INTRODUCTION — Surgical excision is the treatment of choice for most patients with locoregional cutaneous melanoma and is also curative in most cases. However, some patients will subsequently relapse with disseminated disease. Specific clinical features in the primary tumor and regional lymph nodes are associated with increased risk for disease recurrence.
Checkpoint inhibition immunotherapy and targeted therapies are important advances in the treatment of patients with cutaneous melanoma, in the metastatic setting; in the adjuvant setting for patients at high risk for recurrence following initial surgery; and in the neoadjuvant setting prior to definitive surgery. (See "Principles of cancer immunotherapy" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Treatment-naive patients'.)
The use of immunotherapy and targeted therapy as adjuvant and neoadjuvant treatment for cutaneous melanoma will be reviewed here. The initial surgical management of cutaneous melanoma and systemic treatment of patients with metastatic disease are discussed separately.
●(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)
●(See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
●(See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
FACTORS THAT INFLUENCE THERAPY — For patients with resectable cutaneous melanoma, various clinical factors influence both the decision to offer adjuvant or neoadjuvant therapy and the choice of agent. The factors include the risk of disease recurrence, stage at diagnosis, degree of lymph node involvement (microscopic versus macroscopic), BRAF mutation status, and patient characteristics such as age, comorbidities, and treatment preferences. While effective treatments are available, patients can also be encouraged to enroll in clinical trials.
●Risk of disease recurrence – The extent and characteristics of the primary tumor and regional lymph node involvement allow classification of patients into different categories of risk for disease recurrence. The eighth edition of the tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC (table 1A-B)) incorporates the most important determinants of prognosis and is one factor used to select adjuvant or neoadjuvant therapy [1,2]. (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma".)
•For the primary tumor (T), increasing tumor thickness, the presence of ulceration (ie, the loss of the epidermal layer overlying the primary tumor), and increased mitotic rate [3] are all associated with an increased risk of relapse.
•The presence of lymph node involvement is associated with a significant increase in risk of relapse.
●BRAF mutation status – Patients with high-risk node-positive microscopic disease that harbor a BRAF V600 mutation have the option of adjuvant therapy with either immunotherapy or targeted therapy (ie, BRAF plus MEK inhibitors). (See 'BRAF-mutated tumors' below.)
●Patient characteristics – Patient characteristics such as age, comorbidities (eg, active autoimmune disease), and treatment preferences will also influence the choice of therapy. Eligibility for immunotherapy and toxicities associated with targeted therapy are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
LOW-RISK NODE-NEGATIVE DISEASE (STAGE I AND IIA)
Surveillance — Patients with low-risk node-negative melanoma present with AJCC eighth edition stage I or IIA disease (table 1A-B). They have a primary tumor with low-risk features (either ≤2 mm in thickness with or without ulceration or ≤4 mm in thickness without ulceration), but no lymph node involvement. Since these patients are at low risk for disease recurrence, surgery alone is usually curative and adjuvant therapy is not indicated (algorithm 1) [4]. Clinical trials are an alternative to surveillance, where available. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Surveillance'.)
HIGH-RISK NODE-NEGATIVE DISEASE (STAGE IIB AND IIC) — Patients with high-risk node-negative melanoma present with AJCC eighth edition stage IIB and IIC disease (table 1A-B). They have a primary tumor that is thick and/or ulcerated (>4 mm thick with or without ulceration, or >2 to 4 mm thick with ulceration), but no lymph node involvement. Patients with stage IIB and IIC disease are at a similar or increased risk for recurrence and metastatic disease as a subset of those with stage III disease (figure 1).
For patients with resected high-risk node-negative (stage IIB and IIC) melanoma, we suggest one year of adjuvant immunotherapy with either pembrolizumab (table 2) or nivolumab (table 3) rather than surveillance (algorithm 1). However, surveillance or enrollment in a clinical trial are reasonable alternatives, particularly those with stage IIB disease who have a lower risk of disease recurrence, pending longer follow-up data for overall survival (OS) with adjuvant immunotherapy. Patients with stage IIB disease have a lower risk of disease recurrence, so surveillance avoids the potential risks of long-term immunotherapy-related adverse events and preserves immunotherapy as a treatment option if their disease recurs. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
Adjuvant pembrolizumab — In patients with resected, high-risk node-negative (stage IIB and IIC) melanoma, one year of adjuvant pembrolizumab (table 2) improved recurrence-free survival (RFS) over placebo and was well tolerated in a phase III trial [5-7].
Patients with high-risk node-negative disease are at similar or increased risk for recurrence and metastatic disease as other patients with node-positive disease (figure 1). However, they were excluded from initial phase III clinical trials evaluating adjuvant immunotherapy and targeted agents in resected melanoma [8-11]. Subsequently, an international, double-blind, placebo-controlled phase III trial (KEYNOTE-716) was conducted to evaluate the use of adjuvant pembrolizumab (table 2) in 976 patients with completed resected cutaneous stage IIB or IIC melanoma [5,7] including adults and children older than 12 years of age. In this study, patients were randomly assigned to either adjuvant pembrolizumab at a dose of 200 mg intravenously every three weeks (or 2 mg/kg every three weeks for pediatric patients) for up to one year or placebo.
At median follow-up of 27 months, for all patients, pembrolizumab improved RFS over placebo (two-year RFS 81 versus 73 percent, HR 0.64, 95% CI 0.50-0.84) [7]. In a subgroup analysis, adjuvant pembrolizumab also improved RFS for patients with stage IIB disease (T3b, hazard ratio [HR] 0.57, 95% CI 0.36-0.89; T4a, HR 0.48, 95% CI 0.26-0.90) and trended towards improved RFS for stage IIC disease (T4b, HR 0.76, 95% CI 0.51-1.13). Adjuvant pembrolizumab also improved distant metastasis-free survival (DMFS) over placebo (two-year DMFS 88 versus 82 percent, HR 0.64, 95% CI 0.47-0.88), with a consistent benefit across all tumor stages. Grade ≥3 toxicity rates were higher for pembrolizumab compared with placebo (17 versus 5 percent). The most common immune-mediated endocrine adverse events were hypothyroidism (17 versus 4 percent), hypophysitis (2 versus 0 percent), adrenal insufficiency (3 versus 0 percent), hyperthyroidism (2 versus <1 percent), and type I diabetes mellitus (<1 versus 0 percent)
Based on these data, the US Food and Drug Administration (FDA) approved adjuvant pembrolizumab for adult patients with stage IIB and IIC melanoma following complete resection [12]. The use of adjuvant pembrolizumab in pediatric patients is discussed below. (See 'Pediatric and adolescent patients' below.)
