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Meta-Analysis
. 2023 Jan 17;1(1):CD012974.
doi: 10.1002/14651858.CD012974.pub2.

Neoadjuvant treatment for stage III and IV cutaneous melanoma

Claire Gorry  1 , Laura McCullagh  1   2 , Helen O'Donnell  2 , Sarah Barrett  3 , Susanne Schmitz  2 , Michael Barry  2 , Kay Curtin  4 , Eamon Beausang  5 , Rupert Barry  6 , Imelda Coyne  7
Affiliations
Meta-Analysis

Neoadjuvant treatment for stage III and IV cutaneous melanoma

Claire Gorry et al. Cochrane Database Syst Rev. .

Abstract

Background: Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma.

Objectives: To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system.

Search methods: We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive.

Selection criteria: Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion.

Data collection and analysis: We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence.

Main results: We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow-up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta-analysis of all identified studies. We performed a meta-analysis including three studies. We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low-certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low-certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low-certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data. We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low-certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low-certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL. We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low-certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low-certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low-certainty evidence). The study did not report comparative ORRs or measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low-certainty evidence). The study did not report comparative ORRs or measure TTR and QOL. Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate-certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment-related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low-certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low-certainty evidence). The study did not measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune-related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low-certainty evidence). The study did not measure TTR and QOL. No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low-certainty evidence).

Authors' conclusions: We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.

Trial registration: ClinicalTrials.gov NCT02231775 NCT02519322 NCT02437279 NCT02211131 NCT00525031 NCT02977052 NCT01608594 NCT01720407 NCT02036086 NCT02303951 NCT02736123 NCT03313206 NCT03618641 NCT04013854 NCT04495010 NCT02858921 NCT02938299 NCT03567889 NCT03698019 NCT04133948 NCT04139902.

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Conflict of interest statement

Claire Gorry: none known. Laura McCullagh: none known. Helen O'Donnell: none known. Sarah Barrett: none known. Susanne Schmitz: no relevant interests; statistical editor for Cochrane Anaesthesia and Cochrane Emergency and Critical Care. Michael Barry: none known. Kay Curtin: consultant for Cancer Trials Ireland (Patient Consultant to Melanoma Committee). Eamon Beausang: no relevant interest; Plastic Surgeon, St James's Hospital, Dublin. Rupert Barry: Founder of DermView Ltd, a dermatology clinic chain; Dermatologist, St James Hospital, Dublin. Imelda Coyne: none known.

