You might have noticed….or not, that the newspapers have been talking about a new promising set of drugs for advanced skin cancer. From reading these reports, it seems like huge advances in treatment have been found. They way the researchers who sponsored the studies are talking, it makes it seem as if a miracle has occurred. I think this is unfortunate, as in my opinion (thinking about this from the patient’s point of view) this is a tiny advance and not so earth shattering.
So, what’s the fuss. First of all, primary skin cancer is treatable and can even be cured if it is caught early. However, advanced melanoma that has metastasized (or moved to another location) is very difficult to treat and is in no way curable. The standard form of therapy relies on a drug called Dacarbazine, a form of chemotherapy that interferes with DNA synthesis, that is needed by rapidly dividing cancer cells. The problem with this drug is that it only works for about 10% of patients who have advanced melanoma and has little to no overall survival benefits. The drug also does not target cancer cells per say but any dividing cell and is thus not very specific. As more and more was learned about melanoma and indeed other cancers, more specific drugs were developed.
It was discovered that roughly 50% of patients with this deadly form of skin cancer carry a very specific mutation in a gene called BRAF which as a protein controls a very important signaling pathway that controls growth in all cells. Under normal circumstances, the protein is off and only turned on for a very specific amount of time when necessary. The mutation that patients have (V600E) keeps the protein in an open and an ‘always-on’ position. This new information allowed scientists to develop a new drug that targets this specific mutation in the protein BRAF. The drug binds the protein when it is in the ‘on’ position and prevents it from binding to other proteins, and thus making it act as it is ‘off’ (another way of looking at it is to say that it inhibits the function of this mutated protein). Early experiments in the laboratory showed very nice results that blocked the cancer cells from surviving. Animal studies (mostly mice and rats) also looked promising at controlling the injected human cancer cells from growing into large tumors. Then, small-scale clinical trial studies were performed (small numbers of patients) to look at safety issues as well dose and tumor-shrinking properties of the new drug. These also looked promising and allowed the drug companies (Roche/Daiichi Sankyo) to initiate bigger clinical trials. This is what is now being reported.
The median survival for patients with late stage advanced melanoma is about 8 to 18 months on average. Somewhere between 7-12% of patients respond (e.g. tumor shrinks) to the chemotherapy drug alone as treatment. But, the overall survival following treatment is often no better than patients who get no chemotherapy. The addition of this new drug called Vemurafenib (PLX4032) to the standard chemotherapy seemed to produce better results than the chemotherapy alone. The results so far from a phase III clinical trials with about 675 patients showed that 84% of patients surviving after six months with the combination drug treatment while only 64% surviving after 6 months with the single drug alone (the standard chemotherapy). So, in general the new drug when added to the existing drug seems to increase the interm overall survival rates (only assessed at 6 months) and increase what is called the progression free survival of patients. Progression free refers to the fact that the cancer does not get worse and in some cases gets better (tumor shrinks, there is less metastasis, or there is less organ failure for example due to the cancer). In fact, since the 6 months survival data was considered to be good, patients were allowed to cross-over. That means that those patients who were getting the chemotherapy drug alone were allowed (after the first six months) to switch to the new drug and the standard chemotherapy.
Ok, now for the bad news. What are the limitations of this study. Well, for starters for the 50% or so fo the patients without mutations are not going to be suitable for this drug. The second point it perhaps even more troubling, the study was in essence stopped after six months due to cross-over as was explained above. So, although the drug seemed to increase survival rates (not overall long-term survival) by about 60% or so at six months, we have absolutely no clue what will happen to patients with this new drug after one year or more. Finally, the tumor is not gone…there is no data on this but we can be fairly certain that this is not curative and the tumor is not completely eradicated. 9.9999 time out of ten the tumor shrinks (or the number of metastases decrease, etc.) but come back. Tumor shrinkage which often leads to increased survival benefits are very often temporary, when the tumor regrows after therapy is stopped or when the tumor develops resistance it comes back with a vengeance. So, what often happens is that hundreds of millions of dollars are spent on the development of new anti-cancer drugs (personalized cancer drugs that hit a very specific kind of mutation found only a some patients but not others) that show limited amount of response at first but result in very little long-term overall survival. In fact, it is very common that new drugs provide only a few additional months of survival and that overall benefits affect only 10-20% of patients (not including the fact that half of all patients can’t even take this drug).
Please note that I am not against an additional few months of life for patients that have advanced skin cancer. I know that any additional time is welcome by patients. However, that does not make for a successful drug in my opinion. Cancer patients and the public are not thinking to themselves, I hope that new drugs that are developed and cost me tens of thousands of dollars a year give me an additional month or two to live. They want a cure or they at least want a long life with limited complications of the cancer. That is real to them. Even if that is not realistic for most advanced cancers, scientist and clinicans need to be very aware of that. They need to temper their enthusiams and be real abou what the data actually says. News reports should state the limitations of the drugs and state the cost of the drug in terms of development and in terms of what it will cost a patient. These overenthuistic statement by the scientist/clinicans in the papers are misleading at best and discouraging at worst.
Comment/suggestion…they are welcome!
Dr. C Cancer Made Simple
- 2 New Drugs May Treat Advanced Melanoma (webmd.com)
- New treatments for skin cancer emerge (macleans.ca)
- Skin Cancer Drugs a “Breakthrough” (patspapers.com)
- Three New Promising Treatments for Treating Lethal Melanoma | 80beats (blogs.discovermagazine.com)