Adjuvant nivolumab — In patients with high-risk node-negative (stage IIB and IIC) melanoma, one year of adjuvant nivolumab improved RFS over placebo and was well tolerated in a phase III trial [13].
Adjuvant nivolumab was evaluated in a randomized, open-label, placebo-controlled phase III trial (CheckMate-76K) of 760 patients with completely resected stage IIB and IIC melanoma [13]. In preliminary results, at median follow-up of approximately 16 months, one year of adjuvant nivolumab improved RFS (one-year RFS 89 versus 79 percent; HR 0.42, 95% CI 0.30-0.59) and DMFS (one-year DMFS 92 versus 87 percent; HR 0.47, 95% CI 0.30-0.72) over placebo. RFS benefit for adjuvant nivolumab was also seen among the subgroups with stage IIB and IIC disease. Grade ≥3 treatment-related toxicity was higher for nivolumab versus placebo (10 versus 2 percent).
LOW-RISK NODE-POSITIVE DISEASE (STAGE IIIA) — For patients with resected, low-risk node-positive (AJCC eighth edition stage IIIA) melanoma (table 1A-B), the approach to adjuvant therapy is as follows (algorithm 1):
●We suggest surveillance rather than systemic therapy in patients with resected stage IIIA disease (table 1A-B) who have a non-ulcerated primary tumor ≤2 mm in thickness and sentinel lymph nodes containing <1 mm of tumor. Data suggest that these patients with small volume disease have a lower risk of disease recurrence (estimated at less than 20 percent [4,14,15]) and a five-year recurrence-free survival (RFS) of over 90 percent [16,17]. Clinical trials of adjuvant therapy have not typically included these patients due to the low risk of recurrence. Patients who choose surveillance instead of systemic therapy can avoid treatment-related toxicity, and its use can be reserved in the event of recurrent or metastatic disease. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Surveillance'.)
●For all other patients with resected stage IIIA melanoma (table 1A-B), we treat with one year of adjuvant systemic therapy, based upon the BRAF mutation status of the tumor (algorithm 1).
•For patients with BRAF wild-type tumors, we offer a single-agent programmed cell death-1 (PD-1) inhibitor (nivolumab (table 3) or pembrolizumab (table 2)). The choice of therapy is discussed below. (See 'BRAF wild-type tumors' below.)
•For those with BRAF mutant tumors, we offer either a single-agent PD-1 inhibitor (nivolumab (table 3) or pembrolizumab (table 2)) or targeted therapy with dabrafenib plus trametinib. The choice of therapy is discussed below. (See 'BRAF-mutated tumors' below.)
The approach to adjuvant and neoadjuvant therapy for more advanced, higher-risk stage III tumors is discussed separately. (See 'High-risk node-positive disease (stage IIIB, IIIC, IIID)' below.)
HIGH-RISK NODE-POSITIVE DISEASE (STAGE IIIB, IIIC, IIID) — Patients with high-risk node-positive disease (AJCC eighth edition stage IIIB, IIIC, and IIID disease (table 1A-B)) are at significant risk for disease recurrence [4]. Treatment options for these patients include systemic therapy (immune checkpoint inhibitors or targeted therapy) and surgery. Multidisciplinary evaluation is necessary to determine the appropriate sequencing of this treatments, with input from medical oncology, surgical oncology, and radiation oncology.
Macroscopic disease — For patients with high-risk node-positive (AJCC eight edition stage IIIB, IIIC, and IIID (table 1A-B)) melanoma and macroscopic disease that is resectable, we suggest initial treatment with neoadjuvant pembrolizumab rather than primary surgery, based on improved event-free survival (EFS) in a randomized phase II trial (SWOG S1801) [18]. Macroscopic disease is defined as clinically detected lymph nodes on radiographic imaging or physical exam, or visible in-transit or satellite metastases that are subsequently confirmed on pathology (eg, fine needle aspiration [FNA], incisional, or excisional biopsy). For patients who select neoadjuvant pembrolizumab, specific management details are discussed below. (See 'Neoadjuvant pembrolizumab' below.)
Alternative options for neoadjuvant therapy in this population include nivolumab plus ipilimumab, based on data from phase I and II trials, or enrollment in clinical trials investigating other neoadjuvant regimens, where available. (See 'Neoadjuvant nivolumab plus ipilimumab' below and 'Investigational approaches' below.)
Pathologic responses to neoadjuvant immunotherapy — Patients treated with neoadjuvant immunotherapy have varying pathologic responses at surgical resection, which are defined as follows [19]:
●Complete pathologic response (pCR) – No viable tumor cells
●Major pathologic response (mPR) – ≤10 percent viable tumors cells (ie, pathologic complete response [pCR] or near pCR)
●Pathologic partial response (pPR) – Between 10 and 50 percent viable tumor cells
●Pathologic nonresponse (pNR) – Greater than 50 percent viable tumor cells
Neoadjuvant pembrolizumab — Neoadjuvant pembrolizumab is effective in patients with high-risk node-positive macroscopic disease. This approach is based on a randomized phase III trial (SWOG S1801) where one year of perioperative (neoadjuvant and adjuvant) pembrolizumab improved EFS over primary resection plus adjuvant pembrolizumab and was well-tolerated [18]. This study established the concept that neoadjuvant immunotherapy is more effective than primary surgery followed by adjuvant immunotherapy.
