What do all the new approvals mean?

Fair warning–this will likely be a long post!

In the past three weeks or so the FDA has issued three approvals relevant to melanoma. This is great news, of course, but it does raise a number of questions. Iam not a doctor, but have some thoughts on these changes.

Ipi/Nivo:  First was approval of the combination of ipi plus nivo (also known as Yervoy and Opdivo) for Stage IV patients. Ipi was approved as monotherapy in 2011, and nivo was approved last year. Results of the combination were all the buzz at the big cancer meeting, ASCO, this past June. Response rates were over 50%–numbers unheard of in melanoma. But side effects were a major issue, with more than half of patients experiencing problems that led to ending or postponing therapy. Even patients who did not take the full course, though, seemed to have good response rates. A lot remains to be learned about these drugs, and how to make the combination as successful as possible. Still, this is the approach that seems to be the first option for many oncologists now.

T-Vec: This was approved earlier this week. It is a modified Herpes Simplex 1 Virus (HSV-1). HSV-1 is the virus that causes cold sores (and not the virus that is a sexually transmitted disease!). A virus is miniscule in relation to a human cell. This virus only has a few genes. One of those genes blocks the ability of normal human cells to fight off viral infection. In T-Vec, scientists have removed that gene so the virus can no longer infect normal cells. Cancer cells don't have that ability, so the virus can infect them. The virus sticks on the cell surface, opens a hole in the cell membrane, and injects its own genetic material into the cell. That material takes over the cell division functions of the cell and causes it to create more viruses. Ultimately so many viruses are created they burst open the cell, then go out to infect other cells. So, T-Vec preferentially kills cancer cells. But it does more. When the cells burst open the remnants of the cell create a debris field of antigens that sensitizes the immune system to other tumor cells. But T-Vec has one more trick up its sleeve. Remember the deleted gene? Scientists replaced that gene with a different gene that produces GM-CSF, a compound that stimulates the immune system. So T-Vec kills cancer cells, trains the immune system to find other cancer cells, and stimulates the immune system. Sounds great, but the results are somewhat less impressive. T-Vec must be injected in the lesion, and even then the response is mixed. It seems to work best in people with injectable lesions and low tumor burden. Having said that, it is likely to be a major player in the future. If you combine T-Vec with another immunotherapy the results look much better. This could be ipi, one of the anti-PD1 drugs, or even IL-2. Also, it may be possible to inject lesions inside the body (in the liver for example) using ultrasound or some other technology to guide the needle.

Ipi Adjuvant: Finally, today's announcement that the FDA approved ipi for use as adjuvant therapy. The data are clear that ipi reduces the likelihood of recurrence. Some problems exist with this study, though. First, the study did not compare ipi against interferon. This is because some of the sites were in Europe, where Interferon is almost never used. A new study is underway as a head to head of ipi vs. Interferon and that data will be important. Second, the study had a lot of side effects, and even some deaths, among the study group. Finally, (and this may be related to the above) the study was done at a much higher dosage of ipi than is now used for Stage IV treatment. Current approved therapy for Stage IV is at 3 mg per kg of body weight. This adjuvant study was done at 10 mg per kg of body weight. At the time the study was designed some researchers felt the higher dosage would give better results. Further work showed that the added benefit did not outweigh the added severity of side effects. The higher dose for adjuvant work has two issues. First, it may well be that using ipi in the adjuvant setting at the 3 mg/kg dose will result in fewer side effects. Second, because of government regulations, the company cannot discount the price for the higher dosage. They must maintain the same price structure on a $/mg basis regardless of the dosing. This will result in a price per infusion that is more than three times the cost of ipi used for Stage IV patients. The company knows this is not acceptable and so have initiated a novel program. Stage III patients who decide to take ipi to try to lower their risk of recurrence are encouraged to enroll in a special program. Once enrolled, all of their drug is completely free, regardless of financial situation or insurance coverage.  This is a bold step for the company to take, and hopefully everyone will get the information about this program before experiencing significant costs. The program only applies, though, to the approved dosage of 10 mgs/kg.

OK, that was a lot of information. I hope it helps clarify matters a bit. 

Tim–MRF