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Melanoma: New Drugs and New Challenges (Part 2 of 2)

Editor’s note: This is part 2 of a 2-part post on the latest research in melanoma. To learn about research into drug combinations for melanoma that may work better than single drugs, check out Melanoma: New Drugs and New Challenges (Part 1 of 2).

As always, the more new treatments become available in melanoma, the more new challenges arise. With eight new drugs approved for melanoma in the last five years, oncologists may sometimes face the difficult choice of what drugs to choose for a patient’s first-line treatment. Immune checkpoint drugs sometimes cause serious side effects, but progress is being made on how to treat these and also how to treat patients with pre-existing autoimmune conditions. New approaches are needed in efforts to prevent recurrence of melanomas diagnosed at earlier stages of disease progression. These and other challenges are discussed below.

Sequencing of treatments in BRAF-positive melanoma

While the combination of BRAF and MEK inhibitors works very fast to shrink melanoma tumors in close to 70% of patients, most of these patients (especially those with high metastatic burden) eventually develop resistance. Immunotherapy drugs have a lower rate of response and take quite a bit longer to shrink tumors, but many of the patients who do respond experience long-lasting remissions.

How to decide what to use first in BRAF-mutant melanoma? Some data indicate that if a BRAF/MEK inhibitor combination is used up front, response to subsequently needed treatment with immune checkpoint drugs could be adversely affected. On the other hand, patients with metastatic melanoma are sometimes so tumor-ridden and ill that a fast-acting drug is needed, and targeted drugs make more sense as an upfront treatment.

An ongoing clinical trial is designed to answer these questions for BRAF-mutant melanoma patients who have a good performance status. Enrollees will receive either dabrafenib with trametinib first, followed by nivolumab with ipilimumab, or vice versa.

New options for melanoma without BRAF mutation

In terms of treatment, specialists used to consider cutaneous melanomas without BRAF mutations as “BRAF wild-type.” The question of “what to use first” did not exist until now for these cancers, which were uniformly treated with immune checkpoint inhibitors. In reality, molecular subtypes within this group account for at least 50% of skin melanomas. One group is defined by mutations in NRAS, which are generally found in 20% of cutaneous melanomas. There are no direct inhibitors of NRAS, leaving immunotherapy drugs as the only available choice.

Recent results from clinical trials testing a newer MEK inhibitor, binimetinib, suggest it has promise as another treatment option for the NRAS subtype, albeit available only in trials. In the NEMO trial, patients treated with binimetinib had a higher response rate and increased overall survival compared to patients treated with the chemotherapy drug dacarbazine. This included patients who had previously been unsuccessfully treated with immunotherapy—an important finding, considering that NRAS-mutant melanoma nowadays is treated with immunotherapy drugs first.

A significant proportion of melanomas have mutations in the gene NF1. It is possible that these tumors may also respond to inhibition of MEK, and this hypothesis will be addressed in one arm of the NCI MATCH trial. This study will explore the activity of trametinib in NF1-mutant melanoma.

Safety of immune drugs in melanoma patients with autoimmune disease

Patients with pre-existing autoimmune conditions were previously excluded from trials or treatments with immune checkpoint drugs for fear of a major flare in their conditions. An Australian trial examined the safety and outcomes of anti-PD-1 drugs in these patients, including those with conditions such as rheumatoid arthritis, inflammatory bowel disease, hypophysitis, psoriasis, scleroderma, and others. While a flare in symptoms did occur in some patients (38%), most symptoms resolved after immunosuppressive treatments (except in hypophysitis). These patients also tended to develop new immune-related side effects more often (34%) than did patients without autoimmune conditions. The objective response rate was 40%, and only 16% were forced to discontinue anti-PD-1 treatment.

Resected stage III melanoma

Despite new treatment options for other patients, what is thoroughly lacking is adjuvant (after-surgery) treatment of resected melanoma stage III, in particular stage IIIC. This diagnosis carries with it a very high probability of metastatic recurrence after the tumor and all cancerous lymph nodes are removed. Ipilimumab (Yervoy) is the only treatment that has been approved by the FDA to prevent recurrence, but it is not very effective. Very few trials are exploring BRAF inhibitors in an adjuvant setting for resected BRAF-positive melanoma. It is possible that PD-1 inhibitors may have better activity in the adjuvant setting, and trials are addressing this possibility, but the expected FDA-approval of drugs to prevent recurrence may not come soon enough for some patients. 

Intralesional drugs

I wrote a while ago about intralesional drugs, which are injected directly into melanoma tumors. The most advanced of these are T-VEC, developed by Amgen, and PV-10, which is still in a few trials run by the small company Provectus. I predicted that T-VEC would advance to market much faster because of Amgen’s deep pockets, in spite of the very similar efficacy data available at that time. Indeed, T-VEC is now FDA-approved for unresectable melanoma, while PV-10 seems to be frozen in trials. T-VEC is a re-engineered herpes simplex virus that expresses the protein GM-CSF in order to activate the immune response. PV-10 is just a dye, Rose Bengal, that also stimulates immune system, but at a much lower cost.

The use of T-VEC is limited to melanomas that cannot be resected but in which some lesions are amenable to injection of the drug. This combination of lesions is usually seen in a fairly low percentage of patients—a fact that severely limits the use of T-VEC. This drug is not effective in shrinking visceral (internal) metastases, which are often found in patients with metastatic melanoma. The pivotal phase III trial that led to T-VEC’s FDA-approval showed that 16% of patients who received T-VEC injections had durable responses. When analyzed separately, patients with unresectable stage IIIC melanoma had a better response rate of 33%.

T-VEC in combination with ipilimumab has produced encouraging responses in advanced melanoma, with an overall survival rate of 67% at 18 months. Trials of both T-VEC and PV-10 in combination with pembrolizumab are ongoing. T-VEC is also now moving on to testing in resectable advanced melanoma (stage IIIb/C and stage IV with one metastatic lesion). This trial is randomized, and half of the patients will receive T-VEC injections prior to surgery (neoadjuvant treatment), while the other half will not. This is obviously intended to extend the indication for T-VEC to a neoadjuvant setting.

Meanwhile, the fate of PV-10 is unclear.

Image Credit: Malignant melanoma (Credit: KGH)