Neoadjuvant pembrolizumab is administered at 200 mg intravenously (IV) every three weeks over three cycles, followed by surgery (therapeutic lymph node dissection). Patients who complete neoadjuvant pembrolizumab and surgery are then treated with an additional fifteen cycles of adjuvant pembrolizumab to complete up to one year of therapy. Although data are limited, patients with a pNR and BRAF mutant disease may alternatively switch to one year of adjuvant targeted therapy with dabrafenib plus trametinib, since tumors with a pNR are likely resistant to immunotherapy.
Initial phase I and II trials of neoadjuvant PD-1 inhibitors (pembrolizumab or nivolumab) demonstrated mPR rates of up to 30 percent in patients with cutaneous melanoma [19-22]. Based on these data, neoadjuvant pembrolizumab was evaluated in an open-label, randomized phase II trial (SWOG S1801) of 313 patients with resectable macroscopic stage IIIB-IV cutaneous, acral, and mucosal melanoma without brain metastases [18]. In this study, patients were randomly assigned to either neoadjuvant immunotherapy (three cycles of preoperative pembrolizumab at 200 mg administered IV every three weeks followed by surgery and fifteen cycles of adjuvant pembrolizumab) or adjuvant immunotherapy (primary surgery followed by eighteen cycles of adjuvant pembrolizumab).
In preliminary results, at median follow-up of 15 months, neoadjuvant immunotherapy improved EFS compared with adjuvant therapy in the entire study population (two-year EFS 72 versus 49 percent, HR 0.58, 95% CI 0.39-0.87) [18]. An EFS benefit for neoadjuvant immunotherapy was also seen across multiple clinical subgroups including stage (stage IIIB, HR 0.91; stage IIIC, hazard ratio [HR] 0.4; stage IIID/IV, HR 0.45), lactate dehydrogenase (LDH) levels, and BRAF status (BRAF-mutant; HR 0.44, 95% CI 0.21-0.91; BRAF wild-type, HR 0.72, 95% CI 0.38-1.35). Overall survival (OS) data were immature (HR 0.63, 95% CI 0.32-1.24).
Among 142 evaluable patients treated with neoadjuvant therapy, complete and partial radiographic response rates were 6 and 41 percent, respectively. Although a similar proportion of patients were able to proceed to surgery in each treatment arm, tumor-related events (disease progression or recurrence) occurred less frequently with neoadjuvant therapy versus adjuvant therapy (20 versus 40 percent). The pCR rate for neoadjuvant pembrolizumab was 21 percent at initial institutional evaluation. Neoadjuvant pembrolizumab did not significantly increase toxicity in the perioperative period compared with adjuvant therapy, as grade ≥3 toxicity rates were similar during the surgical (12 versus 5 percent) and adjuvant periods (9 versus 16 percent).
Neoadjuvant pembrolizumab also has activity in BRAF mutant disease (mPR rates of approximately 40 percent in one randomized trial [NEOTrio] [20]); and locally advanced desmoplastic melanoma, which is particularly responsive to immunotherapy (pCR rates of approximately 55 percent in one phase II study [SWOG 1512] [23]). (See "Radiation therapy in the management of melanoma", section on 'Desmoplastic melanoma' and "Overview of the management of advanced cutaneous melanoma", section on 'Desmoplastic melanoma'.)
Neoadjuvant nivolumab plus ipilimumab — Neoadjuvant nivolumab plus ipilimumab is another option for patients with high-risk macroscopic node-positive disease, extrapolating from phase I and II trial data [24-28]. In these studies, neoadjuvant nivolumab plus ipilimumab was well tolerated, reduced surgical morbidity, and demonstrated mPR rates between 70 to 80 percent that were durable. (See 'Pathologic responses to neoadjuvant immunotherapy' above and 'Limited nodal resection after neoadjuvant immunotherapy' below.)
Neoadjuvant nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is administered IV every three weeks for up to two cycles total, followed by surgery (therapeutic lymph node dissection). Patients who complete neoadjuvant nivolumab plus ipilimumab as well as surgery can receive adjuvant nivolumab to complete up to one year of systemic therapy. However, for patients with an mPR, the approach to adjuvant therapy is evolving, as data from a phase II trial (PRADO) suggest that a full year of adjuvant therapy may not be required [28]. (See 'Limited nodal resection after neoadjuvant immunotherapy' below.)
Investigational approaches
Limited nodal resection after neoadjuvant immunotherapy — For patients treated with neoadjuvant immunotherapy, data suggest that limited initial resection of a select involved lymph node (rather than a therapeutic lymph node dissection [TLND]) could be used to guide further surgery and adjuvant systemic therapy.
In an open-label phase II trial (PRADO), 99 patients with stage IIIB or IIIC melanoma and an index lymph node (ILN) that was measurable on computed tomography imaging and able to be marked with a fiducial were treated neoadjuvantly with the combination of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every three weeks for up to two doses, followed by resection of the marked ILN [28]. This neoadjuvant treatment strategy had previously been established by a randomized phase II trial (OpACIN-neo) [24]. Patients were subsequently treated using a personalized response-driven approach based on the pathologic response rate of the ILN. (See 'Pathologic responses to neoadjuvant immunotherapy' above.)
●Patients with an mPR (which included those with a pCR) did not receive further surgery (eg, TLND) or systemic therapy and were observed; those with a pPR received TLND followed by observation; those with a pNR received TLND followed by adjuvant systemic therapy (either nivolumab or the combination of dabrafenib plus trametinib in patients with a BRAF V600-mutated tumor).
●In the entire study population, pathologic responses from combination immunotherapy were seen in 71 patients (72 percent), including 60 patients with either a pCR or near pCR (61 percent) and 11 patients with a pPR (11 percent); pNR was seen in 20 patients (21 percent).
●The overall radiologic response rate was 45 percent and accurately identified seven patients (7 percent) who developed distant metastatic disease prior to ILN resection, influencing their subsequent treatment strategies; however, imaging assessment generally underestimated the degree of pathologic responses.
