NBTXR3 Well Tolerated in R/M HNSCC, With Early Efficacy Signals

The unmet need for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rooted in a lack of effective treatment options. Immunotherapies, such as immune checkpoint inhibitor (ICI) therapy, continue to yield poor responses and prognosis in this population; for those who do not respond or are resistant to immunotherapies, the pool of available options narrows down to chemotherapy and symptom management, compounded by the existing toxicities from previous therapies.¹

The advent of radioenhancers, such as the novel agent NBTXR3 (JNJ-1900), represents a potential paradigm shift in addressing this need. Composed of functionalized hafnium oxide nanoparticles activated by radiotherapy, NBTXR3 is designed to amplify the effects of radiotherapy and enhance local control of tumors.

In 2020, NBTXR3 was granted fast track designation in locally advanced head and neck cancers. Since the designation, the agent has been launched in numerous trials and signified potential across multiple tumor indications, most recently in melanoma and R/M HNSCC, underscoring its diverse clinical applications and scalability. The phase 1 Study 1100 (NCT03589339) evaluating NBTXR3 followed by standard radiotherapy and anti–PD-1 therapy of pembrolizumab (Keytruda) and nivolumab (Opdivo) in R/M HNSCC² recently demonstrated tolerability and preliminary efficacy signals in 2 cohorts that were either naive or resistant to prior anti–PD-1 therapy.

In an interview with Targeted Oncology, Colette Shen, MD, PhD, assistant professor at the University of North Carolina (UNC) Chapel Hill and radiation oncologist at the UNC Lineberger Comprehensive Cancer Center, delved into the background of NBTXR3 and findings from Study 1100, the unmet medical needs of this patient population, study methods and key findings, and shared potential areas for future investigation.

Targeted Oncology: What are the unmet needs in this patient population that prompted this research?

Colette Shen, MD, PhD: This [study’s] patient population is patients with recurrent or metastatic [HNSCC]. In general, we have limited options for these patients; they have already had a lot of local therapies, sometimes multiple surgeries, and quite a bit of radiation treatment. So, when they develop recurrent disease, whether it's recurrent in the area [where] it was before, which we call locoregionally recurrent, or if it's metastasized to other areas, they have already had a lot of treatment, and it becomes harder to give more treatment without adding their toxicities from the treatments they've had.

Starting with patients who have locoregionally recurrent disease, those patients oftentimes already have a lot of [adverse effects] from their treatment, whether it's trouble with swallowing, dry mouth, and being able to get the calories that they need on a daily basis, and then adding to that, [a tumor] that [has] grown back already in the same area [of] treatment may affect those types of functions more. If you have a tumor that's growing in your throat, lymph nodes, [or] neck, those can just cause a lot of symptoms by themselves…impacting swallowing, speech, and taste, and then additional treatment on top of that would affect those functions too.

When patients develop metastatic disease, usually we think about drug or systemic therapies. There's a lot of potential promise with immunotherapies right now, but most patients don't necessarily respond well to immunotherapies, with only less than 20% of patients who typically have a good response to immunotherapies. So, for the majority of patients who don't respond to immunotherapies, we're left with either more conventional chemotherapies to try to control the disease or just more palliative treatments, where we're giving radiation, more for symptom management, so their options are very limited.

That's what prompted this research: to try to provide a treatment to control locally where the tumor had developed, whether locoregionally in the area of the head and neck where it may have been before, or a metastatic site. Radiation treatment in general can help provide good local control of tumors where they developed. The other purpose of this particular study was to try to reinvigorate a response to immunotherapy using a form of radiation that's perhaps a little bit more enhanced with nanoparticles.

How does NBTXR3 work mechanistically?

Hafnium oxide nanoparticles [are] actually inert on [their] own.…When they are injected into the tumor and encounter radiation, they absorb radiation in such a way that enhances the effect of the radiation around the area that the radiation is given. That's why it's called a radioenhancer.

Typically, when we give radiation, radiation interacts with water in tissue, creat[ing] a lot of electrons and what we call reactive oxygen species, which indirectly damage DNA and tumor cells. When these nanoparticles are in the tumors that we then give radiation to, the radiation interacts with those nanoparticles in a way that [generates approximately] 9 to 10 times more electrons or reactive oxygen species...with that interaction. So you can think of the radiation potentially being up to 9 to 10 times stronger immediately around the nanoparticles. The benefit of that is that we're potentially generating a lot more tumor cell death and DNA damage around the nanoparticles, without increasing the damage or toxicity of radiation closer to some more sensitive structures near where the tumor might be.

What was the study’s design?

This study was a phase 1 dose-escalation and dose-expansion study. The first part of the study was to find the safe dose of [NBTXR3] to be injected. The dose was measured by the volume of [NBTXR3] within the tumor, starting out with lower doses and then increasing to higher doses. As we did that dose-escalation study, there was no dose-limiting toxicity seen at the highest dose that was tested, which [was] at 33% volume. So that's the dose that was selected for the remainder of the dose-expansion phase 1 trial.

