The nonrandomized data look promising with T-VEC plus PD-1. However, the groups of patients in that study are a different group than those who are treated in most clinical trials because these are all patients with injectable disease. It is hard to compare nonrandomized T-VEC data with PD-1 compared with other studies. We are very eager and are currently recruiting patients to phase III studies of T-VEC with PD-1 agents. Hopefully, that will show benefit in a randomized study.
Are we getting to a point where we investigate triplets or quadruplet combinations?
We are certainly moving towards more and more drugs in these combinations. We must remember that need to demonstrate benefits in randomized studies before we get too excited about building triplets and quadruplets. It will be interesting to see but, from a cost of care and toxicity perspective, it will be important to be convinced that more is better.
Also, we need think about de-escalating patients from certain combinations. Perhaps we need to give a few doses of a 2- or 3-drug combination to patients and, if they start to respond, pare down one or 2 of those drugs. That is an open question that we are starting to explore with ipilimumab and nivolumab in combination, but it is not something that has been flushed out for a lot of these new targets.
Is pseudoprogression something that we see commonly in melanoma with some of these checkpoint inhibitors?
Pseudoprogression can occur in patients with melanoma. We think about it mostly in patients who are treated with immunotherapy drugs. Pseudoprogression comes in a lot of different varieties. It is important to keep in mind what kind of tumor growth we are talking about when we discuss pseudoprogression.
I would emphasize that most patients for whom you believe are really having progressive disease on immunotherapy, will unfortunately continue to progress. I tell oncologists and patients that if the tumors are all really growing, it is unlikely that we will get a later response if it initially isn't showing some favorable effects. Pseudoprogression, in many patients, is something we see if we have a mixed response. Some tumors are disappearing, but a few others are growing, so we may have impressive responses in all of the existing disease at baseline. One thing I would try to offer those patients is new treatments sooner rather than too late.
What biomarker research is being done to determine who is best fit to receive these therapies?
We wish we knew exactly who we had to treat with each individual drug. The only biomarker we have in advanced melanoma still is the BRAF
mutation, which says a patient could be a candidate for BRAF/MEK combination therapy.
PD-L1 is another biomarker that has been extensively explored in patients with melanoma. There is a lot of debate on if we should use it for certain decision-making issues and there is controversy about that.
At the moment, the rest of biomarkers are all research. It is important that we do research in this area.