●The grade ≥3 immune-mediated adverse event rate was 30 percent.
●Using neoadjuvant immunotherapy, TLND was omitted in 59 of 99 patients (60 percent). Additionally, compared with patients treated with TLND, those who received ILN surgery alone reported reduced rates of surgical adverse events (84 versus 46 percent) and improved quality of life.
●At median follow-up of 28 months, in all patients, two-year recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were 85 and 89 percent, respectively. Patients with mPR also demonstrated excellent two-year RFS and DMFS (93 and 98 percent). However, patients with a pPR, who were observed after TLND, may also benefit from adjuvant therapy, as these patients had lower two-year RFS and DMFS (64 percent each) than those with pNR, who received adjuvant therapy after TLND (71 and 76 percent) [28].
Data from the PRADO trial suggest that after neoadjuvant immunotherapy, a limited initial resection of one involved lymph node could be used to determine further surgery and adjuvant therapy. For some patients, this approach could potentially avoid the surgical morbidity associated with more extensive surgery (ie, TLND). Treatment could be selected based on the pathologic response of the resected lymph node. Patients with an mPR may not require further surgery and could be observed or treated with a shorter duration of adjuvant immunotherapy. In contrast, patients with pPR or pNR on surgical pathology could be treated with a TLND followed by adjuvant immunotherapy with a single-agent PD-1 inhibitor to complete up to one year of treatment. Alternatively, patients with a pNR and BRAF-mutant disease may benefit from TLND and switching to adjuvant targeted therapy with dabrafenib plus trametinib, since tumors with a pNR are likely resistant to immunotherapy.
Neoadjuvant targeted therapy — In patients with BRAF-mutant melanoma, the use of neoadjuvant targeted therapy with BRAF plus MEK inhibitors remains investigational. Neoadjuvant targeted therapy results in pCR rates of approximately 50 percent, but durable responses are limited when compared with neoadjuvant immunotherapy [19,25].
As an example, one meta-analysis evaluated clinical trials of neoadjuvant immunotherapy or targeted therapy in 192 patients with melanoma [25]. In the subset of 51 patients with BRAF-mutant melanoma who received neoadjuvant targeted therapy, a pCR was seen in 24 of 51 patients (47 percent) at median follow-up of 21 months. However, patients who achieved a pCR from targeted therapy were still more likely to relapse at two years than those with any pathologic response to neoadjuvant immunotherapy (21 versus 4 percent). In addition, most patients receiving targeted therapy who did not achieve a pCR relapsed within two years (87 percent).
Other agents — Other agents are also being investigated in the neoadjuvant setting, including nivolumab plus relatlimab [29] and talimogene laherparepvec (T-VEC) [30]. The intralesional use of T-VEC to treat unresectable dermal and epidermal melanoma metastases and the use of nivolumab plus relatlimab for metastatic melanoma are discussed separately.
●(See "Cutaneous melanoma: In-transit metastases", section on 'Intralesional therapy (T-VEC)'.)
●(See "Cutaneous melanoma: Management of local recurrence", section on 'Talimogene laherparepvec'.)
Microscopic disease — For patients with high-risk node-positive (AJCC eighth edition stage IIIB, IIIC, and IIID) microscopic disease (table 1A-B) who have undergone primary resection and did not receive neoadjuvant therapy prior to surgery, we offer adjuvant systemic therapy, which reduces recurrence risk and improves survival (algorithm 1). Microscopic disease is defined as tumor burden detected on sentinel lymph node biopsy. In several phase III trials, adjuvant single-agent immunotherapy improved RFS, and targeted therapy with the BRAF plus MEK inhibitors dabrafenib plus trametinib improved OS in those whose tumors also contained a BRAF mutation. (See 'BRAF wild-type tumors' below and 'BRAF-mutated tumors' below.)
Patients with unresectable disease should be evaluated in a multidisciplinary setting to determine appropriate management. Such patients are treated similarly to those with unresectable in-transit or metastatic disease, as indicated, or clinical trials. (See "Cutaneous melanoma: In-transit metastases" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)
BRAF wild-type tumors — For patients with primary resected, high-risk node-positive microscopic disease lacking a BRAF V600 mutation and no prior neoadjuvant therapy, we suggest one year of adjuvant immunotherapy with a PD-1 inhibitor rather than other systemic therapies or surveillance. Options for adjuvant therapy include either nivolumab (table 3) or pembrolizumab (table 2), as both improved RFS as single agents and were well tolerated. (See 'Adjuvant nivolumab' below and 'Adjuvant pembrolizumab' below.)
Adjuvant nivolumab — In patients with resected high-risk node-positive melanoma, one year of adjuvant nivolumab (table 3) improved RFS and reduced toxicity compared with ipilimumab in a phase III trial [10,31,32].
In this study (CheckMate 238), 906 patients with complete resection of AJCC seventh edition stage IIIB, IIIC, or IV melanoma were randomly assigned to nivolumab (3 mg/kg every two weeks for one year) or ipilimumab (10 mg/kg every three weeks for four doses, and then every 12 weeks for up to one year) [10,31,32]. All patients had complete resection of disease within 12 weeks prior to randomization. Approximately 29 percent of patients had microscopic nodal involvement and 71 percent had either macroscopic lymph node disease or resected stage IV disease. The study also enrolled patients with acral and mucosal melanoma but excluded those with ocular melanoma. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment", section on 'Adjuvant checkpoint inhibitor immunotherapy'.)
In preliminary results, at median follow-up of 61 months, compared with ipilimumab [32], results were as follows:
●All patients – In the entire study population, nivolumab improved five-year RFS (50 versus 39 percent, HR 0.72, 95% CI 0.6-0.86). OS was similar between the two treatment arms (five-year OS 76 versus 72 percent, HR 0.86, 95% CI 0.66-1.12).
