In a number of cancers, it remains an open question whether starting immunotherapy before surgery, while the bulk of the tumor is still in place, is a good or neutral/bad thing. Would it result in a significantly more effective immune response against the disease? For patients with high-risk resectable melanoma, it now appears the answer is yes! Starting an immune checkpoint inhibitor neoadjuvantly does make a difference, one that’s markedly beneficial.

This answer, not surprisingly, comes from a SWOG trial, S1801. SWOG melanoma committee chair Dr. Sapna Patel presented results of this clinical study at a Presidential Symposium at the European Society for Medical Oncology’s (ESMO’s) Congress 2022 in Paris last weekend. 

Not only were the results well received in the hall in Paris, oncologists on social media were also uncommonly expressive about the findings: “a new French revolution … Liberté, égalité, fraternité, et neoadjuvanté,” “never thought that I would see near 80% event-free survival in melanoma during my professional lifetime,” “incredible,” “mind blown,” and, the one we really love to see, “practice changing.”

The most memorable line may have come from the NCI’s Dr. Elad Sharon, who said of the event-free survival graph, “you could drive a truck through those curves” (full disclosure, Dr. Sharon is a coauthor of the abstract, so take that into consideration).

Enthusiasm aside, here are the details of the study and its results, also summarized in our press release and available in original form in the ESMO abstract.

The S1801 trial enrolled 345 patients with operable stage IIIB through IV melanoma. Patients were randomized to either upfront surgery followed by 18 cycles of pembrolizumab (given every three weeks) or to an initial three cycles of pembrolizumab before surgery, followed by surgery and then by 15 cycles of pembrolizumab. 

The primary endpoint was event-free survival, measured from randomization to any of these events: the inability to undergo surgery because of progression or toxicity, the inability to start adjuvant therapy within 84 days (the standard window for melanoma), melanoma recurrence after surgery, or death from any cause.

The primary analysis, at a median follow-up time of 14.7 months, found that event-free survival was significantly longer on the neoadjuvant arm than the adjuvant arm. The event rate on the neoadjuvant-plus-adjuvant arm was 42 percent lower than that on the adjuvant-only arm (hence the truck lane on the Kaplan-Meier curve). The rates of events before surgery were similar on both arms – the difference in event rates emerged only after the start of adjuvant therapy.

Importantly, the benefit from neoadjuvant immune checkpoint blockade was consistent across a range of factors, including patient age, sex, performance status, disease stage, and BRAF status. Also, the rates of adverse events attributable to pembrolizumab or surgery were similar on both arms, and the same proportion of patients made it through surgery and to adjuvant therapy on both arms. Finally, the use of neoadjuvant pembrolizumab did not increase the rate of surgical complications or events, and there was no increase in any safety-related signal.

Dr. Patel has said the takeaway from S1801 is that neoadjuvant immunotherapy for resectable melanoma improves outcomes. Or, as she put it more colloquially: “It’s not just what you give, it’s when you give it.”

This trial is an incredibly good example of why we do what we do!

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