‘Anti-PD1 is here to stay’: Treating melanoma
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Findings from a recent retrospective study demonstrated a multiyear decline in the population-level mortality of melanoma. This decline has been associated with the FDA approval of 10 novel treatments for metastatic melanoma since 2011.
Healio spoke with Sanjiv S. Agarwala, MD, professor of medical oncology and hematology at Temple University School of Medicine, about current melanoma treatment options. He discussed regimens and agents he uses – and does not use – in his practice, as well as novel treatments coming down the pike.
Healio: What current treatment regimens are you using in your practice?
Agarwala: For melanoma, the treatment options that we use are still fairly similar to what they have been in the recent past. Obviously, we get the BRAF mutation test, and it depends on if it’s metastatic or adjuvant melanoma. For the adjuvant therapy of melanoma, if BRAF-positive, we have the option of using immunotherapy with an anti-PD1 or targeted therapy with a BRAF/MEK combination. If BRAF-WT, we would use an anti-PD1 immunotherapy agent. In the metastatic setting, if we select immunotherapy, we can use an anti-PD1, anti-CTLA4 combination or an anti-PD1 alone. We also have the option to use BRAF-targeted therapy as in the BRAF-mutated patient as well.
The regimens I use most commonly in my practice, for a patient with a BRAF mutation consist of one of the available combinations of BRAF and MEK inhibitors. Vemurafenib (Zelboraf, Genentech) and trametinib (Mekinist, Novartis) has been my go-to combination for a long time. There are others out there as well, and we know that there is not that much different in efficacy, if at all, between these regimens in these combinations, but some differences in toxicity.
If I pick immunotherapy, I am either picking an anti-PD1 alone or anti-PD1/CTLA4 combination therapy. More and more for metastatic melanoma I am choosing combination therapy, usually ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA4, plus nivolumab (Opdivo, Bristol-Myers Squibb), anti-PD1 combination therapy in standard dosages. In the adjuvant setting, the choice is between the two available anti-PD1 agents, pembrolizumab (Keytruda, Merck) and nivolumab, and often it depends on scheduling.
Recently, pembrolizumab was approved for use every 6 weeks. That’s a plus because that is a less frequent regimen, especially for adjuvant therapy where the patient is healthy and disease free. In this pandemic time, having a less frequent dosing where a patient does not have to come to the hospital or clinic often is helpful.
Healio: What new therapies have you been keeping your eye on?
Agarwala: Probably, the most important one I am keeping my eye on, as is everyone else, is the triple therapy combination for patients who have the BRAF mutation. When you have a BRAF mutation, you tend to choose targeted therapy (which is combination BRAF/MEK) or immunotherapy. However, there are data coming out, and some already available from the recent American Association for Cancer Research meeting, of a triple combination therapy regimen – BRAF/MEK, plus immunotherapy anti-PD1. It is looking like those regimens – at least one of them – showed an improvement in progression free survival as. The question really is, then, for BRAF mutation positive patients, should we not have to worry about the choice between targeted therapy and immunotherapy, and just give everything – that is, immunotherapy but only the monotherapy anti-PD1 (not the CTLA4), and BRAF/MEK combination therapy? Several trials are maturing in that area and it is going to be very interesting because obviously if the triple therapy is more effective than giving BRAF/MEK alone, then that would be the first go-to choice. However, that does add toxicity and it does add expense. So, we really have to look at the data very carefully. I am looking, as are my colleagues, for further follow up in these studies to look for overall survival, for example.
As I mentioned, progression free survival was positive in one of the trials. Now we are waiting for overall survival. If that is positive, that could be a winner. That is certainly on my mind. There are several other, mostly phase 1/phase 2 type things out there, all the way from vaccine combinations to anti-PD1 to some other innovative molecules that are targeting other check points in the pathway, such as GITR or LAG3. There is another IL-2 pegylated molecule out there that we are excited about as well. All of that is coming down the pike, but the triplet data are perhaps the most important data that will come out soon and could be practice changing.
