What we can learn from revolutionary melanoma treatment

The largest analysis of metastatic melanoma patients who received a targeted therapy combination shows the treatment provides long-term survival for some and furnishes new, important context for sorting out treatment options.

“The treatment of metastatic melanoma over the last five years has been revolutionized by both targeted therapies and immune therapies,” says Michael Davies, M.D., Ph.D., associate professor of Melanoma Medical Oncology and senior author of the study in Lancet Oncology.

“The general thought has been that only immunotherapy can achieve long-term benefit in advanced melanoma. However, this large study with two years of follow-up shows long-term survival is accomplished in subsets of patients treated with targeted therapy,” Davies says. “Ultimately we need to determine what factors accurately predict who will benefit the most from targeted therapy and who will benefit from immunotherapy, so that we can optimize and personalize treatments for each patient.”

Previous studies were too small for detailed analysis of factors associated with disease response, progression and patient survival with combination targeted therapy treatment, so Davies and colleagues analyzed 617 patients treated with the same combination in three separate, randomized clinical trials.

BRAF gene mutation

All patients had at an activating mutation of the BRAF gene, which is the most common mutation that occurs in melanoma. All were treated with the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib, a combination approved by the Food and Drug Administration in 2014. Both drugs inhibit the activation of the MAPK pathway, which is a major driver of tumor cell growth and proliferation.

Baseline serum levels of lactate dehydrogenase (LDH), a known prognostic factor for stage IV melanoma, and tumor burden emerged as important factors for predicting long-term benefit from treatment.

In general clinical practice, metastatic melanoma patients with normal levels of LDH and low tumor burden are often treated with immunotherapy, while targeted therapy combinations are frequently reserved for patients with high LDH levels, Davies says.

This study showed that patients with low LDH levels frequently have very good long-term outcomes with targeted therapy treatment. Patients with a normal LDH and metastatic tumors in three or fewer organs had overall survival rates of 90% at one year and 75% at two years after the start of treatment. In contrast, for patients in which the LDH was at least two times the upper limit of normal, the two-year overall survival rate was only 7%.

Complete response with targeted therapy

Particularly impressive results were noted in patients who achieved a complete response (CR) with targeted therapy, which was observed in 16% of patients. The complete responders had a median progression-free survival (PFS) of 3.2 years, compared to 12.6 months for partial responders, 4.6 months for those who had stable disease and 1.8 months for those who progressed. The 2-year overall survival rate for the complete responders was 88%. As many of those patients remain alive and on-treatment, additional follow-up will be needed to fully define their long-term benefit.

The best predictor of achieving a complete response was the sum of tumor diameters at baseline. For patients who had a sum less than the median of the full cohort (58 mm), the chance of achieving a complete response was 34%. An important implication of this is that identifying and treating stage IV patients with smaller disease burden may maximize the benefit of dabrafenib and trametinib combination. The results also suggest that targeted therapies, which have been approved for patients with stage IV melanoma, may also be very effective in patients with earlier stages of disease.

Multiple clinical trials are currently ongoing to evaluate the efficacy of targeted therapies in the adjuvant setting, after melanoma patients with stage III disease have undergone surgery.

Davies also noted that MD Anderson recently reported promising initial results of the first randomized trial of treatment with dabrafenib plus trametinib before surgery in stage III melanoma patients with an activating BRAF mutation. Presurgical trials of both targeted and immune therapies are ongoing at MD Anderson.

This study also helped identify remaining challenges. While over half of the patients with high LDH levels responded initially to the targeted therapy treatment, the duration of those responses was quite short. Davies notes: “Despite tremendous progress, the development of more effective treatments for patients with high LDH remains an unmet medical need.”

Identifying and refining clinical factors that predict outcomes with targeted therapies provides a foundation for future research. “The information from this analysis provides a strong framework for future laboratory investigations to understand the basis of resistance to this treatment — and for the development of rational approaches that may be more effective,” Davies says.

“Conducting this type of analysis will help guide our treatments for patients today and help ensure that our research is focused on the most important and impactful questions that will ultimately reduce the burden of, and deaths from, this highly aggressive disease.”