Immunotherapy Revolutionizes Melanoma Treatment Paradigm

The advent of immunotherapy has revolutionized the treatment of patients with melanoma, irrespective of biomarker status, explained Mario Sznol, MD.

"In melanoma, it is important that patients receive immunotherapy in the frontline setting if they are eligible," explained Sznol. “There’s controversy surrounding the optimal therapy for patients with BRAF mutations, and there are ongoing trials trying to determine that. In my opinion, those patients ought to receive immunotherapy in the frontline setting as well."

As single agents used in the frontline setting, the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have demonstrated efficacy in improving 5-year survival rates, explained Sznol. However, the addition of the CTLA-4 inhibitor ipilimumab (Yervoy) to nivolumab can improve these responses and could be a preferred regimen in this space.

In addition, a slew of novel therapies alone and in combination are under investigation in the melanoma pipeline, said Sznol.

In an interview with OncLive, Sznol, professor of medicine and co-director of Yale SPORE in Skin Cancer at Yale Cancer Center, discussed the current immunotherapy paradigm in melanoma and promising agents that are in development.

OncLive: How has immunotherapy impacted the field of melanoma?

Sznol: The 5-year survival rate for patients with melanoma who are eligible for clinical trials can approach nearly 50% with immunotherapy. However, it is not just the drugs alone that contribute to that response rate. [They have to do with] some of the things we look at to understand why patients respond to these drugs versus not. Primarily, [these outcomes depend on] whether patients have a T-cell response or not. However, for those patients who have a T-cell response, [there are] some reasons why those T cells may not work in the tumor microenvironment.

We should be aware of some of the newer agents that are being studied in phase 2 and phase 3 trials to prepare [us], should they come into the market.

What are some of the currently available immunotherapeutic options in melanoma?

There are 2 major immunotherapeutic options in melanoma. There are 3 if you count talimogene laherparepvec (T-VEC; Imlygic), although that is rarely used in the clinic. The 2 most important drug [classes] are anti–PD-1 agents, which are nivolumab or pembrolizumab, and anti–CTLA-4 agents, such as ipilimumab. Anti–PD-1 agents alone can result in long-term survival rates in the range of 40% to 45%. The addition of an anti–CLTA-4 agent may add another 7% to 10% to that 5-year survival rate.

We tend to use anti–PD-1 agents alone or in combination with an anti–CTLA-4 agent in the frontline setting in patients with metastatic melanoma.

What other treatments are leading to these 5-year survival rates?

The 5-year progression-free survival (PFS) is around 29% to 30% for anti–PD-1 agents alone. With the combination [of anti–PD-1/anti–CTLA-4 agents], the PFS is increased to around 35% to 36%.

What that means is that more people are alive at 5 years [than are progression free with PD-1 inhibition alone]. Other [treatment modalities have to be employed] to manage their disease over that period of time.

One example is surgery. There are patients who have discordant progression in 1 or 2 lesions. If that disease is removed, those patients can remain progression free for a long time.

For patients who respond and go off treatment, we can go back to these drugs and treat them again and [induce] second responses. Additionally, patients with BRAF mutations can progress on immunotherapy. However, since they harbor a BRAF alteration, they can receive BRAF inhibitors subsequently to extend their survival.

A number of interventions beyond initial treatment with checkpoint inhibitors allow our patients to reach that 5-year timepoint.

What is the role of combination immunotherapy in melanoma?

The combination of nivolumab and ipilimumab will likely give us the best long-term 5-year survival rate. However, we have other drugs we can use in the clinic.

T-VEC is being used in combination with pembrolizumab; those phase 3 trial results will be released in the near future.

Ongoing phase 3 trials are evaluating modified cytokines, such as NKTR-214, in combination with nivolumab compared with nivolumab alone. Another phase 3 trial is comparing a VEGF receptor inhibitor with pembrolizumab versus pembrolizumab alone.

There are likely other phase 3 trials that I am unaware of exploring combinations compared with single-agent PD-1 inhibitors. There are [agents] that are being used in the second- and third-line settings that are also investigational like tumor-infiltrating lymphocyte therapy. Novel drugs, such as anti–CD40 and anti–LAG-3 agents, have shown activity in the relapsed/refractory setting. These drugs are being used in combination with anti–PD-1 agents. Eventually, there will be additional combinations that will be used in the first- or second-line setting with the hope of improving survival.

What are some of the most common toxicities with checkpoint inhibitors?

Common toxicities of anti–PD-1 inhibition alone or in combination include skin rash, gastrointestinal adverse effects (AEs), such as colitis and diarrhea, abnormal liver function tests, and endocrine AEs such as thyroiditis, pituitary dysfunction, adrenal insufficiency, and rarely, diabetes mellitus. However, AEs can affect any organ. When treating a patient with immunotherapy, we have to be aware of pneumonitis, nephritis, myositis, arthralgias, and central nervous system toxicities.

It is important to detect these toxicities early and to manage them appropriately with steroids or secondary immunosuppressive agents in some cases. However, we shouldn’t be afraid of the toxicities that are associated with these agents. These are effective agents in almost every cancer, and they are part of the armamentarium in melanoma. My prediction is that checkpoint inhibitors will be the most common agent that we, as a field, prescribe to our patients in the long run.