Martin H. Voss, MD:How do we then decide which second-line regimen to use? I think there are several factors that can be helpful, and it’s not that there’s the 1 decision factor that should drive a decision. Certainly, the experience that patients have had with first-line therapy would go into that decision making. So, for example, patients who have been on kinase inhibitor therapy for an extended period of time with significant toxicity may be better suited to then sequence over to I-O therapy with single-agent nivolumab, which tends to be tolerated quite well. Vice versa, patients who have done very well with TKI therapy with limited toxicity may benefit from continuing that strategy with another VEGF-directed kinase inhibitor, as it has been shown that these can be applied serially.
Again, we can return to cabozantinib as a drug that may have unique activity in patients with bone metastases. And I would not base that so much on the subgroup analyses that have been done off of METEOR because there are subgroup analyses off of other trials like CheckMate-025 that also suggest superiority over everolimus for immunotherapy. But I do think that all the data that are there from preclinical modeling and from serum samples that have been collected as part of cabozantinib development suggest an effect on osteoclast biology, and the remodeling in the bone should be considered. So, I do think that patients with a big burden of disease, including osseous metastatic disease, might be good candidates for cabozantinib therapy. There are no biomarkers that really drive decision making in that space. It has not been proven that immunohistochemistry for PD-L1 must drive decision making towards single-agent nivolumab over these other agents that we have discussed.
c-MET signaling, MET being a target for cabozantinib, has been investigated in terms of the outcomes seen on the various cabozantinib trials. But, again, that has not been compared to other kinase inhibitor trials or immunotherapy. So, there is no biomarker that helps with decision making. I do think that comorbidities are quite relevant. Patients with poorly controlled hypertension are not great candidates for kinase inhibitor therapy. Patients with poorly controlled diabetes may not be the best candidates for lenvatinib/everolimus combination therapy knowing that Afinitor (everolimus) can cause worsening of the glucose intolerance. Again, as mentioned before, patients with an autoimmune disease, specifically those with systemic autoimmune disease that have acquired immunosuppression in the past, should not be considered up front as candidates for I-O therapy if other alternatives can be considered.
Transcript edited for clarity.