●Stage IIIB to IIIC disease – In those with stage IIIB to IIIC disease, nivolumab improved five-year RFS (50 versus 40 percent, HR 0.73, 95% CI 0.60-0.89) and five-year distant metastasis-free survival (DMFS; 58 versus 51 percent, HR 0.79, 95% CI 0.63-0.99). Results for patients with stage IV disease are discussed below. (See 'Adjuvant nivolumab' below.)
●BRAF wild-type tumors – Among the 409 patients with BRAF wild-type disease (45 percent), nivolumab improved five-year RFS (47 versus 36 percent; HR 0.69, 95% CI 0.53-0.9). Results for tumors harboring a BRAF mutation are discussed below. (See 'Adjuvant nivolumab' below.)
●Other subgroups – A similar degree of improvement in RFS with nivolumab was seen in the prespecified major subgroups, including the presence or absence of ulceration, the extent of lymph node involvement (microscopic versus macroscopic), and programmed cell death ligand 1 (PD-L1) expression [31].
●Toxicity – Nivolumab had fewer grade ≥3 toxicity (14 versus 46 percent) and treatment-related adverse events leading to discontinuation of therapy than ipilimumab (4 versus 30 percent) [10]. Late emergent toxicities were similar between the two treatment arms (1 versus 2 percent) [31].
Based on these data, nivolumab received regulatory approval from the FDA for patients with melanoma and lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting [33]. The use of adjuvant single-agent nivolumab in patients with completely resected metastatic disease is discussed below. (See 'Metastatic disease (stage IV)' below.)
The original approval of nivolumab as adjuvant therapy used a schedule of 240 mg every two weeks. Subsequently, an alternative schedule of nivolumab 480 mg every four weeks was approved based upon clinical pharmacology analyses and safety assessments [33,34].
Adjuvant pembrolizumab — In patients with resected high-risk node-positive melanoma, one year of adjuvant pembrolizumab (table 2) improved RFS and DMFS and reduced toxicity in phase III trials [35-39].
The efficacy of adjuvant pembrolizumab (table 2) was initially demonstrated in the placebo-controlled phase III KEYNOTE-054 (European Organisation for Research and Treatment of Cancer [EORTC] 1325) trial [35-38]. In that trial, 1019 patients with completely resected stage III disease were randomly assigned to either pembrolizumab (200 mg every three weeks for 18 doses) or placebo.
At a median follow-up of three years, compared with placebo, data were as follows [36,37]:
●Entire study population – For the entire study population, pembrolizumab improved RFS (60 versus 41 percent at 3.5 years, HR 0.59, 95% CI 0.49-0.7) and DMFS (65 versus 49 percent at 3.5 years, HR 0.6, 95% CI 0.49-0.73) [37].
●Stage IIIA (at least one lymph node metastasis ≥1 mm), IIIB, and IIIC disease – Pembrolizumab improved three-year RFS in patients with stage IIIB and stage IIIC disease (66 versus 47 percent, HR 0.56, 99% CI 0.39-0.81; 54 versus 32 percent, HR 0.57, 99% CI 0.4-0.81, respectively) and trended towards RFS benefit in those with stage IIIA disease, specifically those with ≥1 mm of disease in the lymph nodes (81 versus 66 percent, HR 0.5, 99% CI 0.22-1.16 [36]).
●BRAF V600 wild-type tumors – Among the 449 patients with BRAF V600 wild-type tumors (44 percent), pembrolizumab improved three-year RFS (62 versus 47 percent, HR 0.66, 95% CI 0.46-0.95) and trended towards improved DMFS benefit (62 versus 51 percent at 3.5 years, HR 0.73, 95% CI 0.5-1.07) [36].
●Other subgroups – A similar degree of improvement in RFS with pembrolizumab was seen in the prespecified major subgroups, including the presence or absence of ulceration and the extent of lymph node involvement (microscopic versus macroscopic) [36].
●Toxicity – Serious grade ≥3 adverse events were more common with pembrolizumab than with placebo (14 versus 3 percent), and there was one treatment-related death due to pembrolizumab (myositis).
In a subsequent phase III trial (S1404), one year of adjuvant pembrolizumab improved relapse-free survival and was better tolerated compared with other systemic therapies (high-dose interferon alfa-2b and ipilimumab) [39,40]. In this study, 1303 patients with high-risk (AJCC seventh edition stage IIIA to IVC) resected melanoma were randomly assigned to adjuvant therapy with either pembrolizumab (200 mg every three weeks for one year); high-dose interferon alfa-2b for one year; or high-dose ipilimumab (10 mg/kg every three weeks for four doses, then every 12 weeks for up to three years).
At median follow-up of approximately four years, compared with either high-dose interferon alfa-2b or ipilimumab, adjuvant pembrolizumab improved relapse-free survival (HR 0.77, 99.62% CI 0.59-0.99) but not OS (HR 0.82, 96.3% CI 0.61-1.9) in the total study population [39]. It also did not improve OS among those with PD-L1 positive tumors or those with BRAF-mutant disease. Grade ≥3 treatment-related toxicity was less with pembrolizumab (20 percent) compared with ipilimumab (49 percent) and high-dose interferon alfa-2b (72 percent).
Based on the data from KEYNOTE-054, the FDA granted regulatory approval for adjuvant pembrolizumab in patients with resected stage III (lymph node-involved) disease [12].
Adjuvant therapies not commonly used — Other systemic agents have limited roles as adjuvant therapy in patients with resected high-risk node-positive melanoma, due to toxicity, lack of efficacy, and/or the availability of more effective agents. Examples include:
●Ipilimumab – Ipilimumab, has regulatory approval as adjuvant therapy in patients with resected node-positive melanoma, but it is not commonly used and has essentially been replaced by other agents. Ipilimumab, which targets cytotoxic T lymphocyte-associated protein 4, is a less ideal adjuvant option due to its toxicity profile. However, if ipilimumab is being considered for adjuvant therapy, we suggest dosing at the 3 mg/kg schedule, which is the same dose used for metastatic disease. Previous data from a randomized phase III trial (EORTC 18071), which led to ipilimumab's approval as adjuvant therapy for melanoma, supported ipilimumab at 10 mg/kg dosing over placebo [8,9,41]. However, this dosing is no longer suggested due to toxicities and subsequent data from the E1609 trial supporting lower doses of ipilimumab.
