A Look Inside CONVERGE: Intratumoral Therapy Comes to Locally Advanced NSCLC

David DiBardino, MD, an interventional pulmonologist at the University of Pennsylvania, discussed the emerging field of intratumoral and tumor-directed therapy in non–small cell lung cancer (NSCLC), including the rationale behind combining a radioenhancing agent with chemoradiation and durvalumab (Imfinzi) in the phase 2 CONVERGE study (NCT06667908).¹

Targeted Oncology^TM: For those who aren't familiar, how would you describe intratumoral therapy and where it fits relative to more systemic treatments?

David DiBardino, MD: The way I frame it is you have to go back to the cancers that led the way on systemic immunotherapy: melanoma and lung cancer. People sometimes call these tumors immune-sensitive or immune “hot,” meaning they carry a lot of genetic mutations that let the immune system recognize them as foreign. That's where systemic immunotherapy and targeted therapy in cancer really started, and the story that's emerged over the past 20 years is that it can work incredibly well, which is fantastic and a huge medical breakthrough, but it's also been frustrating, because it left the door open to an unmet need: Why aren't more patients with these immune-sensitive tumors responding to systemic immunotherapy? That logically led to the idea of: What if we just gave more? If some checkpoint inhibition helps 20% to 30% of patients, could giving more push the response rate up to 50%? And to frame that again, the gap in the number of people responding represents a massive unmet need in locally advanced and malignant tumors of those types.

The problem is that giving more systemically doesn't work that well; toxicity becomes the limiting factor. That's how I frame intratumoral therapy, because the next logical question is: What if you give more, but only at the tumor? Initially in melanoma that made a lot of sense, because there are often lymph node metastases visible on ultrasound and skin lesions you can reach with a subcutaneous or skin injection, so melanoma pioneered and led the field. Lung cancer lagged behind, even though you could argue the unmet need was greater, because it just hasn't been easy to inject tumors in the lung. The lung is moving during procedures because the patient is breathing, and the techniques we've had available to localize equipment during bronchoscopy, or a needle through the skin into the chest, were more limited. A lot of that work has now been done, and our ability to localize equipment inside the chest has come a long way, which has really helped launch the same idea in lung cancer: Can we concentrate antitumor treatments in the tumor itself, limit toxicity, and get more patients to respond—maybe pairing it with systemic therapy, maybe on its own? The number of ways you could apply this is enormous, and it's a really exciting, logical next step in the field. Some of this is ready for human research now, and we're at the tip of the iceberg in terms of what we can do and whether it's going to work. It's a really exciting time.

When we talk about standardization of intratumoral drug therapy, what does that actually mean: technique, imaging, workflow, dosing?

DiBardino: It's a bit of a clean slate. One of the daunting parts of intratumoral therapy is that even though all those logical reasons make it seem like a great idea, we don't really know much yet about standardization of delivery, and that's probably going to differ depending on the asset you're injecting. It's a can of worms: There's dosing, frequency, and concentration. Should that concentration deliver a set amount of antitumor medicine, or should it be proportional to tumor volume? Once it's injected, does it stay there, or does it end up in the bloodstream the way it would if you gave it [intravenously (IV)]? Then there's the procedure itself: Are you actually getting the asset into the tumor to begin with? Is the procedure reliable enough that you're delivering it without the drug leaking or coming back out of the tumor? Is the tumor capsule strong enough to receive additional liquid volume without cracking or fissuring? What about lymph nodes vs tumors vs organs? It's a black box we're still sorting out.

We have translational research goals to help delineate some of this, but there's also the question of whether drug efficacy in clinical trials will tell us whether these dosing and standardization choices are working. Are we taking what we know from translational work and coming up with a standardized procedure we think is reproducible and gets the medicine where it needs to go, and then, if it's working, retrofitting the assumption that it must be getting there at an appropriate dose, being retained, and not extravasating? There's tension between doing more translational work to delineate that vs letting efficacy research—with a good safety profile—answer both questions at once.

There's actually a cautionary tale developing in melanoma that we need to take into account as we move into lung. Melanoma has been the model disease for this kind of therapy, and some of the promising assets have worked and even reached commercialization recently, either alone or paired with systemic immunotherapy. But other assets looked promising in every phase 1 and phase 2 trials, and then didn't pan out in phase 3. When those studies have been scrutinized, one comment I tend to agree with is that the procedure manuals—the standardization of injecting the tumors—may have been too loosely defined and weren't reliably getting the asset into the tumor with meaningful retention. So, we need to be careful about relying only on efficacy study design and assuming retroactively that procedure standardization was good enough, because it's a huge investment in time, energy, and money to go straight to an efficacy trial only to find out the study may have been biased toward the null because the procedure manual wasn't rigorous enough. There's tension there, but I think we're really starting from scratch with the limited translational research we have, and building from there.

Can you discuss the CONVERGE study and its design?

DiBardino: CONVERGE is a study in locally advanced NSCLC. To put it in the framework I've been describing, it's a phase 2 safety and efficacy signal study, so it's not looking at whether we can translationally deliver an antitumor asset; it's looking at end points like safety, feasibility, and efficacy against a control.

There's a real unmet need being addressed here. In locally advanced NSCLC, the standard of care for patients who aren't surgical candidates is concurrent chemotherapy and radiation for about 6 weeks, followed by about a year of durvalumab [Imfinzi]. In that setting, the objective response rate is around 30% in the clinical trial literature, with 2-year survival rates around 50% to 60% under ideal conditions. So there's a big unmet need: roughly 70% of patients on that difficult-to-tolerate regimen don't have an objective response in their tumors.

