Immunotherapy for Melanoma: Finding a Response to an Unstoppable Disease

According to the American Cancer Society, an estimated 87,110 new cases of invasive melanoma will be diagnosed in the United States in 2017, and this number will continue to rise globally. In addition, about 9,730 Americans will die from melanoma in 2017. The estimated 5-year survival rate for patients whose melanoma is detected early is about 98% in the United States.

Melanoma can be confused with the common skin cancers basal-cell carcinoma and squamous-cell carcinoma, which are highly curable and are usually removed surgically, without recurrence (coming back). Basal-cell carcinoma and squamous-cell carcinoma are mainly caused by excessive sun exposure or tanning salon use.

Melanoma, by contrast, when detected in later stages, can spread to other parts of the body, including the brain, lungs, bowels, and liver, and like other types of cancer, can appear in distant areas of the body as deep painful lesions. Melanoma used to be viewed as a highly dangerous cancer, with no viable treatment. However, the tide turned just 6 years ago, with the advent of targeted therapies and immunotherapies.

“Jimmy Carter Drug”

Immunotherapy research has long focused on melanoma, a disease recognized as a promising target for this approach, because the immune system alone, in rare cases, was able to eradicate it.

Two of the most prominent immunotherapy drugs for melanoma are Keytruda (pembrolizumab), and Opdivo (nivolumab). Both are anti-PD-1 (PD stands for programmed-cell death), a type of drug that kills cancer.

Keytruda has been called the “Jimmy Carter drug” after former President Jimmy Carter received the drug in his early 90s, after an undiagnosed melanoma lesion spread to his liver, lung, and brain. After 6 months of immunotherapy treatment, along with surgery and radiation, President Carter’s imaging scans showed no evidence of cancer. He stopped taking Keytruda earlier than most patients with melanoma do, but the reason is not confirmed, and it has been speculated that he stopped because of serious side effects.

Immunotherapies for Melanoma

Since 2011, many new drugs have been approved by the FDA for patients with melanoma, including several immunotherapies and targeted drugs that are approved for melanoma with tumor genomic mutations (alterations) of the BRAF or MEK pathway. This deluge of melanoma drugs followed a drought of 40 years with no new therapies with proven results in melanoma.

Immunotherapies for melanoma include the CTLA-4 inhibitor Yervoy (ipilimumab), and the 2 anti-PD-1 drugs Opdivo and Keytruda; the anti-PD-1 drugs are also referred to as checkpoint inhibitors, because they “take the brakes off” the immune system and enable the immune system to stop the cancer from growing, or kill the cancer cells completely.

Yervoy was the first immunotherapy approved by the FDA for melanoma, and is now approved for adjuvant therapy (given after surgery to prevent recurrence) of stage III melanoma; it is used for patients with melanoma that has spread or cannot be removed with surgery, and is given intravenously every 3 weeks.

Keytruda or Opdivo can be used as first-line therapy or after other therapies for metastatic melanoma or melanoma that cannot be removed surgically. Keytruda is given intravenously every 3 weeks.

Opdivo can also be used for patients with metastatic melanoma without the BRAF V600 genetic mutation; in addition, it can be used in combination with Yervoy for patients with or without the BRAF V600 mutation. Opdivo is given intravenously every 2 weeks.

Another new immunotherapy that is a different type of drug is Imlygic (talimogene laherparepvec); unlike the new checkpoint inhibitors, Imlygic is a drug made of a virus that destroys melanoma tumors. Imlygic is approved for patients with melanoma that came back (recurrent) after surgery; Imlygic is injected directly into the melanoma lesions and can be used concurrently with PD-1 therapies. 

The Approach to Treatment

No conclusive melanoma guideline is available to guide doctors on how long patients should continue immunotherapy, whether their melanoma responds to the therapy or not. Many patients have continued to use immunotherapy for 2 years or longer. But when patients have intolerable side effects, they would normally stop immunotherapy early.

Tumor genetic matching to therapy is not required before starting immunotherapy, although having elevated levels of PD-L1 in the blood indicates that the patient may have a better response; testing for PD-L1 levels is a prerequisite for the use of immunotherapy in some other types of cancer, where limited response has been found so far.

The anti-PD-1 immunotherapies have the highest rate of response in melanoma compared with other cancers. We still don’t know if there is a difference between the 2 anti-PD-1 drugs Keytruda and Opdivo, because there has not been a clinical trial that directly compared these 2 drugs one against the other. About 15% of patients with melanoma respond to Yervoy therapy when it is used as a single agent and not in combination with another drug.