In the phase III E1609 trial (NCT01274338), 1670 patients with resected melanoma were randomly assigned to either ipilimumab at 10 or 3 mg/kg dosing or to high-dose interferon alfa-2b [42]. After a median follow-up of 58 months, ipilimumab at the 3 mg/kg dose, in comparison with high-dose interferon alfa-2b, demonstrated improved OS (five-year OS 72 versus 67 percent, HR 0.78, 95% CI 0.61-0.99) and similar RFS. However, ipilimumab at the 10 mg/kg dose did not demonstrate a difference in OS or RFS when compared with interferon alfa-2b, possibly because over 50 percent of patients discontinued therapy due to toxicity. Rates of grade ≥3 toxicities were 37 percent with ipilimumab 3 mg/kg and 58 percent with ipilimumab 10 mg/kg.
●Interferon alfa-2b – Interferon alfa-2b no longer has a well-defined role in the adjuvant setting for cutaneous melanoma. Prior to the development of checkpoint inhibitor immunotherapy, high-dose interferon alfa-2b was the only option for adjuvant treatment of high-risk melanoma that improved OS. The use of high-dose interferon alfa-2b was supported by the results of the Eastern Cooperative Oncology Group 1684 and Intergroup E1694 trials, as well as a meta-analysis that included results from trials with various schedules and doses [43-46]. However, this agent is associated with numerous serious side effects, such as acute constitutional symptoms, chronic fatigue, myelosuppression, hepatotoxicity, as well as neurological and psychological effects [47]. Interferon alfa-2b also has limited availability, as the manufacturer has discontinued production.
●Nivolumab plus ipilimumab – We do not offer the combination of nivolumab plus ipilimumab as adjuvant therapy in patients with resected, high-risk node-positive disease. In a randomized phase III trial (CheckMate 915), adjuvant nivolumab plus ipilimumab did not improve relapse-free survival over adjuvant nivolumab monotherapy in patients with advanced resected stage IIIB-D or IV melanoma [48,49]. Single-agent nivolumab remains one preferred option for adjuvant therapy in this population. (See 'Adjuvant nivolumab' above.)
BRAF-mutated tumors
Choice of therapy — For patients with primary resected, high-risk node-positive microscopic disease with a BRAF V600 driver mutation and no prior neoadjuvant therapy, options for adjuvant therapy include either one year of immunotherapy with either nivolumab (table 3) or pembrolizumab (table 2), or one year of targeted therapy with dabrafenib plus trametinib. In these patients, immunotherapy and targeted therapy are both effective options with different toxicity profiles. However, the optimal adjuvant therapy has not been established, since these agents have not been directly compared in randomized trials. (See 'Factors that influence therapy' above.)
Patient characteristics and preferences can be used to guide selection of therapy. As examples:
●Adjuvant immunotherapy can be offered to patients who are willing to accept the potential long-term toxicities, primarily endocrine, for a chance at achieving durable treatment-free survival. Durable treatment-free survival is a hallmark of immunotherapy in the management of patients with distant metastatic disease, but less commonly seen with BRAF plus MEK inhibitors in that setting. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Previously untreated patients' and "Toxicities associated with checkpoint inhibitor immunotherapy".)
However, adjuvant dabrafenib plus trametinib is also an appropriate option in these patients, as it improved OS in a phase III trial [11]. Additionally, while toxicities from targeted therapy are common and can affect multiple organ systems, they are typically manageable and/or reversible once treatment is discontinued. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
●Adjuvant dabrafenib plus trametinib is an alternative for patients who cannot receive immunotherapy (eg, due to immunosuppressive therapy or corticosteroids); those at greater risk for immune-related adverse events (irAEs); and/or those who prefer the convenience of oral targeted therapy over intravenous treatment with immunotherapy, after a thorough risk-benefit discussion with the treating clinician. (See 'Adjuvant dabrafenib plus trametinib' below.)
Adjuvant nivolumab — One year of adjuvant nivolumab (table 3) is an option for patients with high-risk node-positive disease and a BRAF V600 mutation who are eligible to receive immunotherapy.
In a phase III trial (CheckMate 238), one year of adjuvant nivolumab improved RFS over ipilimumab among 906 patients with complete resection of AJCC seventh edition stage IIIB, IIIC, or IV melanoma [10,31,32]. In preliminary results, among the subset of 381 patients with BRAF mutant tumors (42 percent), nivolumab trended towards improved five-year RFS compared with ipilimumab (50 versus 42 percent, HR 0.8, 95% CI 0.6-1.05) [32]. Results for the entire study population are discussed above. (See 'Adjuvant nivolumab' above.)
Adjuvant pembrolizumab — One year of adjuvant pembrolizumab (table 2) is an option for patients with high-risk node-positive disease and a BRAF V600 mutation who are eligible to receive immunotherapy.
A placebo-controlled phase III trial (KEYNOTE-054) [35-38] of 1019 patients with completely resected stage III (including stage IIIA tumors with ≥1 mm of disease in the lymph nodes) melanoma also included a subset of 440 patients with BRAF V600 mutated tumors. In this subgroup, at median follow-up of three years, pembrolizumab improved three-year RFS (62 versus 37 percent, HR 0.51, 99% CI 0.36-0.73) and DMFS (64 versus 44 percent at 3.5 years, HR 0.53, 95% CI 0.36-0.77) [35,36]. Results for the entire study population are discussed above. (See 'Adjuvant pembrolizumab' above.)
