In resectable stage III to IV melanoma, three cycles of neoadjuvant pembrolizumab followed by adjuvant pembrolizumab was significantly more beneficial than adjuvant pembrolizumab alone, based on the results of the phase II SWOG S1801 trial presented in a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022.¹

Sapna P. Patel, MD

“Compared with the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improved event-free survival in resectable melanoma,” said medical oncologist ­Sapna P. Patel, MD, Associate Professor, Director of the Uveal Melanoma Program, and Melanoma Fellowship Program Director at The University of Texas MD Anderson Cancer Center, Houston.

At a median follow-up of 14.7 months, compared with adjuvant pembrolizumab alone, the addition of pembrolizumab before surgery significantly improved event-free survival, which at the 2-year landmark analysis was 72% vs 49%, respectively (hazard ratio [HR] = 0.58; P = .004). Overall survival data were immature, with just 36 deaths reported, including 14 in the neoadjuvant arm and 22 in the adjuvant arm, but the hazard ratio numerically favored neoadjuvant pembrolizumab (HR = 0.63; P = .18).

“The results really speak for themselves. You can drive a truck through those [Kaplan-Meier] curves. They really are impressive,” said Elad Sharon, MD, MPH, Medical Officer, Investigational Drug Branch, and part of the National Cancer Institute Cancer Therapy Evaluation Program.

Alexander M.M. Eggermont, MD, who led the pivotal ­KEYNOTE-054 trial showing the benefit of adjuvant pembrolizumab, commented after the presentation: “This is the phone call that you’re going to make to your surgeon…. Take stage III patients off the surgical schedule and send them to the medical oncologist for their first of three doses of pembrolizumab. Then do the surgery.”

Elad Sharon, MD, MPH

Alexander M.M. Eggermont, MD

Answering a Fundamental Question

SWOG S1801 aimed to answer what Dr. Patel called one of the fundamental questions for resectable cancer: Can treatment with immune checkpoint blockade before surgery enhance the antitumor response, or does it simply delay curative surgery?

According to Dr. Patel, there is a strong rationale for targeting PD-1 and more so for using a neoadjuvant rather than strictly adjuvant approach in resectable cancer. As she explained, response to PD-1–blocking therapy requires the presence of preexisting antitumor T cells in contact with cancer cells. Adjuvant anti–PD-1 therapy may activate antitumor T cells at sites of systemic micrometastases. But when given before surgery, anti–PD-1 therapy may induce an immune response from a larger population of T cells that reside in the bulk of the tumor. By inhibiting PD-1/PD-L1 immune checkpoints before surgery—ie, before resecting the tumor bed and thus leaving behind larger numbers of antitumor T cells—it is possible to induce a systemic immune response at local and distant sites.

The study randomly assigned 313 patients to surgery followed by 18 cycles of adjuvant pembrolizumab (200 mg every 3 weeks) or to three cycles of neoadjuvant pembrolizumab followed by surgery and 15 more cycles of pembrolizumab. The primary endpoint was event-free survival, defined as the time from randomization to the occurrence of one of the following events: 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.

For 42 patients, target lesions increased during the study, but 30 patients were still able to undergo surgery. One of the patients with a complete response declined surgery and has not had a recurrence of disease after 31.5 months of follow-up. Upon local review, 21% of patients in the neoadjuvant arm also achieved a pathologic complete response.

In the neoadjuvant arm, 8% had disease progression that precluded surgery, and 6.5% had residual disease or developed metastasis prior to starting adjuvant therapy. In the adjuvant arm, 11% had residual disease or developed metastasis before starting adjuvant therapy.

Tumor-related events—including disease progression and melanoma recurrence—occurred in 31 patients (20%) in the neoadjuvant arm and 61 patients (40%) in the adjuvant arm. For all prespecified subgroups, the neoadjuvant arm was favored, leading to relative risk reductions of at least 50% in patients with aged 66 and older; high LDH levels; stage IIIC or IIID/IV disease; presence of ulcerations; and BRAF mutations.

No New Safety Signals Reported

No new safety signals were observed for pembrolizumab, and the rates of grade ≥ 3 treatment-related adverse events were similar between the study arms. The most common adverse event in both arms was infection of the skin or wound, which occurred in three patients in the neoadjuvant arm and two patients in the adjuvant arm. Four patients on adjuvant therapy and one patient on neoadjuvant therapy developed a grade ≥ 3 maculopapular rash. Neoadjuvant pembrolizumab did not increase adverse events in the perioperative period, reported Dr. Patel.

Considering the potential impact of these data, Dr. Patel believes data safety monitoring committees for randomized trials currently underway should discuss whether the adjuvant arms should be “reconsidered or redesigned” and whether additional monitoring should be done. 

DISCLOSURE: Dr. Patel reported financial relationships with TriSalus, Cardinal Health, Castle Biosciences, Novartis, Advance Knowledge in Healthcare, Delcath, Immunocore, Pfizer, Provectus, Lyvgen, Bristol Myers Squibb, InxMed, Foghorn Therapeutics, Ideaya, Novartis, Seagen, Syntrix Bio, and TriSalus Life Sciences. Dr. Sharon reported no conflicts of interest. Dr. Eggermont has served as a consultant to Agenus, BioInvent, CatalYm, Clover, Ellipses, Galecto, IO Biotech, IQVIA France, Merck, Pfizer, SalRoPa, Skyline, TigaTx, and Trained Therapeutics TTX.

REFERENCE

1. Patel S, Othus M, Prieto V, et al: Neoadjuvant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801). ESMO Congress 2022. Abstract LBA6. Presented September 11, 2022.