Neoadjuvant immunotherapy should be considered for patients with high-risk resectable melanoma because it improves event free survival compared to adjuvant therapy, according to results from a pembrolizumab trial presented at ESMO 2022.

Study investigators for the SWOG-S1801 trial said it addressed the questions of whether treatment with immune checkpoint blockade before surgery induces an enhanced anti tumour immune response that leads to better outcomes.

In their study, 345 patients with respectable stage IIIB through stage IV melanoma were randomised to receive either adjuvant or neoadjuvant immunotherapy with pembrolizumab. The adjuvant arm had upfront surgery followed by 18 cycles of 200mg of pembrolizumab. The neoadjuvant therapy received three cycles of pembrolizumab every three weeks before surgery, then an additional 15 cycles following surgery.

The primary endpoint measured was the duration of event-free survival (EFS), defined as the time from randomisation to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

With a median follow-up of 14.7 months, EFS was significantly longer in the neoadjuvant therapy arm, with a hazard ratio of 0.58  (p = 0.004) when compared to the adjuvant therapy arm. Landmark two year EFS was 72% in the neoadjuvant arm and 49% in the adjuvant arm.

With only a limited number of deaths reported in trial participants, the overall survival data was immature and difference between groups did not reach statistical significance, with a hazard ratio of 0.63 (p= 0.18), study lead investigator Dr Sapna Patel of the MD Anderson Cancer Center, Texas, said.

NOW we must change the #melanoma management guidelines across the world. #Neoadjuvant #immunotherapy better than adjuvant in resectable stage 3&4 melanoma SWOG1801 HR 0.58 p0.004 fir event-free survial pic.twitter.com/k08Je75x1Z

— Professor Georgina Long AO (@ProfGLongMIA) September 11, 2022

She noted that EFS favoured neoadjuvant therapy in all subgroups including age, performance status and BRAF mutation status.

The study results showed that a similar proportion of patients made it through surgery to adjuvant pembrolizumab in both arms. Among patients in the neoadjuvant arm, 8% experienced disease progression that precludes surgery.

Tumour-related events such as disease progression or recurrence occurred in 20% of patients in the neoadjuvant arm versus 40% in the adjuvant arm.

For safety outcomes, the rates of adverse events attributed to pembrolizumab or surgery were similar in both arms. In the neoadjuvant arm, 28 of 132 patients (21%) with submitted pathology reports were noted to have complete pathologic response (0% viable tumor) on local review.

Dr Patel said the rationale for neoadjuvant immunotherapy was that inhibiting the PD-1/PD-L1 immune checkpoint before surgery would induces a systemic immune response before resection of the tumour, leaving behind larger numbers of anti-tumour T cells.

“These cells can then be reactivated and circulated systemically to recognise and attack micrometastatic melanoma tumours,” she said.

“Based on the findings from S1801, patients with high-risk melanoma should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact,” Dr Patel suggested

“Future studies can explore de-escalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy.”

Speaking at an ESMO discussion forum, Professor James Larkin of the Royal Marsden Hospital, London, described the SWOG study as a “landmark” trial with a similar and powerful design, that delivered promising results.

However he cautioned that further follow up was necessary and further analysis of how pathology reporting and correlation with EFS was important.

Professor Larkin said there were still many questions to be answered about neoadjuvant immunotherapy, such as the optimal duration of treatment and whether it could be individualised.

There are also questions about whether surgery may be avoided by some patients, and conversely how much post-operative surgery is needed and whether pathology could determine this.

“And there’s a question about who might need anti-CTLA-4 in addition to anti PD-1 … could you decide that on the basis of baseline biopsy and potentially intensify the treatment?”

Also speaking at the ESMO session, Professor Sherene Loi of the Peter Mac Cancer Institute, Melbourne, said the results from SWOG and other trials presented at the meeting provided strong evidence to support neoadjuvant therapy becoming the preferred approach for many cancers.

“Now I think we have a large body of data, clinically, biologically and now a randomised trial that supports the neoadjuvant approach as optimal for facilitating T cell responses in cancer patients,” she said.

“And I suspect that this should be considered for all cancers in early stage settings that are developing immunotherapy combinations or approaches.”

She added that pathological responses and long term outcomes would need to be validated for other tumour types, and there is also a need for bio markers to be identified to guide treatment escalation and de-escalation.

However she cautioned that there were still many unanswered issues in the use of neoadjuvant immunotherapy such as the right balance of radiotherapy, the optimum duration of immune therapy and the implications for fertility in younger patients.