Melanoma Treatments Are Advancing, But Next Steps Remain Unclear

Tim Turnham

Tim Turnham

Since October 1, the FDA has approved two drugs and two drug combinations to treat melanoma: Opdivo (nivolumab) and Yervoy (ipilimumab) for BRAF V600 wild-type unresectable or metastatic disease; Imlygic (talimogene laherparepvec; T-VEC) for advanced melanoma; adjuvant Yervoy for stage 3 disease at high risk of recurrence following complete resection; and Zelboraf (vemurafenib) and Cotellic (cobimetinib) for metastatic or unresectable BRAF V600E/K mutation-positive melanoma.

In this interview to gain further insight into the flurry of FDA activity, Tim Turnham, executive director of the Melanoma Research Foundation, sheds light on the recent drug approvals and what’s next for treating melanoma.

What are your overall thoughts on these three drug approvals? Which do you think will affect more patients immediately or in the long-term?

Obviously, these are all very different situations and it's been an amazing run in melanoma going back to March 2011. We've had three approvals now in just over one month.

The combination of Yervoy and Opdivo shows response rates and durable response rates that are unprecedented in melanoma. We just don't see numbers like this. Though the data are still early and new, I think it's a sign immuno-oncology is breaking out of the limitations that it's faced for many years of having a low response rate.

We've known that there are some people treated with immunotherapy that have durable responses — some would even call them 'cures.' Now, we have a combination where the response rate is approaching 50 percent. Of these three approvals, I think this one will affect the most patients right away. I believe we're seeing a shift and I think this could become the treatment of choice for many patients.

In the long term, the combination of Yervoy and Opdivo will affect a lot of patients. There's some indication in the data that we can begin to predict which populations will see the greatest change in survival when comparing the combination with a PD-1 monotherapy. PD-L1 expression is not a great biomarker, but it's certainly suggestive that if you don't have it in your tumor, the addition of Yervoy seems to make a big difference.

Eventually, we'll figure this out a little more and physicians will only prescribe it to those patients that will see the most benefit, which is important because of toxicities.

What about the approval of Imlygic, formerly known as T-VEC?

The thing that's exciting about Imlygic is that it's a novel approach, using a modified herpes simplex 1 virus to attack cancer. It's a tolerable drug. The toxicities are low and there are almost no side effects.

The challenges are apparent, though, too. It works well in patients with low tumor burden and the patient has to have an injectable lesion. The real interest in this approval is how the drug can be developed further in the future.

And finally, the approval of adjuvant Yervoy.

The approval of adjuvant Yervoy is a major step forward. The standard of care for stage 3 patients now is to watch and wait and that's very scary. Clearly, there are issues regarding toxicities that we'll have to watch carefully and there will be some concern. I don't think we know yet how many patients will decide on taking the therapy despite the risks of toxicity. I suspect it will be highly individualized. A person who is healthy and young, I think, will be much more likely to accept the toxicities than a person who's 85 years old and riddled with arthritis. I don't know for sure, though, so we'll have to see how things work out. Regardless, I hope it's the first of many approvals in the adjuvant space.

What's next for immunotherapies in melanoma? What questions still need to be answered?

We've seen this steady march of progress in melanoma but it's still not clear what the next steps will be. I've heard some researchers say that they need to spend the next five years figuring out what these drugs really do and how to use them. From my perspective as a patient advocate, I think that's unacceptable.

If you look at the very best results we get with Yervoy-Opdivo, there are still about 50 percent of patients who won't respond. Sure, if we get a better understanding of these drugs, we'll creep up higher on that response rate scale, but we have to do more. If we don't push to move research forward, we will stagnate and move into a field of diminishing returns.

We've done a lot of work to understand the drugs we have now — which ones to give to which patients and in which combinations — but we still have unknowns. We have too many patients that will not respond to what's available. We need to push for other checkpoint inhibitors and for other strategies to re-engage the immune system.

What are the questions that remain regarding sequencing therapies in melanoma?

There's a tendency for humans to chase the latest shiny thing. Immuno-oncology is very exciting right now, but it's important that we don't forget about targeted therapies. These can work, do work and should be used in a number of situations.

There's some concern that using targeted therapies first will reduce the response rate if a patient has to move onto an immunotherapy. Should we use immunotherapy first and have targeted therapy as a backup plan? Does it matter how quickly the tumor is growing? What about using Yervoy first? These questions, and more, need to be answered.

What's the significance of so many approvals in such a short time?

Cancer care is not a matter of a single step, but a matter of a number of steps. The best doctors won't just tell a patient about the therapy they're going on now, but they'll talk about the other therapies that they may go to next.

The more of those steps — the therapies — that are available, the higher the likelihood that we'll begin to see long-term survival in melanoma.