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Clinical Trial
. 2023 Mar 2;388(9):813-823.
doi: 10.1056/NEJMoa2211437.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

Affiliations
Clinical Trial

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

Sapna P Patel et al. N Engl J Med. .

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. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

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Figures

Figure 1.
Figure 1.. Kaplan–Meier Estimates of Event-free Survival, as Assessed by the Local Investigators.
The log‑rank test was stratified according to disease stage and lactate dehydrogenase level at randomization. In the intention‑to‑treat analysis of event‑free survival, there were 105 events (38 in the neoadjuvant–adjuvant group and 67 in the adjuvant‑only group). All events that occurred before the start of adjuvant therapy were assigned an event date of 84 days. Tick marks indicate censored data.
Figure 2.
Figure 2.. Forest Plot of Event-free Survival According to Subgroup.
Shown are Kaplan–Meier estimates of 2‑year event‑free survival in the neoadjuvant–adjuvant and adjuvant‑only groups. The difference in 2‑year event‑free survival and 95% confidence intervals (horizontal lines) for the difference are reported. Zubrod’s performance‑status scores range from 0 to 5, with higher scores indicating greater disability; a score of 0 indicates that the patient is fully active, 1 that the patient is restricted in strenuous activity but is ambulatory, and 2 that the patient is unable to work but is ambulatory and capable of self‑care and up and about more than 50% of waking hours. Disease stages are defined according to the American Joint Committee on Cancer Cancer Staging Manual, 8th edition. The diamond represents the overall estimate, with the width of the diamond indicating the 95% confidence interval, and the horizontal lines also represent 95% confidence intervals. The sizes of the boxes are proportional to the numbers of events. LDH indicates lactate dehydrogenase.
Figure 3.
Figure 3.. Overall Response in the Neoadjuvant–Adjuvant Group.
The waterfall plot shows the maximum percentage change in the size of target lesions from baseline in patients who were assigned to receive both neoadjuvant and adjuvant therapy. Each bar represents 1 patient, and the dark green, blue, and light green bars indicate the disease stage at the time of enrollment in patients who underwent imaging assessment after completing neoadjuvant therapy. The thresholds for objective response (≥30% decrease) and disease progression (>20% increase) according to Response Evaluation Criteria in Solid Tumors, version 1.1, are shown. The purple bars indicate 3 patients (1 in each disease-stage subgroup) who had clinical disease progression without a follow-up tumor imaging assessment (1 patient) or discontinued neoadjuvant therapy early because of toxic effects (2 patients; 1 underwent surgery without imaging and 1 did not undergo surgery). Data from 10 patients who were still receiving neoadjuvant therapy and 2 patients who withdrew consent immediately after randomization are excluded from this figure.

Comment in

References

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