Rohit Thakur, PhD
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Jennifer L. McQuade, MD
Department of Melanoma Medical Oncology
The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo, MD
Department of Surgical Oncology and Department of Genomic Medicine
The University of Texas MD Anderson Cancer Center
Neoadjuvant strategies for melanoma have been underway for several years, owing to improved systemic therapy. The use of immune checkpoint blockade (ICB) and targeted therapies in neoadjuvant settings (i.e., prior to surgery) is a promising new treatment strategy for advanced stage melanomas,1-8 though yet to be approved by the FDA. As reported in Vol. 37, No. 1 of The Melanoma Letter,9 the first issue of 2019, this is an exciting area of investigation, with several studies recently reporting successful outcomes, and many more studies underway (Table 2). This research is rapidly evolving, with several additional studies published in the months since that issue of the newsletter. These include studies on neoadjuvant targeted therapy4 as well as a follow-up to the OpACIN-neoadjuvant trial (NCT02977052) exploring optimal dose and scheduling for combination neoadjuvant ICB.5
In the OpACIN trial, the investigators identified treatment of metastatic melanoma with two cycles of ipilimumab (1mg/kg) plus nivolumab (3mg/kg) as the best tolerated dosing schedule for neoadjuvant combined ICB.5 In the NeoCombi neoadjuvant trial (NCT01972347), neoadjuvant targeted therapy with combination dabrafenib-trametinib led to a high rate of complete radiographic and pathological response, and all patients were able to undergo surgery following the neoadjuvant therapy.4
At the 2019 American Society of Clinical Oncology (ASCO) annual meeting, a pooled analysis of neoadjuvant targeted therapy and ICB neoadjuvant therapy for patients with clinical stage III melanoma (n=184) was presented.7 Consistent with previous reports, achievement of pathologic complete response, or pCR (41 percent in the overall cohort, 38 percent with ICB and 47 percent with BRAF-MEK targeted therapy), was associated with better relapse-free survival (RFS) compared with that of patients without a pCR (95 percent vs. 62 percent at 12 months, p<0.001).7 Notably, RFS rates were significantly higher in the neoadjuvant ICB study population compared with neoadjuvant targeted therapy (83 percent vs. 65 percent at 12 months, p<0.001), though inherent limitations exist with this retrospective analysis given that in no studies have patients been randomized to one strategy or the other. Data from this pooled analysis and earlier reported trials demonstrate proof of principal for the neoadjuvant approach and provide the foundation for ongoing work.
During the 2019 ASCO Annual Meeting, there was also a meeting of the International Neoadjuvant Melanoma Consortium — a group established to bring key stakeholders together from research institutions around the world, with the goal of harmonizing approaches to neoadjuvant melanoma therapy. The group recently developed guidelines for design and implementation of clinical trials addressing the proposed duration of therapy, response assessment, biospecimen collection and analysis strategies.8 This group has also provided key resources such as standardized criteria for pathologic assessment after neoadjuvant treatment.10 Numerous additional neoadjuvant trials are currently ongoing (Table 2), and these studies should reveal critical insights on safety, feasibility and response.
Table 2: Clinical trials assessing systemic and/or intralesional therapies for cutaneous melanoma in the neoadjuvant setting
|NCT Number||Patient Population||Intervention||Key Efficacy Endpoints||n|
|NCT02036086||BRAFV600-mutated melanoma, palpable lymph node metastases||vemurafenib + cobimetinib||resectability rate||20|
|NCT02231775||BRAFV600-mutated resectable stage IIIB/IIIC melanoma||dabrafenib + trametinib||RFS, OS and pathological complete response rate||78|
|NCT02434354||clinical stage III or resectable stage IV melanoma||pembrolizumab||Unspecified||30|
|NCT02519322||resectable stage IIIB-IV melanoma||A: nivolumab. B: nivolumab + ipilimumab. C: nivolumab + relatlimab||pathological response rate, T cell infiltration, objective response rates, RFS, OS||53|
|NCT02858921||BRAFV600-mutated resectable stage III
|A: sequential dabrafenib + trametinib, then pembrolizumab.
B: concurrent dabrafenib + trametinib + pembrolizumab.
