Expert on Utomilumab in Anaplastic Thyroid Cancer, Other Solid Tumor Types

In an interview with Targeted Oncology, Anthony Tolcher, MD, Director of Clinical Research at START, discusses the 4-1BB agonist utomilumab. Tolcher points out that utomilumab is one of the first treatments to show any kind of efficacy in anaplastic thyroid cancer, though data for patients with melanoma are largely absent from the findings due to a lack of participating patients.

TARGETED ONCOLOGY:Can you give an overview of the recent phase Ib study of utomilumab in combination with pembrolizumab in patients with advanced solid tumors?

Tolcher:Essentially what this study represents is a combination of utomilumab, which targets the target antigen 4-1BB involved in T cell stimulation, with pembrolizumab, which is the PD-1 inhibitor. The goal is really to test the safety of the combination and to understand the pharmacokinetics and dynamics, as well as to see anti-tumor activity. That's what the abstract is essentially about.

A recent presentation also shows that the combination can be given safely throughout the entire dose range. There is no drug-drug interaction between the two antibodies, and we show that there's a trend towards the fact that responders tended to have more CD8 T cells in the blood compared to the non-responders. There might be an early signal that after treatment, those responders also had a big increase in interferon gamma.

Probably the most important aspect that people tend to want to look at is the response, even though that's not a primary endpoint of the study, but there were a number of different responses including a couple of complete responses and four partial responses. There were also some unconfirmed responses. There were responses in small cell lung cancer, and there was a complete response in renal cell carcinoma.

More interestingly, and perhaps most importantly because it's so difficult to treat, is a response in a patient with anaplastic thyroid cancer. That's pretty important because this is the first time that anaplastic thyroid cancer has been shown to respond to a PD-1 inhibitor in a combination regimen. This is a disease where there's no useful therapy, and it tends to be aggressive in most patients, who die within a few months. This is something that's very interesting and may be important to the community, especially the community of patients who have anaplastic thyroid cancer.

Overall, it's an early study. At this point we can't really say much beyond the fact that it's safe. It appears to be active, and later studies will ultimately demonstrate whether or not it's more effective, equally effective, or less effective than just giving pembrolizumab alone.

TARGETED ONCOLOGY:Was this combination tested on patients with any other cancers?

Tolcher:The patient population was about 23 total. There were some responses in another renal cell carcinoma patient and another lung cancer patient, although their responses were partial. The important point is that there were very few melanoma patients in the study. Although most people would be interested in seeing if utomilumab did improve with pembrolizumab in melanoma, the study coincided with the approval of pembrolizumab and nivolumab (Opdivo).. What actually happened was most of those patients actually went on to get newly approved PD-1 inhibitors. So there are very few patients that came in with melanoma.

From our standpoint, it's really too early to tell if it's going to be more effective or less effective in the melanoma population because we only had 1 patient with melanoma. Even though that would've been a population of interest, it really wasn't included in the study due to circumstance of the breakthrough status and approval of the PD-1 inhibitors.

TARGETED ONCOLOGY:Can you tell us about the mechanism of action of utomilumab?

Tolcher:This is actually what's called an agonist antibody. The complex story is that it binds onto 4-1BB and sends that signal through that pathway, so it's actually turning on T cells. That's in distinction from pembrolizumab, which actually blocks PD-1. The best analogy I can think of is that it's a bit like if pembrolizumab turns on the brakes for immune tolerance; it makes the T cell no longer tolerant to the tumor, and this tries to turn on the gas T lymphocytes. So you're trying to act on those two pathways by increasing the T cell activity, as well as blocking the mechanism by which the tumor avoids the immune system.

It's one of the first of the combinations where we're trying to target the cancer from two different approaches. That's going to be particularly important for us because we know the vast majority of patients, even with melanoma, lung, kidney, or bladder cancer, do not respond to therapy targeting PD-1 alone. So there's a large number of patients in those disease states, as well as many of the other disease states that aren't sensitive to PD-1 inhibitors, and we'd really like to move the field towards seeing if we can improve upon that by increasing immune response to tumors in those patients that have otherwise unsatisfactory responses to PD-1 inhibitors.

TARGETED ONCOLOGY:What are the next steps following this study?

Tolcher:The clear story at least at the end of this study is that it's safe, so one can look at potentially phase II and phase III studies in the future.

TARGETED ONCOLOGY:Would it be worth looking into other combinations with this agent?

Tolcher:I think to some degree, this safety of utomilumab is probably transferrable to whatever PD-1 inhibitor it's going to be combined with. The good news at least with the PD-1 inhibitors is that there's not a lot of evidence that there are significant differences between t many different ones that are out there. So in reality, the safety data should support it being combined in later studies, if it's going to be combined with other agents like nivolumab.

TARGETED ONCOLOGY:Can you tell us about the safety profile of this treatment?

Tolcher:There were no grade 3 and 4 toxicities in more than 15% of patients. So there's not a big, strong signal of synergistic toxicity. There were a couple of patients who did have grade 3 and 4 adverse events. One patient had adrenal insufficiency and another had low potassium, which happened on study, and whether or not it's related to the combination is not clear.