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.

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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.

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References

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