Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma
Open accessAbstract
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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The data provide evidence that (neo)adjuvant administration of immune checkpoint inhibitors results in superior antitumour immune responses compared with adjuvant-only administration.
“Nonetheless, these data provide evidence that (neo)adjuvant administration of ICIs results in superior antitumour immune responses than adjuvant-only administration.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [9]
The Discussion reports better event-free survival with neoadjuvant–adjuvant pembrolizumab and interprets this as consistent with a proposed T-cell mechanism. It also describes a smaller, separate trial that found greater expansion of tumor-resident T-cell clones with preoperative treatment. This paper’s own trial did not establish that its regimen produced superior antitumour immune responses; the claim states that mechanistic inference as a demonstrated result. Page numbers were not supplied. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the S1801 trial, event-free survival at 2 years was significantly improved with neoadjuvant-adjuvant pembrolizumab versus adjuvant-only pembrolizumab (72% vs 49%; HR 0.58, 95% CI 0.39-0.87; P=0.004; median follow-up 14.7 months).
“Event-free survival was significantly improved among patients who received pembrolizumab both before and after surgery (72% versus 49% with adjuvant-only pembrolizumab at 2 years; HR 0.58, 95% CI 0.39–0.87; P = 0.004; median follow-up 14.7 months)9.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [9]
The Results > Efficacy passage reports significantly longer event-free survival with neoadjuvant–adjuvant pembrolizumab, including 72% versus 49% at 2 years, P=0.004, and median follow-up of 14.7 months. Our copy does not report the claimed HR of 0.58 or its 95% CI of 0.39–0.87; the hazard ratio of 0.64 in Methods > Statistical Analysis is a trial-design assumption, not the observed result. No page numbers are provided for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical evidence of resectable stage IIIB to IVC malignant melanoma suggests that neoadjuvant immunotherapy is superior to adjuvant treatment alone in improving relapse-free survival following resection.
“Clinical evidence of resectable stage IIIB to IVC malignant melanoma suggests that neoadjuvant immunotherapy is superior to adjuvant treatment alone in improving relapse-free survival following resection.13”
From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [13]
The Methods (page not provided) match the stated resectable stage IIIB–IVC population, and the Discussion reports longer event-free survival with neoadjuvant plus adjuvant pembrolizumab than with adjuvant pembrolizumab alone. The claim calls this improved relapse-free survival following resection, but the trial’s primary endpoint was event-free survival, which also counted events before surgery; it did not establish the stated postoperative relapse-free-survival comparison. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn other cancer types, the endpoint to define response to neoadjuvant therapy has been pathological complete response (100%) or near-pathological complete response (>90%).
“In other cancer types, the endpoint to define response to neoadjuvant therapy has been pathological complete response (100%)13,15 or near-pathological complete response (>90%).29”
From Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis (2024) · cites this paper as [13]
The Discussion mentions a complete or near-complete pathological response as a criterion being investigated in neoadjuvant melanoma trials. It does not define near-complete response as >90% or establish that threshold as an endpoint in other cancer types. The Results define complete pathological response as no viable tumor, but the citation attached to this source follows the near-complete-response claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe S1801 findings come from a tumour type generally responsive to immune checkpoint inhibitors, so their relevance to less-responsive tumours such as HCC remains to be demonstrated.
