WCLC 2022 | Increased PD-L1 tracer update in recently-irradiated lesions in NSCLC

We developed this study because of the PACIFIC trial. This is a large clinical trial that showed that patients with stage three lung cancer who received adjuvant immunotherapy with an anti PD-L1 antibody after they’d completed chemoradiation had a much better outcome than patients who didn’t get the immunotherapy. And this immunotherapy, it even worked when patients had low levels of PD-L1 based on their biopsy. So, my colleague, Fiona Hegi-Johnson and myself thought this is strange how come the treatment works and when the target isn’t there? So, perhaps the biopsies aren’t representative and perhaps things change over time. So, how would we find out the answer to this question? Well, what if we had an imaging agent that would allow us to see how PD-L1 and the tumor changes over time. So, on the back of an envelope, we came up with the idea of the immunoPET study, which involved attaching a radioactive isotope to the durvalumab molecule.

And then following it over time to see what happened when patients were treated with chemoradiation. So, we got some grant funding and we had fantastic radiochemistry team at the University of Melbourne who led by professor Paul Donelly. They helped us create this new tracer. So, the tracer consists of the durvalumab antibody, the therapeutic agent links to zirconium 89, which is a long half-life tracer by a special linker molecule, which was developed at the University of Melbourne to create our tracer. So, this tracer worked brilliantly in mice. Image PD-L1 positive tumors with great clarity and the tumors that were negative for PD-L1 didn’t take up our tracers. So we thought, perfect. So, we go ahead and design a study.

So, we received some support from AstraZeneca to do a Phase I study in which we will treat 20 patients with stage III lung cancer with chemo radiation, and we’ll do a PD-L1 PET scan at the start, and we’ll do another PD-L1 PET scan during treatment to see what’s the distribution of PD-L1 in the tumor at the beginning of treatment and how that changes over time. So, in order to commence that Phase I study, we needed to do a Phase 0 study, which is a safety study and also to work out how the tracer is distributed in the body.

So, we have conducted our Phase 0 study and five patients with metastatic non-small cell lung cancer. So, the aims of the study weren’t really to study any biology, it was simply to see how the tracer performed and just confirmed that it was safe. So, in the five patients that we treated, the tracer was perfectly safe, but it produced some beautiful images of the distribution of tumor in the patient. So, the patients all had to have stage IV, lung cancer with a known PD-L1 concentration of at least 50% in the tumor. So, our very first patient had received radiotherapy to several of their metastatic lesions just before the tracer was injected about a week before the tracer was injected, and they’d also received stereotactic radiosurgery to two of their brain metastases.

So, we were astonished when we saw our images as the tracer gradually developed uptake in all of the tumors that you could see on the FDG-PET scan. We saw that the tracer was being taken up in all of the tumor sites, but more intensely in the tumors that had been radiated. So, that was an unexpected discovery and it was consistent with our clinical trial aims to show differences between radiated tumors and un-radiated tumors. And the other exciting thing about this was that we could image tumors in the brain. So, ordinary PET scans with FDG aren’t good for detecting metastasis in the brain, but we were able to see brain mets with our PD-L1 PET scan.

So, that was our very first patient. And by chance, our fourth patient had also received some radiation around the time of their imaging. And they told the opposite story, which is also intriguing. So, this is a patient with stage IV non small cell lung cancer, who had been on immunotherapy immune checkpoint inhibitor therapy for a year and had a complete response, but gradually began to get progressive disease in lymph nodes. And then a tumor in the chest began to grow really fast and became very big. And that patient was enrolled in our study and around the time that they were enrolled in the study, they started to receive some radiation. And the PD-L1 distribution in this patient was fascinating because the fast growing tumor that had escaped from the immunotherapy was cold on our PET scan.

So, it no longer showed uptake of the target of the immunotherapy, suggesting that the reason why the immunotherapy was failing was that the tumor had changed. And it was no longer expressing PD-L1. And even doing radiation didn’t seem to change that, because even though we were treating this tumor with radiotherapy there was no change… There was no significant PD-L1 uptake. So, these are just two anecdotes from a study of five patients. We weren’t expecting to find anything of interest in this phase zero study, but we thought that these findings were fascinating and we thought we should present them.