Figures

1
1
Simplified diagram of the RAS‐RAF‐MEK‐ERK pathway
2
2
PRISMA Study flow diagram.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: Neoadjuvant treatment compared to no neoadjuvant treatment, Outcome 1: Overall survival
1.2
1.2. Analysis
Comparison 1: Neoadjuvant treatment compared to no neoadjuvant treatment, Outcome 2: Adverse events
1.3
1.3. Analysis
Comparison 1: Neoadjuvant treatment compared to no neoadjuvant treatment, Outcome 3: Time to recurrence
2.1
2.1. Analysis
Comparison 2: Neoadjuvant targeted treatment (BRAF/MEK inhibition) compared to no neoadjuvant treatment, Outcome 1: Overall survival
2.2
2.2. Analysis
Comparison 2: Neoadjuvant targeted treatment (BRAF/MEK inhibition) compared to no neoadjuvant treatment, Outcome 2: Time to recurrence
3.1
3.1. Analysis
Comparison 3: Neoadjuvant immunotherapy (talimogene laherparepvec) compared to no neoadjuvant treatment, Outcome 1: Overall survival
3.2
3.2. Analysis
Comparison 3: Neoadjuvant immunotherapy (talimogene laherparepvec) compared to no neoadjuvant treatment, Outcome 2: Adverse events
3.3
3.3. Analysis
Comparison 3: Neoadjuvant immunotherapy (talimogene laherparepvec) compared to no neoadjuvant treatment, Outcome 3: Time to recurrence
4.1
4.1. Analysis
Comparison 4: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) compared to adjuvant immunotherapy (combined ipilimumab and nivolumab), Outcome 1: Adverse events
5.1
5.1. Analysis
Comparison 5: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) compared to neoadjuvant immunotherapy (nivolumab), Outcome 1: Adverse events
5.2
5.2. Analysis
Comparison 5: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) compared to neoadjuvant immunotherapy (nivolumab), Outcome 2: Overall response rate
5.3
5.3. Analysis
Comparison 5: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) compared to neoadjuvant immunotherapy (nivolumab), Outcome 3: Pathological Complete Response
6.1
6.1. Analysis
Comparison 6: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab (2 different dosing regimens) compared to neoadjuvant immunotherapy (sequential ipilimumab then nivolumab), Outcome 1: Adverse events
6.2
6.2. Analysis
Comparison 6: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab (2 different dosing regimens) compared to neoadjuvant immunotherapy (sequential ipilimumab then nivolumab), Outcome 2: Overall response rate
6.3
6.3. Analysis
Comparison 6: Neoadjuvant immunotherapy (combined ipilimumab and nivolumab (2 different dosing regimens) compared to neoadjuvant immunotherapy (sequential ipilimumab then nivolumab), Outcome 3: Pathological complete response
7.1
7.1. Analysis
Comparison 7: Neoadjuvant immunotherapy (high dose interferon) and chemotherapy compared to neoadjuvant chemotherapy, Outcome 1: Overall response rate
8.1
8.1. Analysis
Comparison 8: Neoadjuvant immunotherapy (ipilimumab 10mg/kg plus high‐dose interferon) compared to neoadjuvant immunotherapy (ipilimumab 3mg/kg plus high‐dose interferon), Outcome 1: Pathological complete response
8.2
8.2. Analysis
Comparison 8: Neoadjuvant immunotherapy (ipilimumab 10mg/kg plus high‐dose interferon) compared to neoadjuvant immunotherapy (ipilimumab 3mg/kg plus high‐dose interferon), Outcome 2: Objective response rate
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References

