Neoadjuvant therapy for melanoma

Neoadjuvant therapies have the potential to downstage unresectable disease and allow operative resection with a curative intent.

Neoadjuvant immunotherapy leads to a greater expansion of T cells in the blood compared with the adjuvant immunotherapy.

Leaving a tumor in place educates the immune system to generate an anti-tumor immune response, better than if the tumor was removed first.

Preoperative therapy may improve the rate of microscopically margin negative resection.

Neoadjuvant therapy means earlier treatment of systemic micrometastatic disease, fewer delays in systemic therapy caused by surgical complications, and a high likelihood of completion of the planned course of multi modality treatment.

Systemic immunotherapy and targeted BRAF/MEK innovation may be more effective in the neoadjuvant management setting: suggesting the presence of tumor biomass may increase the probability of immunologic activation against tumor antigens.

A neoadjuvant approach allows for biologic response assessment to treatment providing information that can indicate prognosis, decision making regarding additional treatment and information about the cellular molecular effects of therapy on the tumor microenvironment.

A pooled analysis of six clinical trials found a pathological complete response rate to neoadjuvant therapy of 40% overall, 47% with targeted therapy, and 33% with immunotherapy: a pathologic complete response, correlated with improved relapse, free, survival, and overall survival, suggesting the use of pathological complete response as an early surrogate endpoint in clinical trials.

Neoadjuvant therapy for melanoma may delay the time to surgical resection and carries a risk that a disease of some patients will progress and become unresectable. 

Both targeted therapy and checkpoint blockade are associated with toxicities that could delay surgery, preclude surgery altogether, or complicate the surgical course.

There are high rates of durable responses with neoadjuvant targeted therapy for BRAFV V600 positive melanomas which occurs in approximately 50% of patients.

Neoadjuvant therapy with checkpoint blockers is efficacious in melanoma.

Neoadjuvant checkpoint blockers may be associated with a higher recurrence free rate than adjuvant  therapies.

BRAF/MEK plus checkpoint blockade is being evaluated as neoadjuvant melanoma therapy.

The combination of PD-L1 inhibitor Nivolumab  plus relatlimab a lymphocyte antigen gene 3 (LAG-3) inhibitor showed improvement in metastatic melanomas vs Nivolumab alone.

Among patients with resectable stage III or IV melanoma, event free survival was significantly longer among those who receives Pembrolizumab, both before, and after surgery than among those who received adjuvant,Pembrolizumab alone (Patel SP).

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