Innovations in Adjuvant Therapy for Melanoma
If you’re living with melanoma, you may soon have access to a wider variety of therapies to prevent your cancer from coming back, especially in the field of adjuvant therapy.
Adjuvant therapy for melanoma is treatment following the main treatment that helps reduce the risk of your melanoma’s recurrence. Primary treatment for melanoma is usually surgery to remove the malignancy and some of the healthy tissue around it. However, it’s possible that some cancer cells can remain undetected in your body. Some melanoma patients, especially those who are believed to be at higher risk for recurrence, are treated with adjuvant therapies to attempt to remove any lingering microscopic cancer cells that could eventually cause the cancer to return.
This is an exciting time in the development of new adjuvant therapies for melanoma patients, according to Dr. Douglas Johnson, an assistant professor of medicine and clinical director of the Melanoma Research Program at Vanderbilt University Medical Center. Johnson specializes in melanoma treatment and research.
HealthCentral spoke to Dr. Johnson by phone about these new innovations in adjuvant therapy.
HealthCentral: What are some of the major developments in adjuvant therapies, or therapies given after the initial treatment, for melanoma?
Dr. Johnson: Until about three years ago, the only adjuvant therapy available for melanoma patients was interferon (proteins that can boost the immune system), but it was really quite toxic and had many bothersome side effects, and it really didn’t have much impact on patient outcomes or do much to affect cure rates.
However, the last three years have seen a number of effective new treatments, including both immunotherapy and targeted therapies. We now have FDA-approved options for both. We have immunotherapy options such as ipilimumab and nivolumab, and targeted therapy drugs, including dabrafenib and [trametinib].
Immunotherapies are halving the number of recurrences in patients. For example, if there was a 60 percent chance of recurrence in particular patients, it’s dropped to around 30 percent with immunotherapies — specifically nivolumab. We’re not preventing every recurrence, but there is certainly a meaningful difference.
Targeted therapy is probably in the same ballpark, but it’s harder to give an exact percentage of increased cure rates. Targeted therapies are really effective up-front — they stop almost all recurrence for the first year — but recurrences, when they happen, mostly occur after the first year. Overall, targeted therapy also tremendously increases the cure rate.
HC: What sort of patients are adjuvant therapies best suited for?
Dr. Johnson: These adjuvant therapies are for patients with stage 3 melanoma, where cancer has spread to the lymph nodes, or resected or isolated stage 4 melanoma. Isolated stage 4 would be where cancer has spread, for example, to the lungs, but it’s only a single tumor, and that has been removed so the patient doesn’t have any active cancer.
These patients all have a high risk of recurrence, but it’s different than treating someone with active metastatic disease. With adjuvant therapy, the focus is on risk reduction.
There are no approved adjuvant therapies for stage 1 or stage 2 melanoma. At some point in the future, we may offer adjuvant therapies for stage 2 patients who are at a slightly higher risk, and there are currently clinical trials studying this issue. But stage 1 patients are actually at very low risk of recurrence.
HC: What are some challenges that patients have experienced with adjuvant therapies for melanoma?
Dr. Johnson: The first checkpoint inhibitor approved by the FDA was ipilimumab, and that therapy did improve survival rates when compared to the observation group of high-risk patients for recurrence of melanoma. But the ipilimumab therapy was also associated with a lot of toxicities and severe side effects.
About 1 percent of the patients who were treated with ipilimumab died from the side effects, they were so severe. It’s obviously a tragedy if anyone dies from treatment side effects, but this is especially true for patients who didn’t have active cancer, but we're trying to reduce the risk.
More recently, we have seen positive clinical trial results for nivolumab when compared to ipilimumab — which was not surprising, since these drugs work better in the metastatic setting, and they also work better in the adjuvant setting.
At the minimum, nivolumab prolongs relapse-free survival and we expect these drugs to help improve overall survival when compared with ipilimumab. They also have fewer side effects. We’re now using nivolumab routinely for patients with stage 3 disease and resected stage 4 disease, in adjuvant therapy for one year.
HC: How do targeted therapies work and who would benefit from this adjuvant therapy?
Dr. Johnson: Targeted therapies have been approved by the FDA for patients with stage 3 melanoma who have a specific genetic mutation in their cancer tumor. About half of all melanoma tumors have a genetic mutation known as BRAF (pronounced bee-raf). The FDA has approved a combined therapy (dabrafenib and trametinib) for patients who have the BRAF V600E or V600K mutations.
The question we get all the time from patients with this mutation is: which is better, targeted therapy or immunotherapy? At this point, both have had positive trials that look pretty impressive. So, we really don’t know which therapy is better for patients with the BRAF mutation. Now for those patients who don’t have the BRAF mutation who need adjuvant therapy, it’s not even a conversation, they’ll get immunotherapy. But for those with the mutation, they could receive either targeted therapy or immunotherapy.
HC: How are doctors working to improve or avoid some of the more dangerous side effects?
Dr. Johnson: In general, the most common side effect that patients experience are fatigue, rash, and joint pain, while the more serious side effects are diarrhea (colon inflammation), cough/shortness of breath (lung inflammation), severe fatigue (which could indicate thyroid or pituitary inflammation), and liver inflammation. Rare but serious side effects include inflammation of the heart, nerves, brain, and kidneys.
Side effects from therapies are rarely life-threatening — although when they do happen, they are more common with immunotherapy — and in general both types of therapies are well tolerated by patients. One of the things doctors are trying and do is to improve patient education, so we can catch side-effects early on. We do our best to give patients the right information so they can contact us if they start seeing early signs of side effects.
Our group at Vanderbilt and many others are studying the best management strategies and treatments for side effects so we can manage the common events and understand the rare side effects better. As we start to use these therapies with more people, we’re starting to see even the rare side effects more often.
As we start moving to more aggressive combination regimes, we’re trying to determine predictive markers so we can predict who is going to have the most serious side effects, so we can manage those patients with a less aggressive option, or chose a different strategy. The ultimate goal is to be able to pick, based on molecular markers, what’s the right treatment and which will work best without side effects. Unfortunately, we’re still a long way from that, but there is an intensive effort to get there.
The ultimate goal is to be able to pick, based on molecular markers, what’s the right treatment and which will work best without side effects. Unfortunately, we’re still a long way from that, but there is an intensive effort to get there. – Dr. Douglas Johnson, Vanderbilt University Medical Center
A major question is why specific side effects occur in specific patients. Since immunotherapy works by removing the "brakes" from the body’s immune system, sometimes the immune system starts attacking other parts of the body. One idea is that those patients who are prone to autoimmune disease may also be prone to side effects from immunotherapy. There may be some truth to that, but we have studied patients who actually have an autoimmune disease, like rheumatoid arthritis or psoriasis, and they generally tolerate immunotherapy pretty well. So patients with autoimmune diseases don’t necessarily get side effects and flares from autoimmune therapy.
Other things that are being looked at are genetic factors, like gene variants, that predispose people to side effects. Are there antibodies that we can detect in the blood that predispose patients to side effects? Are there certain genetic factors in the tumor or is there a cross-reactivity with something in the tumor? At this point, it's a bit of a black box, and we still don’t have a good idea of what causes these side effects.