which we see as the majority of our patients, we know that this is quite a heterogeneous disease that can arise at multiple places within the head and neck cancer space. As you can see on the right, of course, on the oropharynx we see tumors that are HPV-associated, which is a unique clinical and biological subset with very good prognosis. However, we still see a substantial proportion of patients with HPV-negative head and neck tumors that can arise either in the oropharynx or at other subsites in the head and neck cancer space and even with our multimodality treatment approaches incorporating chemoradiation or surgery, survival remains quite poor despite the fact that we try to cure these patients, we only manage to cure about half of these patients. Next slide. So here, you can see the survival outcomes by HPV status. You can see in the top curve that HPV-associated oropharyngeal cancers are actually associated with quite good prognosis. And actually, in these disease types, much of the clinical trials and research is focused on selecting patients for de-intensified treatment and seeing who we can give less toxic treatment to, to maintain good survival outcomes while reducing treatment-related toxicity. On the other hand, as you can see in the lower survival curve, HPV-negative tumors, which, again, are largely carcinogen-induced diseases attributable to tobacco and alcohol and other carcinogens, that survival remains quite poor even in the curative-intent setting, we only manage to cure about half of these patients with a substantial proportion developing recurrent or metastatic disease. Next slide. So how do we think about the standard of care in the locoregionally advanced setting? Well, for the oral cavity patients, the large -- the first thing we think about in this setting is whether patients are amenable for surgery, most of these patients will go to surgery followed by adjuvant radiation or adjuvant chemoradiation based on pathologic risk. In the oropharynx, these are patients that can have either HPV-positive or HPV-negative disease. Treatment approaches can include either definitive chemoradiation-based approaches or in select very early-stage patients, minimally invasive surgeries such as TORS, followed by adjuvant radiation or adjuvant chemoradiation. In tumors of the larynx, most of these patients will be treated with an organ preservation approach with definitive chemoradiation versus a select subset of patients that are not good candidates for organ preservation that will typically go to laryngectomy in front. The nasopharynx is a unique biological subset of head and neck cancer often associated with Epstein-Barr virus, EBV. In this disease, this is really treated in a distinct way with chemoradiation, often with the addition of induction chemotherapy and/or adjuvant chemotherapy and immunotherapy has an evolving role in this setting. And then you can see here the standard radiation doses in either definitive setting or in the adjuvant setting either alone or in combination with chemotherapy and the standard chemotherapy for eligible patients is cisplatin. Next slide. Unfortunately, a substantial proportion of patients, particularly with non-HPV-associated disease or with high-risk HPV-associated disease will develop recurrent or metastatic patients and this is associated with very poor survival. We see patients develop either locoregionally recurrent disease or distant metastatic disease or a combination of both of these treatments and median survival in this setting is quite poor even with novel immunotherapeutic approaches with median survival of only 11 to 13 months. Next slide. So our current standard approach in the recurrent/metastatic setting was built on the KEYNOTE-048 study, which took patients in the frontline recurrent/metastatic setting and randomized them to 2 experimental [ arm ], either pembrolizumab alone or pembrolizumab with chemotherapy versus the standard of care prior to that, the chemotherapy with cetuximab or the extreme regimen. Next slide. And the results of this study demonstrated that for all comers, pembrolizumab with chemotherapy, as you can see on the right, improved survival compared with the extreme regimen. However, I would like to highlight that at long-term follow-up, only 16% to 19% of these patients remain alive. So even with chemo-immunotherapy approaches, long-term survival remains quite poor. Next slide. And in the PD-L1 enriched population with PD-L1 combined positive score of 1 or greater, we saw a survival advantage of both the pembrolizumab monotherapy arm, which you can see on the left, as well as the pembro plus chemotherapy arm, which you can see on right, so both experimental arms were superior. However, again, long-term survivors remain quite poor, only 15% to 18% of patients. Next slide. And particularly in patients with PD-L1 negative patients, we see really no additional benefit to the addition of immunotherapy compared with chemo cetuximab when you look at the PD-L1 subsets. And in this population, this really highlights that there remains a particularly unmet need, particularly in PD-L1 negative patients, similar to the patient that I presented, who was enrolled on the 1100 study. Next slide. So the standard of care treatment approach in recurrent/metastatic setting in the frontline treatment setting for PD-L1 positive with a combined positive score of 1 or greater, standard approaches remain either pembrolizumab alone or with chemotherapy. For PD-L1 negative patients with CPS of less than 1, similar to the patient that I presented, standard approaches are either pembro plus chemo or chemotherapy with cetuximab. The chemotherapy backbone can be either platinum 5-FU, which was the one evaluated in the 048 study, although platinum taxane is commonly utilized and now studied platinum doublet to be used in the front line setting. And then subsequent line treatment options are really cetuximab with or without chemotherapy or pembrolizumab with or without chemotherapy depending on what patients received in the front line with survival outcomes quite poor in this setting, really on a number -- in terms of median survival of months. And radiation largely has a palliative role. Next slide. And so this provides opportunities to build on these current results and improve outcomes in terms of particularly harnessing the vulnerabilities of the key hallmarks of cancer and head and neck cancer in terms of avoiding immune destruction, building on immune-activating monoclonal antibodies such as PD-1 or PD-L1 immune-targeted therapies which have an established role in building on that but also in resisting cell death and in radio enhancement. This is another space, which we know is quite important for locoregionally advanced head and neck cancer and recurrent/metastatic head and neck tumors, which tend to be more radio-resistant in which there's opportunity to build on this hallmark of cancer vulnerability. Next slide. And so where the biggest unmet needs? Well, in the locoregionally recurrent disease, this is a particular space where there's a true unmet need, not only because of the very poor survival outcomes but also because of substantial morbidity associated with locoregionally recurrent disease. And I actually pulled here on the right side, the 048 data. And if you look at the patients that have recurrent disease alone, the plots actually crossed 1, suggesting that this is really an area of need, where either pembro or pembro plus chemo that we need more improved therapies, particularly for this particularly recurrent subset of head and neck cancer patients. Novel combinations with pembrolizumab in PD-L1 positive patients in the frontline setting remains an important area of interest as well as improved treatments after refractory disease to both immunotherapy and platinum-based chemotherapy. And then particularly, harnessing multimodality treatment approaches that incorporate both radiation and other specialties, even in the recurrent/metastatic head and neck cancer setting remains a great interest. Next slide. So I hope this gives a flavor of the fact that despite curative-intent treatment, most or many patients, I should say, will develop recurrent disease, that survival is quite poor for these patients and that patients with locoregionally recurrent disease demonstrates a unique challenge because of the substantial morbidity as well as impact -- negative impact on function and quality of life of this disease. And there's opportunities to improve outcomes in this patient population. So I'll stop there. and hand it over to the next speaker. Thanks. I'll hand it over to Colette, excuse me.