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    1. NCT01720407. Relevance of imiquimod as neo-adjuvant treatment to reduce excision size and the risk of intralesional excision in lentigo malignant of the face (ImiReduc). clinicaltrials.gov/ct2/show/NCT01720407 (first received 2 November 2012).
NCT02036086 {published data only}
    1. NCT02036086. Study of neo-adjuvant use of vemurafenib plus cobimetinib for BRAF mutant melanoma with palpable lymph node metastases. clinicaltrials.gov/ct2/show/NCT02036086 (first received 14 January 2014).
NCT02303951 {published data only}
    1. NCT02303951. Neoadjuvant vemurafenib + cobimetinib in melanoma: NEO-VC. clinicaltrials.gov/ct2/show/NCT02303951 (first received 1 December 2014).
NCT02736123 {published data only}
    1. NCT02736123. Neoadjuvant combination biotherapy with ipilimumab and nivolumab or nivolumab alone [Neoadjuvant combination biotherapy with ipilimumab and nivolumab or nivolumab alone in patients with locally/regionally advanced/recurrent melanoma: a randomized efficacy, safety and biomarker study]. clinicaltrials.gov/ct2/show/NCT02736123 (first received 13 April 2016).
NCT03313206 {published data only}
    1. NCT03313206. Neoadjuvant treatment associated with maintenance therapy by anti-pd1 immunotherapy in patients with resectable head and neck mucosal melanoma (IMMUQ). clinicaltrials.gov/ct2/show/NCT03313206 (first received 18 October 2017).
NCT03618641 {published data only}
    1. Davar, D, Karunamurthy, A, Hartman, D, DeBlasio, R, Chauvin, J M, Ding, Q et al. Phase ii trial of neoadjuvant nivolumab (NIVO) and intra-tumoral (IT) CMP-001 in high-risk resectable melanoma (neo-c-nivo): Final results. Journal for Immunotherapy of Cancer 2020;8(Suppl 3):A185-186.
    1. Davar D, Karunamurthy A, Hartman D, Ka M, Menna C, Burkette J, et al. O34 Phase II trial of neoadjuvant nivolumab (Nivo) and intra-tumoral (IT) CMP-001 in high risk resectable melanoma (MEL): Preliminary results. Journal for ImmunoTherapy of Cancer 2019;7(Suppl 1):283.
    1. NCT03618641. CMP-001 in combo with nivolumab in stage IIIB/C/D melanoma patients with clinically apparent lymph node disease [Neoadjuvant Phase II study of TLR9 agonist CMP-001 in combination with nivolumab in stage IIIB/C/D melanoma patients with clinically apparent lymph node disease]. clinicaltrials.gov/ct2/show/NCT03618641 (first received 7 August 2021).
NCT04007588 {published data only}
    1. NCT04007588. A phase II trial of neoadjuvant treatment with PD-1 inhibition (Nivolumab) with or without IDO inhibition (BMS-986205) and with or without CTLA-4 inhibition (Ipilimumab) in resectable stage III or IV melanoma. clinicaltrials.gov/ct2/show/NCT04007588 (first received 5 July 2019).
NCT04013854 {published data only}
    1. NCT04013854. Adjuvant treatment determined by pathological response to neoadjvuant nivolumab [Adjuvant nivolumab or ipilimumab + nivolumab determined by pathological response to a single dose of neoadjvuant nivolumab]. clinicaltrials.gov/ct2/show/NCT04013854?term=NCT04013854&draw=2&... (first received 10 July 2019).
NCT04495010 {published data only}
    1. NCT04495010. Neoadjuvant nivolumab+ipilimumab followed by adjuvant nivolumab or neoadjuvant nivolumab+ipilimumab followed by adjuvant observation compared with adjuvant nivolumab in treatment-naive high-risk melanoma participants (CheckMate 7UA) [A phase 2, randomized study of neoadjuvant nivolumab plus ipilimumab followed by adjuvant nivolumab or neoadjuvant nivolumab plus ipilimumab followed by either adjuvant nivolumab or postsurgical observation depending on pathologic response compared with adjuvant nivolumab in treatment-naive patients with resectable clinically detectable stage iii melanoma]. clinicaltrials.gov/ct2/show/NCT04495010 (first received 31 July 2020).
NCT04741997 {published data only}
    1. NCT04741997. Adjuvant therapy based on pathologic response after neoadjuvant encorafenib binimetinib in melanoma [A randomized pilot trial of adjuvant therapy based on pathologic response after neoadjuvant encorafenib and binimetinib in advanced melanoma]. clinicaltrials.gov/ct2/show/NCT04741997 (first received 5 February 2021).
Notohardjo 2020 {published data only}
    1. Notohardjo, JCL, Bekkenk, MW, Van Den Tol, MP, Van Den Eertwegh, AJM, De Gruijl, TD. Local immunotherapy in early stage melanoma - Protocol synopsis for a randomized phase 2 trial. [Dutch] [Lokale immuuntherapie bij melanoom in een vroeg stadium – protocol synopsis voor een gerandomiseerde fase 2-studie]. Nederlands Tijdschrift voor Dermatologie en Venereologie 2020;30(6):16-8.