“These findings are from a study in a tumour type that tends to be responsive to ICIs and thus, their relevance to less-responsive tumour types, such as HCC, remains to be demonstrated.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [9]
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- Authors
- Patel, S. P., Othus, M., Chen, Y., Wright, G. P., Yost, K. J., Hyngstrom, J. R., Hu-Lieskovan, S., Lao, C. D., Fecher, L. A., Truong, T.-G., Eisenstein, J. L., Chandra, S., Sosman, J. A., Kendra, K. L., Wu, R. C., Devoe, C. E., Deutsch, G. B., Hegde, A., Khalil, M., Mangla, A., Reese, A. M., Ross, M. I., Poklepovic, A. S., Phan, G. Q., Onitilo, A. A., Yasar, D. G., Powers, B. C., Doolittle, G. C., In, G. K., Kokot, N., Gibney, G. T., Atkins, M. B., Shaheen, M., Warneke, J. A., Ikeguchi, A., Najera, J. E., Chmielowski, B., Crompton, J. G., Floyd, J. D., Hsueh, E., Margolin, K. A., Chow, W. A., Grossmann, K. F., Dietrich, E., Prieto, V. G., Lowe, M. C., Buchbinder, E. I., Kirkwood, J. M., Korde, L., Moon, J., Sharon, E., Sondak, V. K., & Ribas, A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Fred Hutch Cancer Center (US)
- Michigan Cancer Research Consortium (US)
- Spectrum Health (US)
- University of Utah (US)
- University of Utah Huntsman Cancer Institute, Salt Lake City, UT
- U-M Rogel Cancer Center (US)
- Kaiser Permanente Vallejo Medical Center (US)
- Kaiser Permanente (US)
- Northwestern University (US)
- The Ohio State University Wexner Medical Center (US)
- Northwell Health (US)
- University of Alabama at Birmingham (US)
- University Hospitals Seidman Cancer Center (US)
- VCU Massey Comprehensive Cancer Center (US)
- Marshfield Clinic Weston Center (US)
- Marshfield Medical Center Wisconsin NCORP, Minocqua, WI
- University of Kansas (US)
- The University of Kansas Health System (US)
- USC Norris Comprehensive Cancer Center (US)
- MedStar Georgetown University Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- Banner - University Medical Center Tucson (US)
- University of Oklahoma (US)
- Cancer Centers of Southwest Oklahoma (US)
- University of California, Los Angeles (US)
- Cancer Care Specialists of Illinois (US)
- SSM Health Care (US)
- City Of Hope National Medical Center (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Emory University (US)
- Dana-Farber Cancer Institute (US)
- UPMC Hillman Cancer Center (US)
- National Institutes of Health (US)
- Moffitt Cancer Center (US)
- ORCID
- Patel, Sapna P.
- Othus, Megan
- Chen, Yuanbin
- Wright, G. Paul
- Yost, Kathleen J.
- Hyngstrom, John R.
- Fecher, Leslie A.
- Truong, Thach-Giao
- Chandra, Sunandana
- Sosman, Jeffrey A.
- Kendra, Kari L.
- Wu, Richard C.
- Devoe, Craig E.
- Deutsch, Gary B.
- Hegde, Aparna
- Mangla, Ankit
- Ross, Merrick I.
- Poklepovic, Andrew S.
- Phan, Giao Q.
- Onitilo, Adedayo A.
- Powers, Benjamin C.
- Doolittle, Gary C.
- In, Gino K.
- Kokot, Niels
- Gibney, Geoffrey T.
- Atkins, Michael B.
- Shaheen, Montaser
- Ikeguchi, Alexandra
- Chmielowski, Bartosz
- Crompton, Joseph G.
- Hsueh, Eddy
- Margolin, Kim A.
- Chow, Warren A.
- Grossmann, Kenneth F.
- Dietrich, Eliana
- Prieto, Victor G.
- Lowe, Michael C.
- Buchbinder, Elizabeth I.
- Kirkwood, John M.
- Korde, Larissa
- Sharon, Elad
- Sondak, Vernon K.
- Ribas, Antoni
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2023-03-02
- Volume
- 388
- Issue
- 9
- Pages
- 813-823
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC10410527
- OpenAlex
- W4322718735
- Cited by
- 919
- References
- 20
- Citations by year
- 2026: 219 · 2025: 299 · 2024: 277 · 2023: 121 · 2022: 1
- FWCI
- 112.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Merck
- National Cancer Institute (P30CA014089, P30CA016042, P30CA033572, P30CA076292, U10CA180819, U10CA180820, U10CA180821, U10CA180868, U10CA180888, UG1CA180830, UG1CA189821, UG1CA189830, UG1CA189850, UG1CA189860, UG1CA189869, UG1CA189956, UG1CA233160, UG1CA233178, UG1CA233180, UG1CA233193, UG1CA233234, UG1CA233247, UG1CA233320, UG1CA233328, UG1CA233329, UG1CA233330, UG1CA233331, UG1CA239758, UG1CA239767)
- Topics
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- pembrolizumab, neoadjuvant therapy, adjuvant therapy, advanced melanoma, event-free survival, immune checkpoint inhibitors, PD-1 inhibitors, treatment-related adverse events, surgical resection, melanoma recurrence, landmark analysis, safety and tolerability
- MeSH terms
- Antineoplastic Agents, Immunological, Adjuvants, Immunologic, Humans, Melanoma, Skin Neoplasms, Chemotherapy, Adjuvant, Disease Progression, Neoadjuvant Therapy, Antibodies, Monoclonal, Humanized
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