Thanks so much, Ari. That was a great discussion and really laid out, importantly, the significant unmet need for patients with recurrent head and neck -- metastatic head neck squamous cell cancer. Next slide, please. So I'd like to share with you all some data that we presented just earlier this month at the ASCO meeting. This is our abstract, early signs of efficacy in patients with anti-PD-1 naive and anti-PD-1 resistant head and neck squamous cell cancer treated with NBTXR3 and SBRT in combination with nivolumab or pembrolizumab in the Phase I trial study 1100. Next slide, please. Here are my disclosures. Next slide. So just as a reminder, outcomes remain limited for patients treated with anti-PD-1 in the first, second or further lines of treatment. Progression-free survival is short, many patients do not respond. While there may be a tail -- a small tail of patients with durable response, the majority of patients are primary or secondary nonresponders to anti-PD-1 treatment. And this is highlighted, again, in the KEYNOTE-048, KEYNOTE-040 and CHECKMATE-141 studies. Next slide, please. There has been some thought that perhaps using SBRT or radiation could enhance response to immune checkpoint blockade. And this trial by Memorial Sloan Kettering Cancer Center was exploring nivolumab randomized against nivolumab plus SBRT for patients with recurrent/metastatic head and neck squamous cell cancer. However, there did not seem to be any difference in overall survival with the addition of SBRT in this group, and these were anti-PD-1 naive patients. So prompted by, in particular, some of the very promising preclinical data that Dr. Paris shared, the thought of the 1100 study is that perhaps by providing local control and priming an immune response with NBTXR3 plus radiation, one of the goals is to explore whether this combination with immune checkpoint inhibitor can improve and deepen response to immune therapy for patients naive to anti-PD-1 therapy. In a second goal, can this combination reverse resistance to anti-PD-1 therapy for refractory patients. Next slide, please. And so just to briefly go over the study design for the 1100 study, the patients receive a onetime intratumoral injection of NBTXR3. This is followed by SBRT, over 3 to 5 fractions depending on the site of radiation. And then the day after SBRT completion, patients began anti-PD-1 therapy with pembrolizumab or nivolumab. The dose-escalation portion of the study is complete. In this portion of the study, there were 3 cohorts: the first, locoregionally recurrent or recurrent/metastatic head and neck squamous cell cancer; and then the second and third cohorts were patients with lung or liver metastases from any primary tumor eligible for anti-PD-1 therapy. Now we're on the dose-expansion phase of the study here on the right. The cohorts have been adjusted such that there are 2 cohorts of patients with current recurrent and metastatic head and neck squamous cell cancer, one group anti-PD-1 resistant, the second group anti-PD-1-naive. And then the third cohort is patients with lung or liver metastases from primary tumors eligible for anti-PD-1 therapy, and these patients are anti-PD-1 resistant. The primary objective is to further assess the safety profile. Secondary objectives, evaluating safety, feasibility and antitumor response of this combination of radiation-activated NBTXR3 in combination with anti-PD-1, and then exploratory objectives of survival duration response, biomarkers of response and response in non-injected nonirradiated lesions. Next slide, please. Here are some of the baseline characteristics of patients, specifically in the recurrent/metastatic head and neck squamous cell cancer cohorts. First, Study 1100. I'll just highlight a few of the key areas. And we see here that-- previous slide, please. Patients are separated into in immune checkpoint inhibitor naive or resistant. And we can see that the majority of patients have had multiple prior lines of therapy, especially the immune checkpoint inhibitor-resistant group. The majority of those patients had at least 3 prior lines of therapy. You can also see that a majority of patients have multiple lesions being treated in the naive group, about 65% of patients had at least 2 lesions and then in the resistant group, about 79% of patients had at least 2 lesions. And I will note that, in this trial, patients were limited to have no more than 5 progressing lesions. And then at the bottom, the CPS score, and I apologize, the bottom line is cut off. But in the naive group, 75% of patients had CPS 1 to 20, 25% had greater than 20, and in the resistant group, 15% of patients had CPS less than 1, 42% had 1 to 20, and another about 40% had