O'Connor 1978 {published data only}
    1. O'Connor TP, Labandter HP, Hiles RW, Bodenham DC. A clinical trial of BCG immunotherapy as an adjunct to surgery in the treatment of primary malignant melanoma. British Journal of Plastic Surgery 1978;31(4):317-22. - PubMed
Passalacqua 1996 {published data only}
    1. Passalacqua R, Cocconi G, Dodero A, Bella M, Sarra S, Tonato M, et al. Long-term results of neoadjuvant chemotherapy in patients with local-regional recurrence of melanoma. Melanoma Research 1997;7 Suppl 1:S119.
    1. Passalacqua R, Cocconi G, Dodero A, Bella M, Sarra S, Tonato M, et al. Neoadjuvant chemotherapy in patients with local-regional recurrence of melanoma. Tumori 1996;82(Suppl):108.
Prieto 2016 {published data only}
    1. Prieto PA, Cooper Z, Gopalakrishnan V, Tetzlaff MT, Bassett T, Amaria RN, et al. Treatment with neoadjuvant targeted therapy yields high response rates and pathologic complete responses in patients with resectable metastatic melanoma. Annals of Surgical Oncology 2016;20(Suppl 1):S130-1.
Reijers 2019 {published data only}
    1. Reijers I, Rozeman EA, Menzies AM, Van De Wiel BA, Eriksson H, Suijkerbuijk K, et al. Personalized response-driven adjuvant therapy after combination ipilimumab and nivolumab in high-risk resectable stage III melanoma: PRADO trial. Journal of Clinical Oncology 2019;37(15 Suppl):TPS9605.
    1. Van Den Heuvel NM, Reijers IL, Versluis JM, Rozeman EA, Jozwiak K, Blommers KH, et al. Health-related quality of life in stage III melanoma patients treated with neoadjuvant ipilimumab and nivolumab followed by index lymph node excision only versus therapeutic lymph node dissection: 24-week results of the PRADO trial. Annals of Oncology 2020;31(Suppl 4):S737.
Samoylenko 2019 {published data only}
    1. Samoylenko I, Korotkova OV, Shakhray E, Zabotina T, Berdnikov S, Tabakov D, et al. Recurrence-free survival (RFS) and objective response rate (ORR) phase 1/2 study of intralesional (IL) neoadjuvant (neo) anti-PD1 agents (aPD1) for stage IIIB-IV melanoma (MEL). Journal of Clinical Oncology 2019;37(15 Suppl):e14171.
Schermers 2019 {published data only}
    1. Schermers B, Franke V, Rozeman EA, de Wiel BA, Bruining A, Wouters MW et al. Surgical removal of the index node marked using magnetic seed localization to assess response to neoadjuvant immunotherapy in patients with stage III melanoma. British Journal of Surgery 2019;106(5):519-22. - PMC - PubMed
Shah 2010 {published data only}
    1. Shah GD, Socci ND, Gold JS, Wolchok JD, Carvajal RD, Panageas KS, et al. Phase II trial of neoadjuvant temozolomide in resectable melanoma patients. Annals of Oncology 2010;21(8):1718-22. - PubMed
Stiles 2017 {published data only}
    1. Stiles ZE, Fleming MD, Luce EA, Deneve JL. Neoadjuvant talimogene laherparepvec for the treatment of metastatic melanoma. American Surgeon 2017;83(7):E266-8. - PubMed
Urosevic 1996 {published data only}
    1. Urosevic V, Chollet P, Adenis A, Chauvergne J, Fargeot P, Roche H, et al. Results of a phase II trial with cystemustine in advanced malignant melanoma. A trial of the EORTC Clinical Screening Group. European Journal of Cancer 1996;32A(1):181-2. - PubMed
Van den Hout 2010 {published data only}
    1. Van Den Hout MF, Sluijter BJ, Santegoets SJ, Van Den Eertwegh AJ, Meijer S, Van Den Tol P, et al. Arming the melanoma sentinel lymph node against tumor spread: The effects of local administration of combined low-dose CpG-B PF-3512676 and GM-CSF. Cancer Research 2010;70(8 Suppl):5618.
Van Den Hout 2013 {published data only (unpublished sought but not used)}
    1. Van Den Hout MF, Koster BD, Scheper RJ, Van De Ven R, Sluijter BJ, Molenkamp BG, et al. Pre-operative intradermal administration of CpG-B +/- GM-CSF in stage I-III melanoma patients arms the sentinel lymph node: Evidence for reduced tumor spread. Journal for ImmunoTherapy of Cancer 2013;1(Suppl 1):P92.
Wargo 2015 {published data only}
    1. Wargo J, Gershenwald J, Cormier JN, Lee J, Griffin KC, Amaria R, et al. Is it time for a shift in the treatment of advanced resectable stage III and stage IV oligometastatic melanoma? Results of a pilot trial and plans for a randomized trial of neoadjuvant therapy versus upfront surgery. Annals of Surgical Oncology 2015;22(Suppl 1):S127.