C: pembrolizumab only
|pathological response rate, objective
response rate, RFS, OS
|NCT02977052||stage III melanoma||three dosing schedules for ipilimumab + nivolumab||objective response rate, pathological response rate, RFS||110|
|NCT03554083||clinical stage III melanoma||vemurafenib + cobimetinib + atezolizumab||pathological complete response rate, RFS||30|
|NCT03567889||clinical stage IIIB/IIIC||Daromun (intralesional)||RFS, OS, local recurrence-free survival||248|
|NCT03618641||resectable nodal stage IIIB-D melanoma||CMP-001 + nivolumab||major pathological response rate, RFS, OS||40|
|NCT03698019||resectable stage III/IV melanoma||pembrolizumab||EFS, OS, objective response rate, disease control rate||556|
|NCT03757689||stage IIB/IIC melanoma||pembrolizumab||sentinel lymph node positivity rate||63|
|NCT03972046||BRAFV600-mutated stage IIIB-IVA melanoma||TVEC (intralesional) + dabrafenib + trametinib||RFS, melanoma-specific survival, DMFS, radiographic response rate, pathological response rate||20|
|Not yet recruiting|
|NCT03842943||stage III melanoma||TVEC (intralesional) + pembrolizumab||pathological complete response rate||28|
|Active, not recruiting|
|NCT01321437||stage III melanoma||axitinib||overall response rate, PFS||11|
|NCT01972347||BRAFV600-mutated resectable stage IIIB/IIIC melanoma||dabrafenib + trametinib||pathologic response rate, objective response rate, RFS, OS||35|
|NCT02211131||resectable stage IIIB/IIIC/IVA melanoma||TVEC (intralesional)||overall response rate||150|
|NCT02303951||borderline or unresectable limited metastasis stage IIIC/IV melanoma||vemurafenib + cobimetinib + atezolizumab||conversion to resectability, objective response rate, PFS, OS||90|
|NCT02339324||resectable stage III
|pembrolizumab + high-dose interferon alfa-2b||radiologic response, pathological response rate, PFS, OS||30|
|NCT02437279||palpable axillary or groin nodal stage IIIB melanoma||A: adjuvant ipilimumab + nivolumab. B: neoadjuvant plus
adjuvant ipilimumab + nivolumab
|RFS, T cell response assessment||20|
|NCT03259425||resectable stage IIIB/IIIC/IVA melanoma||nivolumab + HF10||pathological response rate, RFS, OS,
completeness of surgical resection
|NCT00525031||resectable stage IIIC/IVA||temozolomide +/- pegylated interferon alfa-2b||clinical response rate (CR + PR + SD)||55|
|NCT00588341||resectable palpable stage III/IV melanoma||temozolomide||objective response rate (CR or PR)||24|
|NCT00972933||stage IIIB/IIIC melanoma||ipilimumab||unspecified||59|
|NCT01341158||stage IIIB/IIIC melanoma||interferon alfa-2b||overall response rate, disease control rate, pathological complete response rate||42|
|NCT01608594||resectable stage III
|ipilimumab 3mg/kg or 10mg/kg + high-dose interferon alfa-2b||pathological response rate, radiologic
preoperative response rate, PFS, OS
|NCT01781026||untreated BRAFV600-mutated melanoma brain metastases||vemurafenib||radiologic response||2|
|NCT02306850||potentially resectable (currently unresectable) stage III/IV melanoma||pembrolizumab||resectability rate, response rate||10|
RFS = relapse-free survival. PFS = progression-free survival. EFS = event-free survival. OS = overall survival. DMFS = distant metastasis-free survival. PR = partial response.
CR = complete response. SD = stable disease. Note: Due to recent adoption of the AJCC eighth edition staging system, the stage classifications listed may refer to the seventh or eighth edition system. See individual trial listings for details.
- Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018; 19(2):181-193.
- Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018;
- Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018; 24(11):1655.
- Long GV, Saw RP, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol 2019; 20(7):961-971.
- Rozeman EA, Menzies AM, van Akkooi AC, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol 2019; 20(7):948-960.
- Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med 2019; 25(3):454-461.
- Menzies AM, Rozeman EA, Amaria RN, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Presented at the 2019 American Society of Clinical Oncology (ASCO) annual meeting, May 31–June 4, 2019; Chicago. Abstract 9503.
- Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. in press. 2019.
- Zhao J, Galvez C, Sosman J. Neoadjuvant therapy for melanoma. The
Melanoma Letter 2019; 37(1):6-7.
- Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.
Ann Oncol 2018; 29(8):1861-1868.