greater than 20. Next slide, please. In terms of safety, there were very few treatment-emergent adverse events related to NBTXR3. In general, less than 10% of Grade 3 or greater serious treatment-emergent adverse events were related to NBTXR3 injection procedure, radiation therapy or anti-PD-1. About 10% of the Grade 3 or greater treatment-emergent adverse events were related to radiotherapy, which is in line with reported data. There were no unexpected side effects that emerged related to the radiotherapy and NBTXR3 combination or anti-PD-1 exposure or injection procedure. Next slide, please. So now I'd like to move to efficacy in patients naive to anti-PD-1 therapy and I'll separate between naive patients and then later I'll go to efficacy in patients resistant to anti-PD-1 therapy. And please note again that this is an ongoing study. So these data are preliminary based on a data cutoff of April of this year. Next slide, please. So just as a quick reminder of these patients in the anti-PD-1 naive group, this is a similar population to those in the KEYNOTE-040 or CHECKMATE-141 study. These patients did have a fairly heavy tumor burden. 65% of patients had at least 2 lesions. In this group, there were 33 patients evaluable for safety and 25 evaluable for efficacy at the cutoff day. And again, the CPS score below 20% in 75% of patients. 10 of the 33 patients had oropharynx HPV-positive disease. Next slide, please. So here's the waterfall plot of best change in all target lesions, diameter sum. So this is not just the injected, irradiated lesion, but all target lesions. And we could see that there was an objective response rate of 48% with a median duration of 54 days and a disease control rate of 76%, with a median duration of 65 days. We're here potentially seeing systemic control in anti-PD-1 naive patients with a high disease burden. 24% of patients have 4 or more lesions and 66% have 2 or more lesions. And as a reminder, only 1 lesion here has been injected and irradiated. Next slide, please. In terms of progression-free survival and overall survival, again, this is for the immune checkpoint inhibitor naive group. The median progression-free survival from NBTXR3 injection was 7.3 months, and the overall survival from NBTXR3 injection was 26.2 months. Next slide, please. It is very difficult to make any direct comparisons between studies with different patient populations. But just as a rough illustration comparing the results seen in the 1100 study thus far to the KEYNOTE-040 and CHECKMATE-141 studies, both similarly with an immune checkpoint inhibitor naive population. We have an objective response rate of 48% in the 1100 study compared to KEYNOTE-040 and CHECKMATE-141 objective response rates of about 13% to 15%. And the progression-free survival for the 1100 study is very promising when compared to the other KEYNOTE and CHECKMATE studies. Next slide, please. Now moving on to efficacy in patients resistant to anti-PD-1 therapy. Next slide. So this population is those that have developed primary or secondary resistance to prior anti-PD-1 therapy. And so just as a reminder, using the progression-free survival graph from the KEYNOTE-048 study, this would be patients who are kind of in this early refractory setting or patients develop primary and secondary resistance kind of in that 6- to 12-month time frame from starting checkpoint inhibitor therapy. These patients are not those who have responded or have had durable response to immune checkpoint inhibitor therapy. Next slide, please, or next graph. So just as an illustration, the patients who have entered the 1100 study who have been refractory to anti-PD-1 therapy, typically looking at the time from the starting date of prior immune checkpoint inhibitor therapy develop progression within that initial about 6-month window, 6 to 12 months, similar to those in patients who developed resistance to pembrolizumab alone in the KEYNOTE-048 study. Next slide, please. So just as a reminder of some of the key baseline characteristics of this group, there were 35 patients that were evaluable for safety, 25 evaluable for efficacy. The -- all of the patients have developed a progression, but 83% of these have been verified based on the data entered thus far. And these patients do have a heavy tumor burden. About 60% of patients have 4 or more lesions in this group. So a very heavy tumor burden. About 79% have 2 or more lesions. And then this is a heavily pretreated patient population. Nearly 40% of these patients have had 3 or 4 lines of prior therapy and majority of patients have had multiple prior lines of treatment. In terms of CPS score, 15% of patients in this group have a CPS score less than 1%, and 58% below 