[Because] it [was a] phase 1 [trial], there was no randomization, and the efficacy end point [came] as we were treating more patients in the dose expansion portion and continuing to look at toxicities. The study design was such that we enrolled patients with recurrent or metastatic [HNSCC]. We allowed patients to have had prior anti–PD-1 therapy and developed resistance to that therapy—so patients who didn't end up responding to that therapy—or patients who had not had prior anti–PD-1 therapy.

Then, patients all had an injection of the hafnium oxide nanoparticles on the first day of the study treatment. And that was done, typically, to 1 tumor and as a 1-time injection. After that, usually about 1 to 2 weeks later, they would start their radiation treatment, which could be anywhere from 3 to 5 sessions of radiation in the form of stereotactic body radiation [SBRT]. The next day, following completion of radiation, they started their anti–PD-1 therapy, and that continued for as long as the patient was having a response and not having toxicity.

What were the safety and efficacy findings, and were there any findings that surprised you or stood out as an important clinical implication?

In terms of safety, the treatment combination was safe. We saw pretty much expected adverse events, treatment site injection-related events, some pain at the injection site, and very standard [adverse] effects or toxicities related to anti–PD-1 therapy. So, nothing really jumped out there. In fact, I think the fact that it was very well tolerated for most patients was reassuring to see. Most of the patients we treated mentioned how well they did with this therapy compared with some of the other treatments they had had.

In terms of efficacy end points, I would say the main thing that was more surprising to me was that there were quite a few patients who had previously developed resistance to anti–PD-1 therapy who had some long-term response to this combination. These are patients who, if we had continued anti–PD-1 therapy, probably would not have done very well. But I think the fact that those patients who had developed anti–PD-1 resistance had some good outcomes and very favorable overall survival compared to what's been in the literature was a very nice, surprising, perhaps less expected finding.

I think the other thing we noticed was that there were a few patients who [had] responses outside the tumor that was injected with a nanoparticle and irradiated. We [saw] some out-of-field responses, which is not very common to see, and especially in those patients who may have developed resistance to prior anti–PD-1 [therapy], those responses couldn't really have been attributed to just the anti–PD-1 therapy. That response suggested to us that there may be some broader systemic response to this treatment, rather than just at the site that was given radiation and injected with a nanoparticle.

What are the next steps in this line of research? What questions do you wish to further investigate?

For this particular patient population—those with recurrent and metastatic [HNSCC]—I think we will need to [think] about a randomized trial with and without [NBTXR3] to really tell whether this agent is contributing to the responses we're seeing. It's one thing to see something in an early-phase trial; it's another thing to demonstrate, in a randomized fashion, whether this agent is generating a significant response as part of the combination therapy.

In terms of other [questions]….Many of the patients who we treated on this trial may have already had other lines of systemic therapy [or] rounds of previous surgeries or radiation. So, [would we] want to be thinking about [NBTXR3] earlier in the course of treatment?

We are [also] looking at our existing study data [and whether] there are other patient populations who may or may not benefit more. For example, we're looking at patients who had human papillomavirus [HPV]-positive or -negative disease. Was that a driver of response?

In general, we are noticing that the patients we treated on this trial had limited metastatic disease, if they did have metastatic disease, and I think that makes sense given the mechanism. We're really focusing the radiation on a single spot, not treating all the different spots, and we're using that in combination with immunotherapy to try to generate a response elsewhere. But it doesn't really make sense for patients who have widely metastatic disease. We are [also] thinking about whether it makes sense to do multiple injections or radiation to multiple sites, as opposed to just 1.

In terms of next steps, [NBTXR3] is being looked at in a randomized trial right now for definitive treatment of head and neck cancer, [HNSCC], for cisplatin-ineligible patients. There's a study that's being planned for cisplatin-eligible patients in combination with chemotherapy and radiation. So, there are randomized trials in head and neck cancer already underway.

Regarding the scalability of NBTXR3, are there plans to prioritize other tumor types in future studies, and how would this study’s findings inform such research?

This trial had another arm for patients with non-HNSCC, so we are awaiting the results from that arm to decide what other tumor types we want to continue this with moving this forward. I think melanoma, for example, is a promising area that we may want to pursue more.

This agent is being looked at across multiple tumor types. There is a randomized trial for non–small cell lung cancer in the definitive setting; there are studies in esophageal cancer [and] pancreatic cancer. So, because this agent is intratumorally injected and tumor type agnostic, there are a lot of different ways that this can go. We're eagerly awaiting the results from those studies to see where it makes the most sense to move forward in future directions.

REFERENCES

1. NANOBIOTIX announces updated phase 1 results continuing to support JNJ-1900 (NBTXR3) plus anti-PD-1 as a potential new 1L or 2L+ option in anti-PD-1 naïve or resistant R/M-HNSCC. News release. Nanobiotix. September 29, 2025. Accessed October 8, 2025. https://tinyurl.com/yc6xbwu9

2. NBTXR3 activated by radiotherapy for patients with advanced cancers treated with an anti-PD-1 therapy. ClinicalTrials.gov. Updated January 14, 2025. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT03589339