DR SMITH: It is an interesting story. Cabozantinib, or XL-184, is a tyrosine kinase inhibitor that hits a variety of targets, VEGF receptor, MET and RET. It significantly increases progression-free survival in medullary thyroid cancer and is approved in that setting. It’s also shown activity in a variety of other malignancies, including prostate cancer.
At ASCO, we presented data from a nonrandomized expansion cohort study of cabozantinib. And there are a couple of important differences from the prior parent trial.
They were a more extensively pretreated population. All the patients had received prior docetaxel. About a third had also received abiraterone.
About 25% had received cabazitaxel.
Great burden of disease. Median CTC count was about 50. And another important feature of the trial is that we prospectively defined bone scan response based on a computer-assisted method for assessing bone scan lesion area.
What we observed in the trial was a high proportion of patients had bone scan responses defined.
About two thirds of patients met that endpoint. Only about 10% of patients had progressive disease as their best bone scan response. There were few RECIST responses in measurable sites of disease, although 80% of patients had improvements in measurable sites of disease.
PSA often did not correlate with other presumably antitumor outcomes, although it was very gratifying in this trial to see that there was a high proportion of patients who had improvements in CTCs, with about 40% of patients with elevated CTCs converting to normal.
There was other evidence of antitumor activity, including symptomatic improvement. There were also improvements in other biomarkers, including biomarkers of bone turnover.
Importantly, the drug has side effects like other TKIs, with the major ones being fatigue, nausea, diarrhea. And about 80% of the patients on this study with a starting dose of 100 milligrams required 1 or more dose reductions.
DR LOVE: Can you talk a little bit more about one of the things that got so much attention, the bone scans, in terms of what’s going on? Is this just purely antitumor effect or some effect on bone?
DR SMITH: My best understanding would be that it’s an effect on both tumor and bone. There’s a variety of ways you can support that observation. In the past, I used to say that bone scans don’t improve, certainly in the metastatic CRPC space. And really, we only saw dramatic bone scan improvements in a rare patient with a very dramatic antitumor response — for example, to docetaxel or another highly active agent.
But with this drug, we consistently see marked improvements in bone scans. These are very early changes. And they are reversible with discontinuation of the drug. So I don’t believe it’s an entirely antitumor activity. I think it’s a combination of the antitumor effect and potent effect on bone.