20%. And there were 12 patients in this group with oropharynx HPV-positive cancer. And so this group of patients who have developed resistance to anti-PD-1 therapy are similar population as the KEYNOTE-040 or CHECKMATE-141 patients treated beyond progression or failure. Next slide, please. Here's the waterfall plot for the best change in all target lesions from baseline for this immune checkpoint inhibitor-resistant group. We can see an objective response rate of 28% with a median duration of 128 days and a disease control rate of 68% with a median duration of 58 days. And just as a reminder, again, these patients have had a high tumor burden of 60% have 4 or more lesions, but only 1 of the lesions has been injected and irradiated. And so we are potentially seeing some systemic control in these patients who have progressed on prior anti-PD-1 therapy and have high disease burden. Most of these patients do not just have the 1 lesion that was injected or irradiated. Next slide, please. So looking at survival data, the progression-free survival from NBTXR3 injection was a median of 4.2 months, and the overall survival for NBTXR3 injection for this group is a median of 7.8 months. Next slide, please. So as I mentioned, this group of patients have developed progression resistance to anti-PD-1 therapy are similar to those perhaps in the CHECKMATE-141 trial for patients who were treated beyond anti-PD-1 progression. And so there has been an additional analysis of patients from this CHECKMATE-141 trial, those treated beyond anti-PD-1 progression. This is the waterfall plot for those patients. And then the median overall survival from the time of immune checkpoint inhibitor initiation was 12.7 months for this group. Next slide, please. And so for our patients on the 1100 study, there has been a calculation of an overall survival 2, which is the time from first immune checkpoint inhibitor therapy. The prior overall survival data were from the time of NBTXR3 injection. And so here's an additional calculation from time of first immune checkpoint inhibitor therapy as a way to try to have some comparison with patients treated on some of the other studies where survival is reported from the time of immune checkpoint inhibitor initiation. So again, this is just for the patients who are resistant to immune checkpoint inhibitor therapy, and this is a second calculation for the overall survival. And so the overall survival 2 for these patients from the first immune checkpoint inhibitor therapy start date prior to starting on the 1100 study was 31.8 months. Next slide, please. Just as a very rough comparison with, of course, the understanding that these patients are different populations. But just as a very rough illustration, on the left, we have patients in the CHECKMATE-141 study who were treated beyond anti-PD-1 progression. So the waterfall plot on the left there versus the 1100 patients, immune checkpoint inhibitor-resistant patients who are treated beyond progression with the waterfall plot on the right. The survival for the patients on the CHECKMATE-141 study from immune anti-PD-1 initiation was 12.7 months and the overall survival 2 number that I just mentioned for the 1100 study patients from the time of immune checkpoint inhibitor therapy initiation was 31.8 months. Again, this is a very rough comparison. The patients on the 1100 study may have had other treatment lines after the initial anti-PD-1 progression, but really just as a rough illustration. Next slide, please. So just to summarize, I think the data from the 1100 study are promising, very promising and they warrant further exploration in randomized trials for both immune checkpoint inhibitor naive and resistant patients with patients with locoregionally recurrent or metastatic head and neck squamous cell cancer. In general, this treatment was feasible and safe with no unexpected findings. Less than 10% of grade 3 or greater serious treatment-emergent adverse events were related to radiotherapy injection procedure, anti-PD-1 or NBTXR3. There was a high response rate with metastatic patients, both naive and refractory to anti-PD-1 therapy, which suggests some systemic component of control. In the naive patients, the objective response rate was 48%; and the disease control rate, 76%; median progression-free survival, 7.3 months; median overall survival of 26.2 months. In immune checkpoint inhibitor-resistant patients, response rate of 28%; disease control, 68%; median progression-free survival, 4.2 months; and median overall survival 7.8 months. And so these are very promising data that certainly warrant further exploration. Next slide. And I think with that, I'll pass it back to Jeffrey. Dr. Bockman.