One last thing I like to mention is the injectable area where we have talimogene laherparepvec (TVEC; Imlygic, Amgen) approved as an intralesional therapy for some patients with melanoma. A randomized trial of TVEC intralesional plus pembrolizumab combination vs. just pembrolizumab with a TVEC placebo is an important phase 3 trial recently completed. We are waiting for data and that will set into play what happens to the intralesional therapy area for melanoma. There are plenty of drugs that are injected directly into metastatic tumors to produce an immune response and a systemic response at the same time synergistically, perhaps, with an anti-PD1.
Healio: How have new treatment options contributed to decline in overall population mortality?
Agarwala: It is a little bit early today, in terms of mortality. Some of these trials are showing a benefit in overall survival; so that is great. The longest follow up we have with CTLA4 monotherapy is 10 years and we know there is a complete flattening of the curve at 20%. That means 20% of patients with just the older drug monotherapy anti-CTLA4 are alive who wouldn’t be alive.
With anti-PD1 alone, we potentially cure another 20% of patients. The long-term follow-up there is 5 to 6 years, 40% with anti-PD1 alone with pembrolizumab and nivolumab as well. Then, with combination therapy of ipilimumab and nivolumab and the 5 to 6 years of follow-up shows 48% to 50% of patients are still alive.
I’d say the mortality is now approximately half of what is was, but of course that’s with only 5 to 6 years of follow-up. This has been a huge impact on mortality because metastatic melanoma was previously at 100% mortality. In the adjuvant setting, also, we are seeing trials showing a benefit in RFS and overall survival. So, we are improving mortality there.
It is a little difficult to give a specific number, but we are night and day compared with how we were even 5 to 10 years ago. The way things are going, if I had to pick a number, we already cut mortality down or metastatic melanoma by 50%, and hopefully that is going to get even better.
Healio: What role does anti-PD1 therapy play in the treatment regimen for melanoma?
Agarwala: Anti-PD1 therapy in melanoma is divided up into metastatic and adjuvant. In the metastatic area, it is a component of almost every treatment. Certainly, for a BRAF mutation you may choose BRAF/MEK therapy instead of immunotherapy. But, if you choose immunotherapy, you are going to use an anti-PD1, for sure. Whether you combine that with an anti-CTLA4 or not, that is still a choice right now. Many of us are using the combination therapy because it seems to be more effective, although more toxic. Anti-PD1 in metastatic melanoma is an important component of almost everyone’s treatment. Even in BRAF positive patients, we often use immunotherapy so anti-PD1 gets in there. If you choose BRAF/MEK targeted therapy instead, if there is progression, we would go towards anti-PD1.
In the adjuvant setting, anti-PD1 is an important part of therapy because if you have high-risk melanoma and you do not have the BRAF mutation, the only choice is an anti-PD1.
Anti-PD1 is here to stay for both adjuvant and metastatic melanoma.
Healio: What are the benefits and drawbacks of adjuvant low-dose ipilimumab?
Agarwala: Ipilimumab is an anti-CTLA4 that revolutionized not only melanoma, but immunotherapy for everyone because it was the first positive trial with a checkpoint inhibitor. We know ipilimumab has some issues in terms of toxicity. So, there has been a move to see if we can lower the dose of ipilimumab to maintain efficacy and lower toxicity. This is generally done in combination with an anti-PD1 in the metastatic setting.
In the adjuvant setting, a lower dose of ipilimumab could be interesting simple because of the lower toxicity. However, there is no randomized trial yet that has shown ipilimumab is the way to go. There are good data for metastatic melanoma, but not yet for adjuvant melanoma. For metastatic, combination therapy using a lower dose of ipilimumab may produce lower toxicity and, right now, the efficacy looks similar to higher dose ipilimumab in combination with anti-PD1.
The jury is still out on low-dose ipilimumab. There are theoretical advantages – that the toxicity could be lower – but it could also be a disadvantage of less efficacy. We do not know that for sure right now, so I am not using low-dose ipilimumab in my practice currently.
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