References to studies awaiting assessment

de Braud 1994 {published data only}
    1. Braud F, Bajetta E, Comella G, Queirolo P, Sertoli M, Calabresi F, et al. A pilot study with dacarbazine (DTIC) and tamoxifen (TAM) and interferon alpha-2A (rIFN-a 2A) and IL-2 or CVD (CDDP and VDS and DTIC) and TAM and rIFN-a 2A +/- IL-2 in metastatic melanoma for the B.R.E.M.I.M (BRM in Melanoma) Italian Cooperative Group. Annals of Oncology 1994;5(Suppl 8):171.
EudraCT 2014‐000334‐30 {published data only (unpublished sought but not used)}
    1. EudraCT 2014-000334-30. Immunomodulatory effect of esomeprazole antitumoral and high-dose under neoadjuvant and adjuvant in patients with melanoma in stage III. Randomized pilot study treatment vs control. www.clinicaltrialsregister.eu/ctr-search/trial/2014-000334-30/results (first received 27 March 2014).
Kleeberg 1986 {published data only}
    1. Kleeberg UR, Brocker EB, Carrel S, Hoffman J, Kerekjarto M, Leujeune F. Clinical trial in patients with malignant melanoma: comparison of adjuvant Interferon-alpha-2 with Interferon-gamma with Iscador M and a control group without treatment after resection of high-risk primaries (+ 3mm) of stage I and/or lymph-node metastases [Adjuvante Therapiestudie bei Patienten mit malignem Melanom: vergleich von Interferon r Alpha‐2 mit r Gamma mit Iscador M und einer unbehandelten Kontrollgruppe nach Resektion prognostisch ungünstiger Primärtumoren (+ 3mm) im Stadium I bzw. nach kurativer Resektion von Lymphknotennetastasen (Stadium IIb) MMCG 18871/DK 80/1]. Cochrane Central Register of Controlled Trials (CENTRAL) 1986:2-46.