Great, thank you, Sebastien, Ari and Colette. Let me turn it over to Anne so we can begin our Q&A session.

[Operator Instructions]

So maybe I'll get us started while we're waiting for some questions to come in. Maybe I'll ask a broad question, really, to Dr. Rosenberg and Shen and that is kind of, with the data, preliminary data we've seen to date, where do you see R3 fitting into medical practice in the future, potentially?

Yes, absolutely. I mean, I think Colette really wonderfully demonstrated sort of 2 particular settings where I think those of us that have been using this on the clinical trial, see a potential role. One is patients who are PD-1 naive, who -- particularly those that have locoregionally recurrent disease and in whom standard treatment approaches of immunotherapy or immunochemotherapy are suboptimal, and where R3 with SBRT in immunotherapy may be a strategy not only to reduce some of the locoregional disease burden, improve function, quality of life and symptoms related to their recurrent disease, but also enhancing the antitumor immunity driven by the PD-1 with some of the immunogenicity data that Sebastien demonstrated in the preclinical side and then Colette illustrated as well, which -- what we've observed in the clinic. I think the second space is the 040 and 141 population of patients that are subsequent line therapy who are IO refractory. We really don't have good treatment in that population. Survival is quite poor after PD-1. We don't have good systemic treatment options, I'm a medical oncologist, so I can speak to that piece. And there, I think there is another unique opportunity to resensitize tumors to anti-PD-1. We know that treating beyond progression with PD-1 alone is a suboptimal strategy. And so if there's a way to resensitize tumors to be visible to the immune system through immunogenic manipulation, that would be, hopefully, greatly advantageous to patients.

Great.

I would absolutely agree with all of what Ari said. And as a radiation oncologist, I'm always very excited when there's a modality that can enhance the effect of radiation therapy. And I think, certainly, for some of the settings that Ari mentioned, we're very excited about the possibility of combining R3 with radiation to help stimulate perhaps a systemic response in patients with very advanced disease. I. Think the other setting is just to improve local control. So for example, in the NANORAY-312 study, that's for patients who are being treated upfront definitively for head and neck squamous cell cancer who aren't eligible for cisplatin. I mean, that's a situation where R3 is being used as a radio enhancer in lieu of cisplatin to really achieve continued excellent levels of local control or locoregional control for those patients. So I think, really, in that type of setting, improving loco control is really important. There may be situations where we might want to try to reduce the dose of radiation to improve tolerance and that may be a setting where we could use R3. And so I think there are many possibilities. I think one of the very unique things about this treatment modality is that it's tumor tech-agnostic essentially, you can use it wherever it can be introduced and injected intratumorally. And it can also be combined with other systemic therapies. It doesn't have to be either/or, so really, anywhere where we're giving radiation and there can be a tumor that's injected, this can be a modality that we can use. And so that's something that I would be thinking about not necessarily instead of some of the newer systemic therapies, perhaps in conjunction and in situations where we either want to boost the radiation effect of locoregional control or even be able to reduce the dose of radiation.

Great. Thank you both. I have seen that a number of people have been in the Q&A session. If anyone can raise their hand so I can [indiscernible] and recognize [indiscernible].

Our first question will be from Dylan Drakes of Leerink Partners.

This is Dylan on for Jonathan. First question, how much additional effort would be required to coordinate injection with radiation therapy? Is this something that would be feasible across both academic and community-based centers?

I think that's a great question and something that has been really worked out over the first several studies with this -- with R3. I would say at academic centers, we found it quite -- nothing is easy to set up initially, but I think we have a nice workflow now where we have injectors, both from ENT for head and neck sites. We have injectors from interventional radiology as well as interventional pulmonology for the lung lesions. And so we've developed a really nice workflow working with those colleagues. I do think it may be a bit more of a challenge in a community setting, but I do know that there are a lot of really large well-organized community practices that have good relationships that could set this up. One other thing that we could think about, too, is perhaps, for any of these things, it's a onetime intratumoral injection, perhaps the injection could be done at a larger center and the subsequent treatment, whether radiation or immunotherapy or systemic therapy can be done locally. I think those would be ways to set that up as well.

Yes. And I completely agree with Colette. And I'll just add to what she said, which is that head and neck cancer is unique in that -- particularly, in that the head and neck surgeon remains very much connected to these patients even when they develop recurrent/metastatic disease. And even though they're not offering surgery for the vast majority of patients with recurrent/metastatic disease, they remain intimately involved in that patient's care with scopes, with symptom management, even as patients are getting immunotherapy and other types of systemic therapy or palliative radiation with current standard treatment approaches. And counterintuitively, reincorporating head and neck surgeons to have a therapeutic role in the recurrent/metastatic setting, at our center at least, has been one of the major reasons why the coordination has actually been met with enthusiasm. Head and neck surgeons are excited to be able to inject this asset, to have an active therapeutic role in improving outcomes with some of these approaches. So that's what we found, and I think that's true at other places as well.

And for head and neck cancer, a lot of times, these injections don't need to be done in an OR, for example. They can be done in -- sometimes, we just have a procedure room or even our infusion suite right at the bedside. So it can be pretty straightforward.

Great. Great. I think Michael from Guggenheim was next.

Yes. I had a question on the study 1100 data from ASCO. Did you break out the data by HPV status for the 2 arms? Just curious how that looks. And the other question I had was, in the PD-1 inhibitor naive cohort, what percentage of those patients had prior chemo and was that in the metastatic or the local setting?

