Abstract

Background

Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

Methods

In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant–adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.

Results

At a median follow-up of 14.7 months, the neoadjuvant–adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P=0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant–adjuvant group and 14% in the adjuvant-only group.

Conclusions

Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified.

Discussion

In this phase 2, randomized trial involving patients with resectable stage III or IV melanoma, the percentage of patients with event-free survival at 2 years was 23 percentage points higher among those who received neoadjuvant pembrolizumab followed by adjuvant pembrolizumab than among those who received adjuvant pembrolizumab alone. In the neoadjuvant–adjuvant group, disease progression or toxic effects resulting in an inability to undergo surgery occurred in less than 10% of the patients, and the overall incidences of grade 3 or 4 toxic effects were lower than those reported in studies of neoadjuvant immune-checkpoint blockade combining anti–PD-1 and anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapies.^8,10

Previous studies of neoadjuvant therapy with anti–PD-1 monotherapy in patients with resectable melanoma showed radiographic responses and an acceptable side-effect profile that were similar to what we report for this trial.^10,11 In our trial, the incidence of surgery-related adverse events did not appear to be higher with the use of neoadjuvant pembrolizumab than with surgery first in the adjuvant therapy group. The benefit of neoadjuvant pembrolizumab was seen across all subgroups, although sample sizes are too small to draw conclusions in some distinct subgroups. Because only nine patients had acral melanoma and four patients had mucosal melanoma, we are unable to conclude whether the value of neoadjuvant pembrolizumab would be different for these melanoma subtypes.

Our trial included an adjuvant-therapy period for both treatment groups. However, some adaptively designed trials of neoadjuvant therapy for melanoma are investigating the de-escalation of surgery, the elimination of adjuvant therapy, or both in patients with a complete or near-complete pathological response (ClinicalTrials.gov numbers, NCT02977052. opens in new tab, NCT04949113. opens in new tab, and NCT04133948. opens in new tab).^12,13

In a phase 1b, randomized trial involving 20 patients with stage III melanoma, neoadjuvant administration of the anti–PD-1 antibody nivolumab and the anti–CTLA-4 antibody ipilimumab for two cycles before surgery resulted in a larger expansion of tumor-resident T-cell clones than administration of the same therapy postoperatively.⁸ Several small studies involving patients with resectable melanoma have shown the feasibility and potential clinical benefit of administering neoadjuvant therapy with pembrolizumab,¹¹ the combination of nivolumab and ipilimumab,^10,12,13 or the combination of nivolumab and relatlimab.¹⁴ Tumor response, as assessed by means of pathological analysis of a surgical specimen obtained after neoadjuvant therapy, is a promising marker of long-term therapeutic benefit. In a pooled analysis of previously reported results of trials of immune-checkpoint blockade as neoadjuvant therapy for melanoma, the combined incidence of pathological complete response was 33% (42% with the combination of anti–PD-1 antibody and anti–CTLA-4 antibody and 20% with anti–PD-1 monotherapy).¹⁵ Balanced against the putative benefits of neoadjuvant therapy is the potential for tumor progression or treatment-related toxic effects to interfere with the patient’s ability to undergo surgery in a timely fashion.¹⁶

Our trial shows that the timing of administration of an immune-checkpoint inhibitor relative to surgery can have a large effect on patient outcomes, even though the same systemic therapy was given to both trial groups. Our results, combined with our understanding of the mechanism of action of PD-1 blockade therapy, support the concept that neoadjuvant administration functionally inhibits the immune checkpoint before antitumor T cells are surgically resected. These data add to the body of knowledge supporting the use of neoadjuvant therapy in oncology. A recent trial showed that among patients with resectable non–small-cell lung cancer, those who received neoadjuvant immune-checkpoint blockade with the use of anti-PD1 therapy in combination with chemotherapy had longer event-free survival than those who received chemotherapy followed by surgery.¹⁷ A meta-analysis showed that in patients with breast cancer, neoadjuvant chemotherapy resulted in tumor downsizing and increased use of breast-conserving surgical procedures but was associated with a higher frequency of local recurrence in the breast than the use of adjuvant chemotherapy.¹⁸ In other trials involving patients with bladder cancer, the use of neoadjuvant chemotherapy led to tumor downstaging and improved long-term outcomes.^19,20

Our trial showed that among patients with high-risk, resectable stage III and stage IV melanoma, those who received pembrolizumab as neoadjuvant therapy followed by adjuvant therapy had longer event-free survival than those who received standard-care adjuvant pembrolizumab alone.

Source: NEJM