Adjuvant dabrafenib plus trametinib — One year of adjuvant therapy with dabrafenib plus trametinib is a reasonable alternative to immunotherapy for select patients with high-risk node-positive disease whose tumor contains a BRAF V600 mutation. For example, targeted therapy may be offered to those at greater risk for irAEs (eg, due to medical comorbidities, and/or active autoimmune disease) or those who cannot receive immunotherapy due to immunosuppressive therapy or corticosteroid use. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)
Dabrafenib plus trametinib is also acceptable adjuvant therapy for those with a BRAF V600 mutation at lower risk for disease recurrence (stage IIIA). (See 'Low-risk node-positive disease (stage IIIA)' above.)
Dabrafenib plus trametinib improved RFS and OS in the adjuvant setting [11,50-52]. Based on initial phase III data confirming the efficacy of adjuvant vemurafenib, a single-agent BRAF inhibitor [53], the combination of dabrafenib plus trametinib was evaluated in a phase III trial (COMBI-AD). In this study, 870 patients with completely resected BRAF V600 mutation-positive stage III melanoma were randomly assigned to the combination of dabrafenib (150 mg twice a day) plus trametinib (2 mg once a day) or to matching placebos for one year [11,50-52].
At a median follow-up of five years, compared with placebo, the combination of dabrafenib plus trametinib improved both five-year RFS (52 versus 36 percent; HR 0.51, 95% CI 0.42-0.61) and DMFS at five years (65 versus 54 percent, HR 0.55, 95% CI 0.44-0.7) [52]. The combination also improved OS at three years (86 versus 77 percent; HR 0.57, 95% CI 0.42-0.79) [11]. Treatment benefit for the combination was observed irrespective of baseline factors, according to subgroup analysis [50].
Based upon this trial, the combination of dabrafenib plus trametinib was approved by the FDA for adjuvant use for patients with lymph node involvement and a BRAF V600E or V600K mutation [54,55].
METASTATIC DISEASE (STAGE IV)
Adjuvant nivolumab plus ipilimumab — For patients with stage IV disease, regardless of BRAF V600 mutation status, who have undergone primary definitive treatment of all sites of disease with either surgery or radiation therapy, we suggest adjuvant immunotherapy with the combination of nivolumab (1 mg/kg every three weeks) plus ipilimumab (3 mg/kg every three weeks) for four doses, followed by maintenance nivolumab to complete a year of therapy, rather than surveillance alone, as this approach improved overall survival (OS) in a randomized trial [56,57].
Some UpToDate experts also offer an alternative dosing strategy for nivolumab plus ipilimumab (ie, nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses), based on results of a randomized trial comparing dosing strategies in patients with measurable metastatic disease. This study, although underpowered, demonstrated similar efficacy for both regimens and reduced toxicity for the alternative regimen [58]. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)
Adjuvant nivolumab plus ipilimumab improved recurrence-free survival (RFS) and OS in a double-blind, placebo-controlled phase II trial (IMMUNED). In this study, 167 patients with stage IV melanoma with no evidence of disease after treatment with surgery or radiation therapy were randomly assigned to adjuvant immunotherapy with either four cycles of nivolumab plus ipilimumab followed maintenance nivolumab monotherapy, nivolumab monotherapy, or placebo [56,57]. In all treatment arms, maintenance therapy was continued up to one year, unacceptable toxicity, or disease recurrence.
At median follow-up of 49 months, results for the entire study population were as follows:
●Nivolumab plus ipilimumab improved RFS compared with placebo (four-year RFS 64 versus 15 percent, hazard ratio [HR] 0.25, 97.5% CI 0.13-0.48) and nivolumab monotherapy (four-year RFS 64 versus 31 percent, HR 0.41, 97.5% CI 0.22-0.78) [57].
●Nivolumab plus ipilimumab also improved OS compared with placebo (four-year OS 84 versus 63 percent, HR 0.41, 97.5% CI 0.77-0.99) but not nivolumab (four-year OS 84 versus 73 percent, HR 0.55, 97.5% CI 0.22-1.38).
●Nivolumab monotherapy also improved RFS but failed to improve OS compared with placebo (four-year RFS 31 versus 15 percent, HR 0.6, 97.5% CI 0.36-1.00; four-year OS 73 versus 63 percent, HR 0.75, 97.5% 0.36-1.56).
●Grade ≥3 toxicities were higher for combination immunotherapy versus nivolumab alone (71 versus 29 percent).
Among those with a BRAF V600 mutation, the combination also improved RFS compared with nivolumab monotherapy (HR 0.25, 95% CI 0.09-0.69) and placebo (HR 0.11, 95% CI 0.04-0.29).
A separate phase III trial (CheckMate 915) which also evaluated nivolumab plus ipilimumab in a subset of patients with stage IV disease did not show an RFS benefit over single agent nivolumab. However, this trial used an alternative dosing for the combination (nivolumab 240 mg every two weeks and ipilimumab 1 mg/kg every six weeks) whereas the IMMUNED trial used standard dosing. (See 'Adjuvant therapies not commonly used' above.)
The use of combination of nivolumab plus ipilimumab in those with unresectable metastatic (stage IV) disease is discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)
Adjuvant nivolumab — For those who are unable to tolerate the potential toxicities of combination nivolumab plus ipilimumab, we alternatively offer adjuvant nivolumab monotherapy for one year (table 3). Although nivolumab has not been shown to improve OS, it has a more manageable toxicity profile and has regulatory approval as adjuvant therapy in patients with completely resected stage IV disease. (See 'Adjuvant nivolumab' above.)
A randomized phase III trial (CheckMate 238) of 906 patients with high-risk resected melanoma included a subset of 169 patients with stage IV disease [31,32]. In preliminary results, among this subset of patients, adjuvant nivolumab trended towards higher five-year RFS over ipilimumab, although the results were not statistically significant (49 versus 34 percent, HR 0.71, 95% CI 0.47-1.06) [32].
Similarly, in a randomized trial (IMMUNED) of patients with definitively treated stage IV melanoma, adjuvant nivolumab monotherapy improved RFS versus placebo but failed to improve OS versus adjuvant nivolumab plus ipilimumab [57]. These data are discussed above. (See 'Adjuvant nivolumab plus ipilimumab' above.)