So for the HPV question, that was not presented in the ASCO poster from this year. But last year, we did break things down, at least for the patients to date there. In terms of HPV status there, the disease control rate was pretty similar between HPV-positive and negative. It was about 70% for HPV-positive, about 67% for HPV-negative and the injective response rate was perhaps a little bit higher with the HPV-positive patients, 29% versus 17% for HPV-negative. Again, that was based on data from last year. So -- so certainly, that analysis will be updated as we have more patients. And I think your other question was for the resistant group, I think you were asking -- sorry, the naive group, I think you're asking about prior systemic therapy. Those patients, I would say, some have had chemotherapy, but fewer of those patients were treated with as many lines prior to enrolling on the 1100 study. So in many cases, those patients saw chemotherapy as part of their initial chemoradiation as opposed to subsequent chemo for recurrent/metastatic disease.

Yes. Can I just ask a quick follow-up? I think you said the other plays where our R3 could be interesting would be in the patients that are ineligible for systemic therapy upfront, so the chemotherapy-ineligible patients. And we've heard different estimates there, what percentage of patients would fall into that category. What has your experience been there?

Yes. The data suggests that about 1/3 of head and neck cancer patients are ineligible for cisplatin. So it's quite a substantial proportion. There's some disagreement within the field of what constitutes ineligibility for cisplatin and there are certainly patients that are on the border, that there's some heterogeneity in the approach. But it's a substantial proportion of patients. We know that head and neck cancer patients is largely diagnosed and increases in incidence with older age. So over 70 years old is quite a common area of cancer patients. With HPV-positive disease, we've actually seen a big uptick in elderly patients in their 80s and even 90s with HPV-positive. Historically, we used to think about those largely in younger patients, but there's actually data suggesting that, that's increasing in incidence in older patients now as sort of time passes as well. So it's a substantial proportion either because of age or comorbidities or frailty that may make cisplatin a suboptimal treatment approach. As you know, cis RT is a tough regimen. We cause a lot of substantial toxicities for patients. It's not -- that's something that we sort of see in the clinic.

Thanks. I think Lucy from Jefferies was next.

So I guess -- and you may not be able to answer this, but I would be interested to get your thoughts on how you would think about designing the next trial or trials for the head and neck cancer setting in combination with immunotherapy. And I guess, would you do you think it would be best to split that into 2 separate trials in terms of prior resistance or naivety and also potentially stratifying by HPV status just given some of the developments we're seeing in terms of HPV-directed cancer vaccines and just better delineating where this might best sit?

I can start, and Ari can add. But I do think we do need a randomized trial to really demonstrate this combination versus standard of care. For the -- and I would agree with you that probably there needs to be 2 designs for the immune checkpoint inhibitor naive and refractory. They're just different patient populations. So for naive, probably randomized to pembrolizumab alone, there did not seem to be any benefit to just adding SBRT in that memorial study. So I think probably a randomization with pembrolizumab alone. And then for the prior resistance to immune checkpoint inhibitor probably, perhaps, a randomization with a physician's choice, depending on perhaps HPV status. And I think maybe Ari can add to that as well.

Yes. No, I completely agree with Colette. I mean I think a randomized study is needed. And I think that's exactly right. The one thing I'll just add is that, right, this is not a systemic therapy in the classical sense. And so the design can be adapted if the systemic therapy standard of care changes. I know you highlighted some of the other assets that are being developed in the head and neck cancer space. But I think R3 is unique because it's an intratumoral injection, it's immune-enhancing, but it's not a systemic therapy. And so a design could be easily adapted with what an appropriate control arm would be.

I think Ramakanth from Wainwright next.

There are 2 of them, the first one being talking about the patient that Dr. Rosenberg put out from study on 1100 where you are talking about a patient being PD-1 negative -- having PD-1 negative status and also being difficult surgical resection. How often do you see such patients? That's question number one. And question number two is, based on the data that you have seen from KEYNOTE-040 or CHECKMATE-141, where we see mid-teen response rates and really -- and 7 to 8 months of OS. And I'm learning what we have learned from R3, is that is there any meaning in reversing the sequence in a sense, trying to initiate therapy with R3 and then going to PD-1 therapy in some of these patients?

Yes. So to answer your first question, I would say, having some component of locoregionally recurrent disease is, I would say, actually more common than not when we see patients with recurrent disease. I think I showed some of -- a slide, I usually think about sort of 1/3 of patients developing locoregionally recurrent disease, 1/3 having distant-only disease, and that other 1/3 having some combination. I would say that's pretty consistent with what I see in clinical practice. Of course, the additional component is that most of the time in the clinic the recurrence -- the component of the disease that's having most of the impact on in terms of pain, quality life and function is the recurrent disease, right? This is a previous -- largely previously irradiated disease setting. This is a space with high value real estate, eating, speaking, swallowing, a lot of nerves, a lot of complex structures. This is why head and neck cancer is a very challenging disease to treat even in the upfront setting. So I think that's also important to highlight for your first question. Your second question, maybe I didn't totally hear, but are you asking about the sequencing of R3 and immunotherapy? Can you clarify a little more?

