Neoadjuvant Initiation of Pembrolizumab Improves Outcomes vs Adjuvant Therapy Alone in Advanced Melanoma


Starting immunotherapy prior to surgical resection led to better outcomes vs standard, adjuvant-only immunotherapy in a phase 2 trial of patients with advanced melanoma.

Treatment with neoadjuvant and adjuvant pembrolizumab (Keytruda) led to improved event-free survival (EFS) compared with adjuvant pembrolizumab alone for patients with resectable stage III or IV melanoma, a study published in The New England Journal of Medicine found.1

The phase 2 trial (NCT03698019) randomized patients with clinically confirmed advanced, resectable melanoma to receive either 3 doses of neoadjuvant pembrolizumab followed by surgery and 15 doses of adjuvant pembrolizumab, or surgery followed by adjuvant pembrolizumab given every 3 weeks for approximately 1 year (18 doses total) or until disease recurrence or significant toxicity.

“This is the first clinical trial demonstrating that neoadjuvant therapy—that given before surgery—is superior to the same therapy given in the adjuvant setting—after surgery,” senior study author Antoni Ribas, MD, director of the Tumor Immunology Program at UCLA Jonsson Comprehensive Cancer Center, said in a statement.2 “This is because it is best to turn on the immune system inside the cancer before it is taken out with the surgery.”

Pembrolizumab, a programmed death 1 (PD-1)–blocking antibody, is currently FDA approved for the treatment of patients with a host of cancer types, including certain patients with melanoma: those with unresectable or metastatic melanoma, and patients with stage IIB, IIC, or III melanoma who have already undergone complete surgical resection.3 The new trial results suggest that starting immunotherapy with pembrolizumab in the neoadjuvant setting could benefit patients without increasing the total number of doses.

The main end point of the trial was EFS in the intention-to-treat population, and safety was also evaluated.

A total of 313 patients from 90 US sites were eligible for the study and randomized to the neoadjuvant-adjuvant cohort (n = 154) or the adjuvant-only cohort (n = 159). At a median of 14.7 months of follow-up, EFS was significantly longer in the neoadjuvant-adjuvant group compared with the adjuvant-only cohort (P = .004 by the log-rank test). At 2 years, EFS was 72% in the neoadjuvant-adjuvant cohort (95% CI, 64%-80%) and 49% in the adjuvant-only cohort (95% CI, 41%-59%).

“Based on this understanding, removing the bulk of the tumor, along with the tumor-infiltrating immune cells contained in the surgical specimen, is likely to take away some or even most of the potential antitumor immune cells that would proliferate after PD-1 blockade,” Ribas said in the statement. “Our theory has been—and this study confirms it—that starting anti-PD-1 blocking therapy before surgery could activate more antitumor immune cells and improve clinical outcomes compared with the same amount of drug delivered after the surgery.”

Grade 3 or higher adverse events during adjuvant therapy occurred in 12% of patients in the neoadjuvant-adjuvant cohort and 14% of patients in the adjuvant-only group. Overall survival was not evaluable due to the small number of deaths in the overall cohort—14 among patients who received neoadjuvant and adjuvant therapy and 22 in the adjuvant-only cohort. No new toxic effects or deaths attributed to pembrolizumab were seen in either of the cohorts.

Past studies of PD-1 inhibitor monotherapy in resectable melanoma have shown radiographic responses and tolerable adverse effects similar to those reported in the trial, the authors noted. Some ongoing trials are exploring neoadjuvant immunotherapy and de-escalation of surgery, foregoing adjuvant therapy, or both, they added.

Overall, the findings suggest that patients with high-risk, resectable, advanced melanoma could potentially benefit more from neoadjuvant and adjuvant pembrolizumab compared with adjuvant therapy alone.

“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,” the authors concluded. “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.”


1. Patel SP, Othus M, Chen Y, et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437

2. Immunotherapy before surgery significantly improves outcomes of patients with melanoma. News release. UCLA Health. March 1, 2023. Accessed March 1, 2023.

3. Keytruda. Prescribing information. Merck; 2023. Accessed March 1, 2023.

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