Shreyaskumar R. Patel, MD: Following a patient’s journey, the orthopedic surgery team has had their chance at it a couple of times, the patient’s being discussed at the multidisciplinary conference, and the collective decision is that we need to do something other than surgery. Walk us through what molecular genetic testing would you order, Bob, and can you walk us through the rationale for CSF1 [colony-stimulating factor-1] receptor inhibition?

Robert G. Maki, MD, PhD: The more you look, the more you find, and we haven’t always had the great molecular genetic tools that we now have access to. Happily, at least for this diagnosis of tenosynovial giant cell tumor [TSGCT], you don’t need those. Our pathologists can generally identify these with simple immunohistochemistry. On a research basis, at least, we’re understanding more about these tumors and what, at first glance, looked like something pretty simple may actually end up being more complicated. Although at the end of the day, CSF1 receptor blockade is the answer to these problems.

The initial work was done about 10 years ago. The first paper came out from Stanford University and showed that there was a translocation between chromosomes 1 and 2, which led to activation and production of CSF1 in these tumors. It turned out that when you have a lot of CSF1, it is not just causing growth of the tumor on an autocrine basis; it’s basically serving as a signal beacon for other cells to come into that area, and they get a very strong proinflammatory response by the nature of having a lot of CSF1 around. It may be trophic, allowing the tumor cells to grow themselves, but also brings in a very brisk lymphocytic infiltrate and secondary cytokines that arise from that.

There is some new work showing that there are different translocations that can be involved in these tumors, and it’s not entirely clear that it’s the collagen gene that’s driving this. There may be some other reason for having extra CSF1 around as shown by some recent work, but by and large, you’ve got more CSF1 around, and that’s what’s driving the tumor growth and a lot of the symptoms of this tumor.

Shreyaskumar R. Patel, MD: That’s a wonderful hypothesis and that leads to hypothesis driven research. Ever since we’ve known about the CSF1 receptor overexpression, we’ve used the weaker agents that we’ve had available to us to try to treat these patients. We’ll come back to that a little bit later, but clearly a more potent and specific CSF1 receptor inhibitor was approved by the FDA for the treatment of patients with symptomatic and advanced tenosynovial giant cell tumor. Let me see if Dr D’Amato can walk us through the FDA approval, the trial design, and some of the evidence supporting the use of pexidartinib [Turalio] in patients who do require systemic therapy. Gina?

Gina Z. D’Amato, MD: Pexidartinib was FDA approved, and this was based on what we call the ENLIVEN clinical trial, which was a multicenter randomized, double-blind placebo-controlled, phase 3 study. Patients had to have symptomatic TSGCT, which we used to call PVNS or pigmented villonodular synovitis. Now we’ve changed it over to TGCT, and these patients were deemed unfit for surgery. Patients were randomized in a 1:1 fashion. They were given Turalio, 400 mg in the morning and 600 mg in the evening, and then 400 mg twice daily. That was based on part 1, and then part 2 was 400 mg twice daily.

Overall response rate was the primary end point using RECIST [Response Evaluation Criteria in Solid Tumors] criteria, and the secondary end points were overall response rate by tumor volume score, mean change from baseline, range of motion, and duration of response. As Dr Abraham discussed, the majority of these patients do have knee as their primary location. That was 61% with the ankle, and 18% did have a foot and wrist. The majority did not have prior systemic therapy, although 9% did. It was split where some patients had prior surgery where others did not, and the majority were diffuse type.

The overall response rate by RECIST criteria was 38% versus 0% in the placebo, with a 15% complete response rate, which is really astounding. About 80% of these patients were on it for more than 6 months and two-thirds were on it for over a year. We looked at tumor volume, which is difficult to measure by RECIST criteria. As we know, RECIST criteria are the sum of the longest diameters, but these aren’t always perfectly round tumors; that’s the reason for the name, diffuse. It’s hard to measure. If you look at tumor volume, that’s a better way to measure that, and by tumor volume the response rate was 56%, so that’s very impressive as well. There was also a significantly improved range of motion compared to the placebo. Those are the efficacy data.

Shreyaskumar R. Patel, MD: This is an important summary. The response rates were good, the tumor volume reduction was good. I think this brings up the difficulties of RECIST response rates in oncology in general. I think at the end of the day, what matters to the patient is symptom control, improvement in range of motion, stiffness, and PROMIS [Patient Reported Outcome Measurement Information System] scores, if you will. I think the trial does indeed show a broad range of benefits that these patients experience, which was obviously the reason why the drug got approved.

Transcript Edited for Clarity