Yes. So trying to sensitize the tumor more. So does it make sense to first do R3 with SBRT and then treat with any of the anti-PD-1 therapies, so that you're sensitizing the tumor ahead of giving anti-PD-1?

Yes. So that's actually how the trial is designed currently, for exactly the rationale that you provided, that's exactly right, which is that the idea is to sensitize first and then do people -- and we actually start the PD-1, the day after -- the business day after the SBRT is done. And we coordinate that closely with Colette or our radiation oncologists in terms of that timing to try to start the PD-1 as soon as that radio enhancement occurs, so -- and that immunogenic timing occurs. So I think that's exactly the rationale. And I think the data that Colette showed in terms of IO naive versus IO refractory is also very important to illustrate that as well, right? On the IO-naive population, you see incredible activity with that time before patients have received any anti-PD-1, I think that's important to highlight as well.

And then, I think that may be what you were trying to get at with the question is, should we try to move this ahead and not allow them to develop that resistance to anti-PD-1 therapy, but start it early. And I think that makes sense, especially for patients who have maybe not widely metastatic disease, but more limited oligometastatic disease or locoregionally recurrent where we can try to really trying to get as much of the tumor control with both local control and immune therapy earlier as opposed to waiting until they've had multiple lines of treatment. It just becomes harder and harder once they become more heavily pretreated. So I think that's a good point, and that's one of the goals.

Great. We have another question from Dylan, Leerink.

Just one more question from me. Would you be able to comment on how common the practice, the reradiation is in R/M head and neck cancer. And do you envision the data from Study 1100 will increase the adoption of this practice?

That really varies. I think it varies institution to institution. We tend to do a lot of reirradiation, I know there are places that tend to be less comfortable. I would say most larger academic centers are probably quite comfortable with reirradiation and most places are doing it fairly frequently, at least at the larger centers. In terms of reirradiation, it's all over the place. We do a fair amount of SBRT reirradiation both because patients have already been through a round of 6 or 7 weeks of radiation and may not want to do that again or be able to. Oftentimes, the recurrent disease may be more focused than the initial external disease. And -- but on the flip side, the other way that we sometimes do reirradiation is with a really long course of twice-a-day radiation. And so I think there's a pretty big space to work with in terms of achieving better disease outcomes in that setting. I do think ways to enhance reradiation with some of these modalities combination with systemic therapy, checkpoint inhibitor therapy, R3 can really enhance the outcomes with it while limiting side effects. Because like Ari mentioned, the side effects of one round of treatment are already really hard. You put in another round of treatment and there are risks. We are finding more comfort with avoiding some of the more serious side effects with reirradiation like carotid blowout, for example. There are ways that we've been developing dose constraints around those vessels or ways to plan around it. So and we're becoming quite comfortable with reirradiation, especially with SBRT.

Yes, I completely agree. And the other thing I'll just highlight is that I think the thinking around reirradiation has shifted in the era of immunotherapy because we see, as you saw from Colette's data that she showed and my data as well, which is that with PD-1, we do see a subset of patients who are -- who have deep, durable responses in the immunotherapy era. And so reirradiation, rather than being a be-all, end-all, last-ditch effort for lack of a better term, I think now has more of a role of how do we incorporate it in a way to improve symptom burden and overall tumor burden for these patients that have quite extensive recurrent disease. And furthermore, how do we use that to leverage all of the progress we've made with anti-PD-1-based therapy in combination and hope to continue to improve with sort of the evolving landscape. So I do think -- agree with Colette completely that the strategy of how best to incorporate reirradiation has shifted and requires very close collaboration between medical oncologists, radiation oncologists and surgeons.

All right. Thank you. All right, so I have a few questions of our own. So Dr. Rosenberg, you touched on to the question about the randomized study, the potential value of an adaptive because of the ability with R3 to potentially be added to some of these other pipeline agents that are in development. Could you and also Dr. Shen kind of elaborate on that idea of R3 being used in combination above and beyond kind of current checkpoint inhibitors?

Yes. I mean, I think what's unique about R3 is that, again, it's not a systemic therapy that has a lot of overlapping toxicities, but other agents that are being developed. And we have emerging safety data of R3 with SBRT, not only with immunotherapy, but other assets as well. And we should continue to hopefully see more of that. I think that the enhancement or the priming of antitumor immunity is beneficial not only across anti-PD-1, but other potential IO assets beyond anti-PD-1 or in combination with PD-1, which I think situates it uniquely in terms of opportunities for incorporation and treatment paradigms for recurrent/metastatic head and neck cancer.

Yes, I'll just add to that. I would agree with combinations with other immunotherapies, but there have been some early safety data with other chemotherapy agents, cisplatin, 5FU, gemcitabine. So I think in those situations, we could have imagine using R3 to enhance the response, for example, for unresectable tumors, locally advanced that may not be eligible for surgery. We could think about it for perhaps HPV-negative head and neck patients where we know we need to do better. And we can't really de-escalate like we can with HPV-positive patients. Can we do a combination of R3 with radiation and cisplatin for those patients or other systemic therapies that are being developed? So like Ari said, it's not either/ or with some of the newer agents. We can use them in combination pretty much anywhere where we're going to be giving radiation.

