Immunotherapy for Resectable Advanced Melanoma: Before or After Surgery?

Melanoma, the most aggressive form of skin cancer, is also the cancer in which immunotherapies are most effective. According to global cancer statistics, melanoma accounted for 4% of skin cancer cases worldwide in 2020.

Melanomas are classified by stage and certain genetic features. Stage 3 melanoma has spread to tissues beneath the skin or to lymph nodes, but not to distant organs. Standard treatment involves surgery to remove the tumour, followed by removal of lymph nodes. Stage 4 is the stage in which the tumour has metastasised (spread) to other parts of the body.

A New Concept in Melanoma: Periadjuvant Treatment

In patients receiving treatment for surgically resectable stage 3 and 4 melanoma, periadjuvant treatment (starting before surgery and continuing afterwards) pembrolizumab immunotherapy may produce better outcomes than adjuvant (postoperative) pembrolizumab alone. These results were published in New England Journal of Medicine on 2 March 2023.

This new approach combines neoadjuvant and adjuvant immunotherapy.

The study tested the hypothesis that, although postoperative adjuvant immunotherapy benefits patients with stage 3 or 4 melanoma, its use before surgery might produce greater antitumour T-cell activation.

The researchers observed that patients receiving periadjuvant pembrolizumab had longer event-free survival (EFS) than those in the adjuvant group.

The SWOG S1801 Study

This open-label, phase 2 clinical trial included 313 patients with surgically resectable stage IIIB-IVC melanoma.

• 154 patients were randomly assigned to receive 3 doses of neoadjuvant (preoperative) pembrolizumab followed by 15 doses of adjuvant pembrolizumab, or
• 159 patients were assigned to receive 18 doses of adjuvant pembrolizumab alone.

During 14.7 months of follow-up, event-free survival was significantly longer in the periadjuvant group (P = 0.004).

The 2-year event-free survival rate was 72% in the periadjuvant group and 49% in the adjuvant-only group.

At 2 years, event-free survival favoured periadjuvant treatment across all subgroups.

In the periadjuvant group, 50 patients completed all adjuvant treatment cycles, and none experienced recurrence. In the adjuvant group, 38 completed all adjuvant cycles, and 4 (11%) experienced recurrence.

Most patients in both treatment groups underwent surgery: 88% of those receiving periadjuvant treatment and 95% of those receiving adjuvant treatment alone. At the time of analysis, 10 patients in the periadjuvant group were still receiving neoadjuvant pembrolizumab.

Reasons for not undergoing surgery in the periadjuvant group included progression (12 patients), withdrawal of trial consent (2 patients), toxicity (1 patient) and coexisting illness (1 patient). One additional patient who achieved a complete clinical response declined surgery and remained event-free after 31.5 months of follow-up.

In the adjuvant-only group, reasons for not undergoing surgery included withdrawal of consent (7 patients) and scheduling issues (1 patient).

In the periadjuvant group, 19 grade 3-4 (severe) adverse events were attributed to neoadjuvant therapy and 7 severe adverse events to adjuvant therapy. In the adjuvant-only group, 11 severe adverse events were attributed to adjuvant therapy. Neither group had any deaths attributed to pembrolizumab.

In conclusion, this study shows greater efficacy with periadjuvant pembrolizumab than with adjuvant pembrolizumab. The findings demonstrate the benefits of combining neoadjuvant and adjuvant immunotherapy for patients with resectable stage 3 and 4 melanoma. Treatment-related adverse effects must also be considered. The study further shows that the timing of immunotherapy may substantially affect patient outcomes.