Combination Immunotherapies

So the ideal treatment strategy for melanoma is to combine these drugs with one another; that is, using Yervoy with an anti-PD-1 drug, or with other new drugs being tested in clinical trials in the search for combination therapies that will increase the number of patients with melanoma who respond to therapy. This has been a slow and arduous process.

In one clinical trial that used the combination of Yervoy and Opdivo, 50% of the patients had regression of the disease with this combination, which is a high response rate; however, the side effects were so severe that 60% of patients had to stop Yervoy and continue with the anti-PD-1 drug alone. Nevertheless, the combination of these 2 drugs did have significant results.

Many other combination therapies are being studied in clinical trials and will be showcased as their effectiveness and safety in melanoma are proved.

Immune-Related Side Effects

The side effects with the anti-PD-1 drugs were underestimated from the outset. We are just now beginning to learn more about the side-effect profiles of immunotherapies, especially the anti-PD-1 drugs. Similar to most therapies, each patient has different side effects, ranging from mild to severe events.

Whereas chemotherapy’s side effects—especially nausea, vomiting, and hair loss—stem from the chemotherapy’s destruction of rapidly dividing healthy and cancerous cells, the side effects associated with immunotherapies are usually related to the immune system. These side effects often include inflammatory symptoms, such as rash, diarrhea, fevers, colitis (inflammation of the colon), and heart issues.

These immune-related adverse events can be quite serious, and even fatal; however, they are typically reversible when effective treatment guidelines on side-effect management are being followed correctly.

Steroids are frequently given to counter these side effects (the theory that steroids could block the effectiveness of immunotherapies has been disproved); stopping the immunotherapy altogether may also be needed if the side effects are particularly serious.

Serious heart issues, diabetes, and issues with thyroid function have been reported in some patients receiving immunotherapies. One of the more common side effects of immunotherapies is a change in the function of the thyroid gland. This can sometimes be corrected with thyroid replacement medication. Your doctor will likely monitor your thyroid function through a blood test.

Is It Worth It?

The cost of immunotherapies is enormous. Keytruda costs $12,500 a month per patient, or $150,000 per year. In a recent combination clinical trial, the cost of Yervoy alone was $158,282 (with a median progression-free survival of 2.9 months), the cost of Opdivo alone was $103,220 (with a progression-free survival of 6.9 months), and the cost of using Yervoy plus Opdivo together was $295,566 (progression-free survival of 11.4 months—nearly 4 times what was seen with Yervoy alone, which is currently the standard of care).

How will patients afford these new therapies? Patients in Medicare have a 20% copayment, so for the combination of Yervoy and Opdivo, which costs nearly $300,000 a year, patients would pay $60,000 out-of-pocket. The cost is much lower in other countries, in part because of their different healthcare systems. Japan cut the cost of Opdivo in half, probably because it was developed there and is the exception.

Yes, I believe the answer to the question whether immunotherapies are worth the cost is yes, if patients have access to them. More than 33% of patients with advanced-stage melanoma who have received one of the new immunotherapy drugs in an early clinical trial were alive 5 years after starting treatment, which is double the survival rate that is typical for this type of cancer.

In fact, 2 patients I worked with, both heading into end-of-life hospice care, were able to get into open-access clinical trials of Keytruda. Today, 2 years later, both are free of disease.

Finding out how to get all patients to respond to immunotherapies is the next frontier that will help unlock the door for all patients to tackle this disease. And if Japan can cut the cost of immunotherapies, maybe American companies can too.

The reality is that patients with melanoma are living far longer than ever before with immunotherapies and can lead productive lives while taking these drugs. If a 90-plus-year-old patient can tolerate immunotherapy and maintain an active life, then it is certainly worth its weight in gold, even when it costs about the same.

EDITOR’S NOTE: Other drugs approved by the FDA for melanoma and also involve the immune system are known as cytokine therapies, but these are older drugs that are not as effective as the newer immunotherapies, such as checkpoint inhibitors or monoclonal antibodies, and are therefore not included in this discussion.
The cytokines approved for melanoma include Sylatron (peginterferon alfa-2b), Proleukin (aldesleukin), and Intron A (interferon alfa-2b). The response to these drugs is very low and they are very toxic. A recent study showed that interferon was not better than observation alone.