Management of Patients With Advanced Melanoma

Presenter: Genevieve Boland

For treatment of melanoma, accumulated research has allowed the transition of the most effective treatments into earlier stages of disease management. To this end, immunotherapy has become approved for high-risk stage II and resected stage III melanoma, and is currently being evaluated in the neoadjuvant setting. BRAF/MEK-targeted therapy is also approved in the adjuvant setting and is being evaluated in neoadjuvant trials. In stage IV disease, the optimal sequencing of these 2 main approaches is with immunotherapy initiated first. Recently, the LAG-3 antibody relatlimab, in combination with nivolumab, has produced impressive responses with low toxicity and has become a new standard of care compared with anti–PD-1 monotherapy. As heterogeneity within disease stages has become better appreciated, staging and risk classification have been refined.

Recent advances in treating cutaneous melanoma have resulted in impressive survival gains. The recent refinement of disease staging and risk classification has also improved the prognostic information that may help to optimize treatment. At the NCCN 2022 Annual Conference, Genevieve Boland, MD, PhD, Associate Professor of Surgery, Harvard Medical School; Section Head, Melanoma/Sarcoma Surgery; and Surgical Director, Temeer Center for Targeted Therapies, Massachusetts General Hospital, identified factors impacting tumor staging, discussed the relevance of the staging criteria and its use for risk stratification, compared treatment options for patients with advanced melanoma, and reviewed emerging data for adjuvant and neoadjuvant approaches.

Disease Staging

Changes from the 7th edition to the 8th edition of the AJCC TNM staging criteria serve as a reminder of the heterogeneity of the disease process. The changes were aimed at consolidating risk categories that grouped patients together who had similar risks and outcomes, within and across TNM stages.

The 8th AJCC edition created a stage IIID category that identifies patients with very high-risk primary tumors and high-risk nodal disease, and distinguishes them from patients with other stage III disease who have better prognoses.1 By refining the staging classifications, comparisons were made demonstrating that patients with stage IIC disease (with a high-risk primary, but no nodal metastases) have similar outcomes to those with stage IIIB disease who have thinner or intermediate-thickness melanoma and nodal metastases, and with worse outcomes than patients with stage IIIA disease (low-risk primary and microscopic nodal disease).

“I think these staging classifications are focused on trying to place patients in the appropriate baskets to help us make clinical decisions,” Dr. Boland said. “The staging tools are very helpful for this risk stratification, so we can advise our patients on what treatments they should have and how we should surveil them.”

Lymph Node Dissection

Dr. Boland reminded clinicians that many patients with early-stage disease can be cured with surgery alone. Management of this patient population begins with a wide local excision and in some cases with sentinel node sampling. The seminal MSLT-I study found no survival benefit for sentinel node biopsy compared with nodal observation following wide excision of intermediate-thickness melanoma.2 The study, however, affirmed the benefit of nodal pathologic staging in identifying patients with microscopic disease. Sentinel node status was the strongest predictor of disease recurrence (hazard ratio [HR], 2.64 for positive vs negative; P<.001) or death from melanoma (HR, 2.40; P<.001).

Subsequently, the phase III MSLT-II trial changed the surgical management of patients with a positive sentinel node for whom complete lymph node dissection (LND) was the standard of care at the time.3 The study of 1,755 patients showed that complete LND compared with nodal observation did not improve melanoma-specific survival or distant metastasis–free survival in patients with sentinel node metastases, but did significantly increase rates of lymphedema (24.1% vs 6.3%; P<.001). There was a 20% failure rate in the locoregional basin that could be successfully managed with surgery without compromising distant disease control.

“Surgical management of early-stage disease continues to evolve in patients who present with palpable clinically positive lymph nodes,” Dr. Boland said. Patients need to be tested for BRAF mutation status, staged appropriately, and surgically managed (wide excision, LND), with consideration given to enrolling appropriate patients in neoadjuvant trials.

Adjuvant Therapy

Approximately 10 years ago, the 1-year overall survival for patients with stage IV melanoma was around 25%.4 In the modern era, this figure has surpassed 50%.5 This improvement demonstrates the significant impact of improved treatments and care of these patients, Dr. Boland said.

“As we become more familiar with agents we now use in the setting of widespread metastatic disease, we have begun to move them earlier into the care trajectory of patients,” she said. Figure 1 describes adjuvant therapy trials of immune checkpoint inhibitors (ICIs) in stage III–IV melanoma and their outcomes.

Figure 1.
Figure 1.

Adjuvant therapy in stage III–IV melanoma.

Abbreviations: D/T, dabrafenib + trametinib; DMFS, distant metastasis–free survival; HR, hazard ratio; Ipi, ipilimumab; Nivo, nivolumab; NR, not reached; Pembro, pembrolizumab; RFS, relapse-free survival.

