Ipilimumab 'Greased the Wheel' for Newer Agents in Melanoma

Zosia Chustecka

November 14, 2014

ZURICH, Switzerland — There has been a paradigm shift in the treatment of melanoma, and immunotherapy now has center stage. There was a steep learning curve with the development of the first of these agents, ipilimumab (Yervoy, Bristol-Myers Squibb), but it has paved the way for a wave of new products.

Ipilimumab was the first immune checkpoint inhibitor to be tested in patients, and the initial results showed responses were "quite remarkable," but the drug had unusual kinetics and unusual adverse events, commented Steven Bernstein, MD, from Bristol-Myers Squibb.

Speaking at a company-sponsored satellite symposium here at the Society for Melanoma Research meeting, he emphasized that it was investigator experience with the drug that guided the protocols in clinical trials. Later, investigators also developed a new way of assessing immune responses as a better way of capturing the results that were being seen than the RECIST criteria that are used with chemotherapy.

Recalling some of the lessons learned was Steven O'Day, MD, director of the Los Angeles Skin Cancer Institute, who was involved in the pivotal trial (N Engl J Med. 2010;363:711-723) that led to ipilimumab approval. This was the first time that a drug had been shown to improve overall survival in metastatic melanoma. That achievement was all the more remarkable considering that the response rate was only around 10%, he said.

Dr O'Day commented that the responses to ipilimumab were different from anything that had been seen before. Even though previously there had been some success in melanoma with nonspecific immune activation using interleukin-2, that drug had rapid kinetics, and also it required a complete response for long-term overall survival benefit (seen in about 5% to 10% of patients).

In contrast, with ipilumumab, the long-term survival was seen in patients who had durable clinical responses, whether that involved a complete or partial response, or it was stable disease. This again was something new, Dr O'Day said, noting that, with cytotoxics, stable disease is very short-lived, whereas with ipilimumab, some patients have stable disease for a long time. Altogether, these durable clinical responses (including stable disease) are seen in about 20% to 30% of patients. In about 10% of patients, the responses are seen late, and develop only three to six months after being on the drug, he added.

Long-term data now show a survival curve that plateaus at around three years and then remains flat — and some patients on ipilimumab are still alive after 10 years. It appears that treatment with ipilimumab has reset the immune system and reached a new balance, where tumor cells are still present but held in check.

This same survival plateau at around three years was also seen with interleukin-2, but that was with fewer patients (between 5% and 10%), Dr O'Day commented. With ipilimumab, this has now risen to around 10%, and with the newer immune checkpoint inhibitors that act on the programmed death (PD) pathway this is has risen again to about 30%.

The new PD inhibitors, which include nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co), are "generally better drugs," commented Dr O'Day, with tumor control rates of around 50% compared with 30% with ipilimumab, and seemingly less toxicity, but "also we know now what to look out for," he said.

Ipilimumab has "greased the wheel" for the next generation, he said.

When ipilimumab was first being tested in patients, there was a steep learning curve about toxicity, with unusual immune reactions, including colon and liver perforation, and even some treatment-related deaths, he commented. This is now managed with the use of steroids, which are immunosuppressive, so there had been concern that they may interfere with ipilimumab's efficacy, but it turns out that the T cells that attack the host are very sensitive to steroids, while the T cells that attack the tumor are not, he commented.

There is now a guideline for using steroids to manage toxicity, and in severe cases, ipilimumab is stopped, he said. There is also a risk evaluation and mitigation strategy with recommendations for healthcare professionals to ensure that the benefits of ipilimumab outweigh the immune-associated adverse events. However, it appears that the toxicity is a necessary evil — it is part of the drug's effect on the immune system, as there is a correlation between toxicity and efficacy, Dr O'Day noted.

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