And a follow-up question about a comment about potential patients who are not eligible for resection. What's the status right now of some of the checkpoint inhibitors in terms of neoadjuvant head and neck that already has approval like non-small cell and some other settings?

Yes, that's a good question. Locally recurrent disease are some of the most contentious discussions in our tumor board. And that's because it is a challenging disease to treat and one that requires a lot of input, multimodality input -- multidisciplinary input from [ MEDAC redac ] surgery, but also from the patient and also from other specialists, right? I mean speech pathology and et cetera, et cetera. So I'll start with that. I think for small recurrences that are easily surgically salvageable with, for example, a neck dissection, for example, I would say that still remains the standard of care, curative-intent treatment approach for those diseases. And we do see a subset of those, although many of the recurrences that we see are much more extensive and not amenable to an easy -- easy -- a feasible surgical salvage with good functional outcomes and things like that. And then that's where we think about going down these other potential pathways. So I would say there are clinical trials that are trying to look at neoadjuvant immunotherapy in the context of easily surgically resectable disease, and those trials are ongoing. I think that's a different patient population, different setting than much of which what we're talking about, which is really recurrent disease that's not amenable to a true curative-intent surgical salvage that's going to give patients cure with long-term function. I don't know, Colette, how are your tumor boards for the recurrent cases?

Very similar to what you described. If it's resectable, anyway, the surgeons are going to want to take it out. So we're talking about different populations, I agree.

Great. I might also maybe bring in Sebastien, too, to this next question. So we touched on combinations. But given the biology, some of the data that's been generated that's preclinically and correlative data, are there particular types of agents that one would see as making a lot of sense? And I'm specifically thinking of IO-type agents, right? So one, some people there a fair amount of activity in head and neck. A lot of them are IO, many different flavors, rather than thinking of those as potentially competitive, it's quite conceivable given how R3 works to think of them as being combinable.

So as you can -- as you have seen on the slide that I presented, we have combined different types of checkpoint inhibitors. Like for example, the complexity PD-1, which is a very standard combination of CPIs. But we can also imagine to combine anti-PD-1, which worked very well with different type of CPI, for example, with antibody targeting the macrophages because we know that macrophages have a very impact -- important impact on the efficacy of the treatment. There are, most of the time, [ for tumor ] immune cells. So if we are able to maybe target both populations, I mean the CD8 T cells and eventually, if we are able to combine this treatment with NBTXR3 radiotherapy and something that maybe can block the activity of these macrophages, we can maybe have a kind of synergy between all these checkpoint inhibitors to have a better immune response.

Great. So of course, with the recognition that both you, Ari, and Colette are focused in head and neck. But in thinking about kind of the potential broader utility of R3. Any comments you want to make there in terms of additional tumor types? Clearly there's potential for other settings within head and neck cancer.

Yes. I mean I'll just briefly touch on the 1100 study has another cohort of patients who aren't head and neck cancer patients. And we've been seeing some really promising activity. First, we don't really have very complete data for that cohort 3 yet. But for example, I've had quite a few patients with melanoma who have been treated on study who have done quite well and I think that group makes sense because of the use of immune checkpoint inhibitor therapy for those patients, but perhaps there may be some limited locoregional disease that's being a little stubborn. We can make use of R3 and SBRT to help jump-start that response a little bit more again. So I think that's a very promising patient population for this. I work with quite a few lung cancer specialists who are very excited about R3, both in kind of earlier stage as well as more advanced stage. The PACIFIC study showed promising activity with immunotherapy in the locally advanced setting for non-small cell lung cancer. Could this be used for earlier stage disease, perhaps for larger tumors that may be unresectable but need a little bit more of that response to radiation? And could that be combined with immunotherapy? So there are different ways that I think those are just a couple of the settings in addition to soft tissue sarcoma, which has already been studied with R3, but I think that's another area that would be really nice to continue to look at.

Great, thank you.

Yes. And I would just add to that, I completely agree. And one of the nice things about the nature of the injection is that it engages specialists beyond head and neck cancer. So our interventional pulmonologist has injected a lot of R3, our interventional radiologist for liver metastases, for example, has been very engaged, and that's generated enthusiasm across the multidisciplinary subtypes, even if they're not within our head and neck cancer tumor board, but in parallel, other disease-specialized tumor boards. And we do get referrals for lung -- metastatic lung cancer patients, melanoma and such for consideration for R3. And so I think awareness of this beyond head and neck is taking hold.

Does anyone have any further comments? There are no further questions that I see from covering analysts. Anything else that Dr. Shen or Dr. Rosenberg or you, Sebastien, that you want to comment on? All right. Well, I thank everyone for their attendance. That concludes today's presentation. Thanks again for your participation.