Citation: Journal of the National Comprehensive Cancer Network 20, 5.5; 10.6004/jnccn.2022.5003

In 2014, the CTLA-4 inhibitor ipilimumab became the first approved immunotherapy for the adjuvant treatment of melanoma, but its association with significant toxicity at the approved 10-mg/kg dose thwarted widespread adoption. Since then, CheckMate 238 established the PD-1 antibody nivolumab, 3 mg, as producing improved outcomes with less toxicity than ipilimumab, 10 mg.6 Thereafter, KEYNOTE-054 found the anti–PD-1 agent pembrolizumab to be effective.7 Current trials are evaluating new dosing schedules and combinations.

An exciting step forward was the recent FDA approval of pembrolizumab as adjuvant treatment for resected stage IIB and IIC melanoma based on an improvement in recurrence-free survival in KEYNOTE-716, from 83.1% with placebo to 90.5% at 12 months (HR, 0.65; P=.00658).8 The approval was good news for patients with stage IIB/C disease, which has lacked effective options after surgery. “There is a lot of excitement and discussion about how to identify, manage, and counsel these patients now,” she commented.

BRAF-targeted therapy has also improved outcomes when given in the adjuvant setting to patients with BRAF mutations, such as was shown with dabrafenib + trametinib in COMBI-AD.9 Dabrafenib/trametinib has not been compared with an anti–PD-1 agent, so the choice between immunotherapy and targeted therapy is not informed by trial data. The choice, she said, involves “integrating a lot of variables,” including molecular profile and patient-specific factors, into the decision. “I’d say this is a place where there is quite a bit of difference across institutions and across patients,” Dr. Boland commented.

Neoadjuvant Therapy

Neoadjuvant therapy usually involves 6 weeks of systemic treatment before planned curative-intent surgery. Besides its value in downstaging patients for resection, neoadjuvant therapy offers an opportunity to assess response to treatment and thus tailor subsequent treatment decisions. The main concern with neoadjuvant therapy is disease progression or complications related to toxicity occurring before the patient’s tumor is resected, Dr. Boland said. However, she added that these concerns have not panned out in other malignancies in which neoadjuvant therapy is established. Recent neoadjuvant studies have evaluated many different drugs and combinations (Figure 2).

Figure 2.
Figure 2.

Recent neoadjuvant studies.

Abbreviations: Ipi, ipilimumab; Nivo, nivolumab.

Slide courtesy of Roda N. Amaria, MD, The University of Texas MD Anderson Cancer Center.

Citation: Journal of the National Comprehensive Cancer Network 20, 5.5; 10.6004/jnccn.2022.5003

Neoadjuvant therapy with BRAF-targeted therapies and immune checkpoint blockade, both single agents and combinations, has been evaluated in many trials, but the optimal strategy remains unclear. Of particular interest is the relative benefit of neoadjuvant versus adjuvant therapy. To address this question, Blank et al10 treated 20 patients with bulky stage III disease with ipilimumab, 3 mg/kg, + nivolumab, 1 mg/kg, as either 2 courses before and after surgery (neoadjuvant arm) or 4 courses after surgery (adjuvant arm). The neoadjuvant approach yielded responses in 78% of patients, although toxicity rates were high and its superiority over adjuvant therapy was not proven. The study did, however, show that combination ICI given neoadjuvantly expands tumor-resident T-cell clones and thus provides additional support for the neoadjuvant approach.

The subsequent OpACIN-neo study identified 2 courses of neoadjuvant ipilimumab, 1 mg/kg, + nivolumab, 3 mg/kg, as the optimal treatment schema, based on a 77% pathologic response rate and a 20% rate of grade 3–4 toxicities.11 This regimen was compared with ipilimumab, 3 mg/kg, + nivolumab, 1 mg/kg, and with the sequential use of these 2 drugs. At 2 years, 1 of 64 responders had experienced relapse. The estimated recurrence-free survival was 84% for the total population, 97% for patients with pathologic responses, and 36% for nonresponders.

“It’s pretty clear that the winning regimen was ipilimumab at 1 mg/kg + nivolumab at 3 mg/kg, which gave similar pathologic responses with significantly less toxicity. There’s been acceptance of this as one of the optimal dosing regimens in the neoadjuvant setting,” Dr. Boland said.

Value of Pathologic Response

Recent adjuvant trials have confirmed that many patients who achieve a pathologic complete or near complete response after neoadjuvant therapy fare well over time, suggesting that it may be a good surrogate marker for outcomes. Furthermore, pathologic response in the index node appears to be representative of the whole nodal basin—this knowledge may help to determine further management.