Part of the reason is that the radiation dose in those regimens—about 60 Gy total—is close to the maximum tolerable dose; you can't really push it higher, with some nuances related to anatomy. For the purposes of this discussion, you're not going to get around the lack of efficacy in this disease by giving more radiation. But we know radiation generally works well in NSCLC, so CONVERGE tries to get at that logic by giving a radioenhancing agent—NBTXR3 [JNJ-1900], a hafnium oxide nanoparticle—designed to generate more reactive oxygen species, or radiation-mediated cell death, than the molecules radiation normally relies on in a tumor, which is essentially water. So it's a radioenhancer that could make radiation work better, and it can be injected into any known tumor—mediastinal lymph nodes or the primary tumor in the lung itself—which, for locally advanced lung cancer, are the areas affected.

The study is split into 2 parts. There was a small part 1 of 7 patients, that we just presented, dealing with procedural standardization, feasibility, and reproducibility. The study as a whole will enroll 120 patients and is randomized: one-third get standard-of-care treatment alone [consisting of] chemotherapy, radiation, followed by durvalumab; one-third get the same regimen plus a single injection into all injectable tumors with a lower dose of the radioenhancing hafnium oxide nanoparticle; and one-third get the same chemotherapy, radiation, and durvalumab plus a higher dose of the radioenhancing drug. That lets us compare safety signals between patients who don't get the injection and those who get it at 2 doses, and start to hypothesis-generate about efficacy in a study that, as a phase 2, is fairly large.

It's exciting because the study addresses procedural standardization first, in part 1—the small run-in part, where we used our best guess in a procedure manual for the best way to do this injection for this specific asset—and confirmed it was reproducibly feasible. Again, we're literally starting from scratch. But if that first run-in phase looks promising, in terms of reproducibility and the injection being delivered where we wanted and retained, then the larger study isn't about refining the procedure anymore; it's about the safety and efficacy hypothesis-generation outcomes.

How does multidisciplinary care have to come together for a trial like this?

DiBardino: In a lot of ways, the anticancer approaches in intratumoral therapy are novel, and beyond the problems I mentioned in the clinical trial piece, and even eventually in operationalizing or generalizing these techniques for commercial use, there's another opportunity to work together more closely. In clinical care we already work together quite a bit in lung cancer, but we still have fairly separate silos. Things like radiation planning software, radiation dose, and contouring radiation fields are generally something the medical oncologist or interventional pulmonologist will know about or have input on, but with intratumoral therapy it becomes much more nuanced than that.

We need to get together more with the medical oncologists, who often quarterback treatment regimens that include systemic therapy and radiotherapy, and make sure they're aware of these new options in this brand-new field of tumor-directed therapy, and help us understand what competing options patients have and where intratumoral options might be better prioritized in clinical trials or eventual commercial use vs other new systemic options. We really need their help understanding that full landscape. And working with the radiation oncologists is more intimate now too, because they can help us understand their concerns about dose, contouring, and simulation mapping, which is directly related to a radioenhancer like this one.

The old model was a standard clinical care model where there were touch points together at the beginning, and then a treatment regimen was assigned and everyone went along in their own silo. Now it's much more frequent touch points: a proposition about whether the medicine might help the patient and whether they're appropriate for the study or treatment; then a touch point about radiation mapping; and then, throughout the trial, touch points about toxicity, safety issues, and how to interpret the CT scans as we go—things we usually wouldn't necessarily talk about as often, but now we're talking about more and more. It's brought us together in a way that's been really fun. It's a lot of effort, and that can be difficult at times, but it's been overwhelmingly positive to be brought together more intimately. As an interventional pulmonologist, it's probably been the most fun for me, because I'm much more active in learning about medical and radiation oncology than I've been before, and I love learning new things. It's helped us all come together so much more and work together in a lot of ways. It's been really fun.

Where does enrollment stand, and what have the early data shown?

DiBardino: We're over halfway done enrolling the full 120-patient study, and enrollment globally has gone well. We're excited to get the final outcome measurements with a control arm; it's a really informative study design. Moving forward, given the clean slate we're dealing with, it's nice to have CONVERGE as a starting point for procedural standardization, for how radioenhancing clinical trials might look, and for how you define procedural success in this space. It creates a little ground to stand on as we move forward.

The objective response rate is something we're measuring as a hypothesis-generating signal about efficacy, to see whether a phase 3 definitive efficacy study, with a larger number of patients, should be done. We've only analyzed part 1 so far, the first 7 patients, but it's quite interesting and eye-catching: 6 of 7 patients had an objective response, against a historical control of around 30% for that treatment paradigm. It's eye-catching, and I'm eager to see where it goes.

As we look at these first well-designed, larger studies, there's always a question of what's been done before; this isn't the first study ever injecting tumors in lung cancer. One thing that has me excited is that there are roughly 3 to 4 dozen lower-quality feasibility and pilot studies in this space, across a wide range of patient populations and assets, that were really just early data asking whether this is safe and feasible at all. Those studies typically had small numbers, mixed populations, and fairly chaotic procedural protocols, so you'd logically expect them to be biased toward not showing much of an effect at the tumor level, in terms of tumor shrinkage. But surprisingly, even in those studies, there's a consistent signal of tumors shrinking, even with the most rudimentary assets and injection techniques. It really is exciting to think that in a cancer with a lot of unmet need, where the toxicity of the most effective therapies is high, we could really be onto something here. I think the future is bright, and, like I said, we're at the tip of the iceberg. I say that in part because there are a lot of reasons to think this might work, and we're just really excited about it.

REFERENCE

1. A Study of JNJ-90301900 in Combination With Chemoradiation Followed by Consolidation Immunotherapy for Non-Small Cell Lung Cancer (NSCLC). National Institutes of Health. Accessed September 18, 2026. https://tinyurl.com/45j9rs6h