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The American Cancer Society

Big Steps Forward In Melanoma Treatment But Tread Carefully

by Dr. Len June 02, 2014

The brave new world of melanoma treatment continues at the Annual Meeting of the American Society of Clinical Oncology in Chicago. And notwithstanding the excitement, there are some other pieces of information around the edges that remind us once again that a breakthrough today may not be quite as promising when viewed a couple of years from now.

First the good news: reports at the meeting today will introduce a new immunotherapy drug that has shown significant promise as an effective treatment for advanced melanoma. More importantly, the company says in a press release that it is going to making the drug immediately to patients through an "expanded access" program if those patients have been previously treated with ipilimumab or a BRAF inhibitor, such as vemurafenib.

The drug is now designated as MK-3475, and it is a drug which allows our bodies' immune cells to fight melanoma (and other) cancer cells in a unique fashion by helping restore their immune function. It's too complicated to explain here, but basically cancer cells can overwhelm the body's natural defense mechanisms and shut them down by exhaustion. This new type of drug blocks that process and reawakens the immune cells which can then recognize the cancer cells as "foreign" and attack them.

In this study, which is billed as the largest phase I (initial) drug trial ever done, 411 patients received the drug. 34% of the patients-including patients who had received prior immune treatment using a different approach-responded. In those patients who responded, 88% continued to show evidence of benefit at the time the study was analyzed. The researchers estimated that 74% of the patients who had not received prior treatment with ipilimumab would be alive at one year, while the one year survival for those who had received prior ipilimumab was 65%.

In another report, researchers described a study which included a small number (53) of patients with advanced melanoma who received a combination of the immunotherapy drugs ipilimumab and nivolumab. These patients had received up to three prior treatments for their disease, meaning that any responses for some of them would be truly remarkable.

The results showed that 41 percent of the patients responded, and 17% (or 9) patients had complete responses. Median survival (meaning half lived less and half lived more) was 39.7 months, a remarkable result. And according to the researchers, the toxicities of the combination were tolerable and treatable-notwithstanding that ipilimumab is well known to be a drug with considerable side effects.

And last but not least, there was another report that the same ipilimumab when used in the adjuvant setting to prevent cancer spread after primary treatment reduced recurrence rates for patients who had melanoma cells in their lymph nodes at the time of presentation. Although the percentage decrease of recurrence was impressive-in 951 patients randomly assigned to receive ipilimumab or placebo, there was a reduction of 33% in recurrence rates in patients whose lymph nodes showed only small microscopic amounts of melanoma cells and a 17% reduction in recurrence in patients where their lymph nodes had more clearly visible (macroscopic) disease-the benefit came at a cost: five patients died as a result of treatment, and a little over half (52% ) of the patients stopped because of side effects. And even with the new treatment, many people in that group still developed recurrent disease.

So where does all of this lead us?

First, the new immunotherapy approaches are producing some impressive results in improving the outlook for patients with advanced melanoma. Of that there is no doubt. This is a new era.

Second, we are building on our recent successes to create even more success by combining new drugs which work at different points on the immune cells to get even better results.

Third, some of these treatments appear to give us new options to decrease the risk of recurrence in patients who have high risk that their disease may come back after initial treatment.

But if the lessons of the past have taught us anything it is that we must always temper our excitement with a healthy dose of caution. We all hope and pray that these results are durable and really work as effectively as they appear to. But when you sit in the rooms and listen to the lectures, you learn that the breakthrough drug of a couple of years ago-where melanoma responded quickly and sometimes completely-now shows those patients who responded have the same survival as the patients who didn't respond. You hear that drugs that were promising can't cope with the intelligence of the cancer cell which develops a workaround ("resistance" is the medical term) and the disease progresses. Or that just because two new drugs work well in melanoma doesn't mean that when you combine them they will work even better. To the contrary, in at least one such experience, there were reports of significant, fatal side effects that were not anticipated when the study was started ( a caution to patients and doctors out there who think this would be a good idea to try on their own).

And then the reminder that some of these are early results on small numbers of patients. Good research sometimes takes time to learn everything we need to know. And even with good research, there are things we learn years later than can dampen our enthusiasm. Some of these drugs are very toxic and not every doctor and every hospital is equipped to handle the side effects that can occur, and which if not treated properly can lead to deaths.

So we end where we begin: it's a brave new world, full of promise, excitement and enthusiasm. And, yes, I still think this time is different. But I wouldn't be honest if I didn't admit that I am holding my breath just a bit. Sometimes experience can be a barrier to accepting great new ideas. But experience can also teach us that we have been here before, we have had great hopes before, and we have seen that our dreams have not been met with reality.

The lesson? Always temper enthusiasm with caution. It's better to be lifted up by exceeding expectations than brought down by damaged hope. We unfortunately have had too much of the latter. We really need a heavy dose of the former.

 

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About Dr. Len

Dr. Len

J. Leonard Lichtenfeld, MD, MACP - Dr. Lichtenfeld is Deputy Chief Medical Officer for the national office of the American Cancer Society.

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