SPECIAL POPULATIONS
Pediatric and adolescent patients — Adjuvant therapy is offered to pediatric and adolescent patients with localized melanoma at increased risk for disease recurrence, extrapolating from the same treatment approach used in adults. (See 'Factors that influence therapy' above.)
Adjuvant pembrolizumab — In the United States, pembrolizumab has regulatory approval for the adjuvant treatment of pediatric patients (12 years and older) with stage IIB, IIC, or III melanoma following complete resection [12]. Pediatric dosing for adjuvant pembrolizumab is available at 2 mg/kg (up to a maximum of 200 mg) every three weeks for up to 12 months (table 2).
Data are limited for the efficacy of adjuvant pembrolizumab in children and adolescents. As an example, one phase III trial (KEYNOTE-716) evaluated the use of adjuvant pembrolizumab in patients with high-risk node-negative disease [5]. This trial only enrolled two pediatric patients (children between the ages of 12 and 17 years), who were treated with a pediatric dosing of pembrolizumab. Results of this trial for the entire study population are discussed above. (See 'Adjuvant pembrolizumab' above.)
RECURRENCE AFTER ADJUVANT THERAPY — For patients who recur with metastatic disease after initial adjuvant therapy, the approach to therapy is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Prior adjuvant systemic therapy' and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Factors that influence therapy – For patients with resectable cutaneous melanoma, the choice of adjuvant or neoadjuvant therapy is influenced by risk of disease recurrence (based upon thickness and ulceration of the primary tumor and/or the presence of lymph node metastases), tumor stage, and BRAF mutation status (algorithm 1). (See 'Factors that influence therapy' above.)
●Low-risk node-negative disease – For patients with low-risk node-negative (American Joint Committee on Cancer [AJCC] eighth edition stage I or IIA (table 1A-B)) disease, we perform surveillance alone after surgery without adjuvant therapy. Since these patients are at low risk for disease recurrence, surgery alone is usually curative. (See 'Low-risk node-negative disease (stage I and IIA)' above.)
●High-risk node-negative disease – For patients with high-risk node-negative (stage IIB and IIC (table 1A-B)) disease, we suggest one year of adjuvant immunotherapy with either pembrolizumab (table 2) or nivolumab (table 3) rather than surveillance (Grade 2B). However, surveillance or enrollment in a clinical trial are reasonable alternatives, particularly for those with stage IIB disease given their likely lower recurrence risk. (See 'High-risk node-negative disease (stage IIB and IIC)' above.)
●Low-risk node-positive disease – For patients with low-risk node-positive (stage IIIA (table 1A-B)) disease, our approach is as follows (see 'Low-risk node-positive disease (stage IIIA)' above):
•For patients with resected stage IIIA disease who have a non-ulcerated tumor ≤2 mm in thickness and sentinel lymph nodes containing <1 mm of tumor, we suggest surveillance rather than systemic therapy (Grade 2C), as these patients have a lower risk of disease recurrence (estimated at less than 20 percent).
•For all other patients with resected stage IIIA melanoma, we treat with one year of adjuvant systemic therapy. The choice of therapy is based upon the BRAF mutation status of the tumor.
●High-risk node-positive disease – For patients with high-risk node-positive (AJCC eighth edition stage IIIB, IIIC, and IIID (table 1A-B)) melanoma, our treatment approach is as follows (see 'High-risk node-positive disease (stage IIIB, IIIC, IIID)' above):
•Macroscopic disease – For patients with macroscopic disease that is resectable, we suggest initial treatment with neoadjuvant pembrolizumab rather than primary surgery (Grade 2B), based on improved event-free survival (EFS) in a randomized trial. Macroscopic disease is defined as clinically detected lymph nodes on radiographic imaging or physical exam, or visible in-transit or satellite metastases that are subsequently confirmed on pathology (eg, fine needle aspiration [FNA] or excisional biopsy). (See 'Macroscopic disease' above and 'Neoadjuvant pembrolizumab' above.)
Alternative options for neoadjuvant therapy include nivolumab plus ipilimumab or enrollment in clinical trials investigating other neoadjuvant regimens. (See 'Neoadjuvant nivolumab plus ipilimumab' above and 'Investigational approaches' above.)
•Microscopic disease – For patients with primary resected microscopic disease and no prior neoadjuvant therapy, options for adjuvant systemic therapy include immunotherapy or targeted therapy for BRAF V600 mutated tumors. Microscopic disease is defined as tumor burden detected on sentinel lymph node biopsy. (See 'Microscopic disease' above.)
-BRAF wild-type tumors – For tumors lacking a BRAF V600 mutation, we suggest one year of adjuvant immunotherapy with a programmed cell death-1 (PD-1) inhibitor rather than other systemic therapies or surveillance (Grade 2B), as this approach improves RFS and is well tolerated. Options for adjuvant therapy include either single-agent nivolumab (table 3) or pembrolizumab (table 2). (See 'BRAF wild-type tumors' above.)
-BRAF-mutated tumors – For tumors with a BRAF V600 driver mutation, options include either one year of adjuvant immunotherapy with either nivolumab (table 3) or pembrolizumab (table 2) or one year of targeted therapy with a combination of the BRAF plus MEK inhibitors dabrafenib plus trametinib. Both are effective options with different toxicity profiles, and patient characteristics and preferences are used to guide selection of therapy. (See 'BRAF-mutated tumors' above.)
●Metastatic disease – For patients with metastatic (stage IV) disease, regardless of BRAF V600 mutation status, who have undergone primary definitive treatment of all sites of metastatic disease, we suggest adjuvant nivolumab plus ipilimumab followed by maintenance nivolumab, rather than surveillance alone (Grade 2B), which improved overall survival (OS). (See 'Metastatic disease (stage IV)' above.)
While adjuvant nivolumab alone is an acceptable alternative for those who are unable to tolerate the potential toxicities of combination immunotherapy, it has not been shown to improve OS. (See 'Adjuvant nivolumab' above.)