References to ongoing studies

NCT02858921 {published data only}
    1. Gonzalez M, Menzies AM, Saw R, Spillane AJ, Nieweg OE, Shannon KF, et al. Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: a phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial). Journal of Clinical Oncology 2018;36(15_suppl):TPS9604.
    1. Gonzalez M, Menzies AM, Saw R, Thompson JF, Spillane AJ, Howle J, et al. A phase II, randomised, open label study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D/T) in BRAF V600 mutant resectable stage IIIB/C/D melanoma (NeoTrio Trial). Annals of Oncology 2017;28(Suppl 5):v445.
    1. NCT02858921. Neoadjuvant dabrafenib, trametinib and/or pembrolizumab in BRAF mutant resectable stage III melanoma (NeoTrio). clinicaltrials.gov/ct2/show/NCT02858921 (first received 8 August 2016).
NCT02938299 {published data only (unpublished sought but not used)}
    1. 2015-002549-72. A Phase III, open-label, randomized, controlled multi-center study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment followed by surgery versus surgery alone in clinical stage IIIB and IIIC melanoma patients. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received July 2015).
    1. NCT02938299. Neoadjuvant L19IL2/L19TNF- Pivotal Study (Pivotal) [A Phase III, open-label, randomized, controlled multi-centre study of the efficacy of L19IL2/L19TNF neoadjuvant intratumoral treatment followed by surgery versus surgery alone in clinical stage IIIB and IIIC melanoma patients]. clinicaltrials.gov/ct2/show/NCT02938299 (first received 19 October 2016).
NCT03567889 {published data only}
    1. EUDRA CT 2021-003064-27. An open-label, randomized, controlled multi-center study of the efficacy of daromun (L19IL2 + L19TNF) neoadjuvant intratumoral treatment followed by surgery and adjuvant therapy versus surgery and adjuvant therapy in clinical stage IIIB/C melanoma patients [Estudio multicéntrico controlado, aleatorizado y abierto sobre la eficacia del tratamiento intratumoral neoadyuvante con Daromun (L19IL2 + L19TNF) seguido de cirugía y una terapia adyuvante frente a cirugía y una terapia adyuvante en pacientes con melanoma en estadio IIIB/C]. www.clinicaltrialsregister.eu/ctr-search/trial/2021-003064-27/ES (first received 19 November 2021).
    1. Miura JT, Zager JS. Neo-DREAM study investigating Daromun for the treatment of clinical stage IIIB/C melanoma. Future Oncology 2019;15(32):3665-74. [DOI: 10.2217/fon-2019-0433] - DOI - PubMed
    1. NCT03567889. Efficacy of daromun neoadjuvant intratumoral treatment in clinical stage IIIB/C melanoma patients (Neo-DREAM) [An open-label, randomized, controlled multi-center study of the efficacy of daromun (L19IL2 + L19TNF) neoadjuvant intratumoral treatment followed by surgery and adjuvant therapy versus surgery and adjuvant therapy in clinical stage IIIB/C melanoma patients]. clinicaltrials.gov/ct2/show/NCT03567889 (first received 26 June 2018).
NCT03698019 {published data only}
    1. NCT03698019. Pembrolizumab in treating patients with stage III/IV high-risk melanoma before and after surgery [A phase II randomized study of adjuvant versus neoadjuvant pembrolizumab (MK-3475) for clinically detectable stage III/IV high-risk melanoma]. clinicaltrials.gov/ct2/show/NCT03698019 (first received 5 October 2018).
    1. Patel SP, Othus M, Moon J, Tetzlaff M, Buchbinder EI, Sondak VK, et al. S1801: A randomized trial of adjuvant versus neoadjuvant pembrolizumab for melanoma. Journal of Clinical Oncology 2021;39(15_suppl):TPS9585.
    1. Patel SP, Othus M, Moon J, Tetzlaff MT, Buchbinder EI, Sondak VK, et al. S1801: A randomized phase II trial of adjuvant versus neoadjuvant pembrolizumab (PEM) for melanoma. Journal of Clinical Oncology 2020;38(15_suppl):TPS10090.
NCT04133948 {published data only}
    1. NCT04133948. Multicenter phase 1b trial testing the neoadjuvant combination of domatinostat, nivolumab and ipilimumab in ifn-gamma signature-low and ifn-gamma signature-high recist 1.1-measurable stage iii cutaneous or unknown primary melanoma. clinicaltrials.gov/ct2/show/NCT04133948 (first received 21 October 2019).
    1. Reijers IL, Rozeman EA, Dimitriadis P, Krijgsman O, Bosch LJ, Cornelissen S, et al. P01.15 Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in macroscopic stage III melanoma patients stratified according to interferon-gamma (IFN-gamma) signature – the DONIMI study. Journal for Immunotherpy of Cancer 2020;8. [DOI: 10.1136/jitc-2020-ITOC7.28] - DOI
