The impact of age on treatment decisions in high-risk and metastatic melanoma

June 2021 EADO 2021 Tom Feys

Reinhard Dummer, MD, PhD, Vice-Chairman of the Department of Dermatology, University Hospital Zurich, Switserland

In melanoma, age is known to be associated with several tumour characteristics, including tumour type and tumour mutational burden. As a result, melanoma in older patients represents a different clinical situation than what is seen in younger population. Physicians thus have to carefully balance the patient’s age against other patient and disease characteristics to determine the optimal treatment pathway for each individual patient.

Patient and disease characteristics

In order to decide on the optimal treatment for each individual patient, both the characteristics of the patient and the tumour should be taken into account. For the patient, potential co-morbidities, concurrent medications, mobility, motivation and quality of life (QoL) should all be considered. Patients often have the perspective that taking medications inevitably reduces their QoL. However, results from the COMBI-v study, comparing the dabrafenib and trametinib combination with vemurafenib monotherapy in patients with unresectable or metastatic cutaneous BRAFV600 mutation positive melanoma, clearly indicate that this is not always the case. In this trial, the combination of dabrafenib and trametinib even improved the QoL.

Also characteristics of the tumour itself should be taken into account in the decision-making process. In this respect, the tumour location, melanoma subtype, driver mutations and tumour mutation burden are all important aspects. For patients with advanced age, melanomas are often originating in chronically UV-exposed skin such as the face. Especially NF1-mutant tumours are common in patients older than 65-years, while mutations in BRAF and RAS are rather rare. In many cases, these tumours have a high tumour mutational burden and are therefore considered to be good candidates for immunotherapy. In line with this hypothesis, many older melanoma patients show very high response rates with immunotherapy monotherapy alone.

Treatment decisions

According to the ESMO guidelines, sentinel node biopsies are not recommended for patients older than 75 years. However, Prof. Dummer does consider sentinel node biopsy in patients above 75 years old in case the patient is believed to be a candidate for adjuvant therapy (sentinel node biopsy can result in upstaging).

For patients with resected stage III disease treated with adjuvant dabrafenib and trametinib, age does not negatively impact treatment outcomes. One might even assume that patients above 65 years old have a better disease outcome with this strategy (HR 0.54 for <65 year old and HR: 0.41 for ≥65 years). As such, a higher age alone should not be an argument to omit adjuvant therapy with targeted medication. Importantly, the same holds true for adjuvant treatment with anti-PD1.

For patients with inoperable stage III/IV melanoma, immunotherapy is one of the preferred first-line treatment options. However, a number of factors should be taken into account before starting immunotherapy; symptoms, patient’s spirit, melanoma subtype, age, tumour load, tumour mutational burden, the presence of T-cell infiltration and the expression of PD-L1. Although the combination of nivolumab and ipilimumab is very powerful and survival seems to be improved as compared to monotherapy with these drugs, this advantage is more pronounced in the younger population (HR[95%CI]: 0.73[0.56-0.94] for age <65 years and HR[95%CI]: 0.89[0.65-1.23] for age ≥65 years). Considering the significant toxicity of the combination regimen, monotherapy might therefore be the better choice for the elderly population. However, also other clinical elements such as elevated LDH or brain metastases should be considered. For example, in patients with BRAF-mutated melanoma, the benefit of encorafenib + binimetinib regimen was mainly observed in patients with normal LDH levels. Importantly, however, the advantage of combined MEK-BRAF inhibition with encorafenib + binimetinib over vemurafenib monotherapy was fairly similar in patients below or above 65 years old (HR[95%CI]: 0.65[0.49-0.88] for age <65 years and HR[95%CI]: 0.64[0.41-1.01] for age ≥65 years.

Conclusion

Age can have an important impact on treatment decisions in patients with melanoma. If adjuvant therapy is considered for an older patient, sentinel node biopsy should also be considered for patients above 75 years old. When adjuvant therapy is being deemed necessary, both targeted therapy and immunotherapy are good treatment options. However, in the current COVID-19 pandemic, less frequent hospital visits associated with targeted therapy might be preferred. In patients older than 65 years with stage IV disease, immunotherapy monotherapy should be preferred above immunotherapy combination regimens. In BRAF-mutant patients, age does not seem to have an impact on treatment outcomes with combined BRAF-MEK inhibition.

Reference

Dummer R, Mangana J, Levesque M. How age impacts on my treatment decisions in high risk and metastatic melanoma. Presented at EADO 2021.

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