The Melanoma Letter

Neoadjuvant Therapy for Melanoma



Rohit Thakur, PhD
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston

Jennifer L. McQuade, MD
Department of Melanoma Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston

Jennifer A. Wargo, MD
Department of Surgical Oncology and Department of Genomic Medicine
The University of Texas MD Anderson Cancer Center
Houston

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
Recruiting
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
melanoma
A: sequential dabrafenib + trametinib, then pembrolizumab.
B: concurrent dabrafenib + trametinib + pembrolizumab.
C: pembrolizumab only
pathological response rate, objective
response rate, RFS, OS
60
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
melanoma
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
7
Completed
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
melanoma
ipilimumab 3mg/kg or 10mg/kg + high-dose interferon alfa-2b pathological response rate, radiologic
preoperative response rate, PFS, OS
30
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.


References

  1. 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.
  2. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018;
    24(11):1649-1654.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. in press. 2019.
  9. Zhao J, Galvez C, Sosman J. Neoadjuvant therapy for melanoma. The
    Melanoma Letter
    2019; 37(1):6-7.
  10. 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.