NCT04139902 {published data only}
    1. Kelly Z, Najjar Y, Zarour H, et al. Randomized phase II neoadjuvant study: PD-1 inhibitor TSR-042 vs. combination PD-1 inhibitor TSR-042 and Tim-3 inhibitor TSR-022 in borderline resectable stage III or oligometastatic stage IV melanoma. Journal for Immunotherapy of Cancer 2019;7(Suppl 1):P457.
    1. NCT04139902. PD-1 inhibitor dostarlimab (TSR-042) vs. combination of Tim-3 inhibitor TSR-022 and PD-1 inhibitor dostarlimab (TSR-042) [Randomized phase II neoadjuvant study of PD-1 inhibitor dostarlimab (TSR-042) vs. combination of Tim-3 inhibitor TSR-022 and PD-1 inhibitor dostarlimab (TSR-042) in resectable stage III or oligometastatic stage IV melanoma (Neo-MEL-T)]. clinicaltrials.gov/ct2/show/NCT04139902 (first received 25 October 2019).
NCT04303169 {published data only}
    1. EUDRA-CT 2019-003978-22. A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants with Melanoma (KEYNOTE-U02): Substudy 02C [Ph 1/2 Substudy of Neoadjuvant Oncological Treatment(s) in MEL]. www.clinicaltrialsregister.eu/ctr-search/trial/2019-003978-22/IT (first received 21 January 2021).
    1. NCT04303169. Substudy 02C: Safety and efficacy of pembrolizumab in combination with investigational agents or pembrolizumab alone in participants with stage III melanoma who are candidates for neoadjuvant therapy (MK-3475-02C) [A phase 1/2 open-label rolling-arm umbrella platform design of investigational agents with or without pembrolizumab or pembrolizumab alone in participants with melanoma (KEYMAKER-U02): Substudy 02C]. clinicaltrials.gov/ct2/show/NCT04303169 (first received 10 March 2020).
NCT04401995 {published data only}
    1. NCT04401995. Study of TLR9 agonist CMP-001 in combination with nivolumab vs. nivolumab [Randomized neoadjuvant pilot phase II study of TLR9 agonist CMP-001 in combination with nivolumab vs. nivolumab in stage IIIB/C/D melanoma patients with an integrated imaging biomarker]. clinicaltrials.gov/ct2/show/NCT04401995 (first received 26 May 2020).
NCT04708418 {published data only}
    1. NCT04708418. A study evaluating whether pembrolizumab alone or in combination with CMP-001 improves efficacy in patients with operable melanoma [Phase II randomized study of neoadjuvant pembrolizumab alone or in combination with CMP-001 in patients with operable melanoma: efficacy and biomarker study]. clinicaltrials.gov/show/NCT04708418 (first posted 14 January 2021).
NCT04722575 {published data only}
    1. EUCTR2018-004841-17-IT. A phase II randomized non-comparative study, with neoadjuvant plus adjuvant therapy with combination or sequence of vemurafenib, cobImetinib, and atezolizuMab in patients with high-risk, surgically resectable BRAF mutated and wild-type Melanoma. trialsearch.who.int/?TrialID=EUCTR2018-004841-17-IT (first received October 2020).
    1. NCT04722575. Combination or sequence of vemurafenib, cobimetinib, and atezolizumab in high-risk, resectable melanoma (NEO-TIM) [NEOadjuvant Plus adjuvant therapy with combination or sequence of vemurafenib, cobimetinib, and atezolizumab in patients with high-risk, surgically resectable BRAF mutated and wild-type melanoma]. clinicaltrials.gov/ct2/show/NCT04722575 (first posted 25 January 2021).
NCT04949113 {published data only}
    1. EUCTR2021-001492-16-NL. Multicenter phase 3 trial comparing NeoADjuvant Ipilimumab + Nivolumab versus standard Adjuvant nivolumab in macroscopic stage III melanoma – NADINA - NADINA [Onderzoek bij melanoom patiënten met uitzaaiingen in de lymfeklieren naar behandeling met ipilimumab en nivolumab voorafgaand aan de operatie in vergelijking met standaard nivolumab behandeling na de operatie.]. trialsearch.who.int/?TrialID=EUCTR2021-001492-16-NL (first received 1 June 2021).
    1. NCT04949113. Neoadjuvant ipilimumab plus nivolumab versus standard adjuvant nivolumab in macroscopic stage III melanoma (NADINA) [Multicenter phase 3 trial comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant nivolumab in macroscopic stage III melanoma - NADINA]. clinicaltrials.gov/ct2/show/NCT04949113 (first received 2 July 2021).

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