The PRADO trial evaluated outcomes by response rate in patients with stage IIIB/C disease undergoing neoadjuvant treatment with ipilimumab/nivolumab followed by index node resection.12 Patients with pathologic complete or near complete responses received no additional treatment, those with pathologic partial responses underwent therapeutic LND, and nonresponders underwent therapeutic LND plus treatment with BRAF-targeted therapy (if BRAF-mutated disease) with or without radiotherapy. This study confirmed high pathologic response rates (71%) and that the toxicity was acceptable with this regimen. Through patient selection based on response, LND could be omitted in 60% of patients, allowing many to have index node–alone surgery, thereby experiencing less surgical morbidity.

“This study speaks to the power of these new adjuvant approaches to maybe refine and personalize the care we provide to our patients,” Dr. Boland commented. “But again, these data are from clinical trials. This is not the standard of care. But it’s certainly a conversation we are all having.”

Stage IV Melanoma

“In the setting of stage IV melanoma, we’ve been excited about having 2 main types of therapies: ICIs and molecular targeted therapy,” she said. With immunotherapy, the kinetics of response are less predictable, but the durability of control can be prolonged. Targeted therapy “buys a window of time,” although most patients develop acquired resistance and experience disease recurrence. “The question is how best to integrate these 2 valuable but distinct therapies.”

Dr. Boland summarized the current use of immunotherapy in stage IV disease:

  • Ipilimumab is associated with a durable benefit in 20% of patients.

  • Anti–PD-1 antibodies are superior to ipilimumab and chemotherapy and are better tolerated.

  • Combination ipilimumab/nivolumab is associated with unprecedented responses but high toxicity.

  • In sequencing, nivolumab followed by ipilimumab is superior to nivolumab followed by ipilimumab, but also more toxic.

  • For first-line treatment, ipilimumab/nivolumab is generally preferred; less-fit patients can receive nivolumab or pembrolizumab monotherapy.

  • Second-line dual ICI may be effective as salvage therapy.

For BRAF-mutated disease, regimens combining BRAF and MEK inhibitors have yielded median overall survival times of >2 years. A subset of patients (up to one-third) remain progression-free for 3 to 5 years, but the factors heralding this better prognosis have not been identified.

Recently, exciting results from the RELATIVITY-047 trial were reported for relatlimab, an antibody targeting LAG-3. Relatlimab + nivolumab resulted in a median progression-free survival of 10.12 months versus 4.63 months with nivolumab alone (HR, 0.75; P=.0055), with improved tolerability.13 These encouraging results led to FDA approval in March 2022 for relatlimab + nivolumab in unresectable or metastatic melanoma. For many patients, this should be considered the new usual care to replace anti–PD-1 monotherapy, although it may not be ideal for patient subsets in whom ipilimumab/nivolumab or anti–PD-1 monotherapy have proved to be effective. These subsets include (1) patients with rapidly progressing disease, high lactate dehydrogenase levels, bulky disease, or metastases to the liver, brain, and bone; (2) patients experiencing disease progression on adjuvant ICI; or (3) patients with severe autoimmune disease.

Sequencing Targeted Therapy and Immunotherapy

Nivolumab + ipilimumab followed by BRAF/MEK inhibition (if necessary) should be the preferred treatment sequence for patients with BRAF-mutant melanoma. This was the conclusion of the DREAMseq study,14 in which nivolumab/ipilimumab followed by dabrafenib/trametinib yielded better overall survival at 2 years (72% vs 52%; P=.0095) and more rapid, durable, and ongoing responses than the converse sequence. Dabrafenib/trametinib was, however, a critical contributor to overall efficacy when given in the second line.

Clearly, better treatment is translating into better survival of patients with melanoma, as in recent years melanoma-related deaths have decreased by 5% per year—the largest drop ever observed for any cancer.15 However, disparities in care and access to care still exist and should be both acknowledged and addressed by clinicians, said Dr. Boland, who also advocated for multidisciplinary teams. “Clinical decision-making for these patients is complex and continues to change,” she commented.

References

  • 1.

    Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual, 8th edition. New York, NY: Springer Cham; 2017.

  • 2.

    Morton DL, Thompson FJ, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599609.

  • 3.

    Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:22112222.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008;26:527534.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ugurel S, Röhmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer 2017;83:247257.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:18241835.

  • 7.

    Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:643654.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial [published online March 31, 2022]. Lancet, doi: 10.1016/S0140-6736(22)00562-1

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017;377:18131823.

  • 10.

    Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:16551661.

  • 11.

    Rozeman EA, Reijers ILM, Hoefsmit EP, et al. Twenty-four months RFS and updated toxicity data from OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant ipilimumab and nivolumab in stage III melanoma [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 10015.

    • Search Google Scholar
    • Export Citation
  • 12.

    Blank CU, Reijers ILM, Pennington T, et al. First safety and efficacy results of PRADO: a phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in resectable stage III melanoma [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 10002.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Long GV, Hodi S, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047) [abstract]. J Clin Oncol 2022;40(Suppl):Abstract 360385.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq: a phase III trial—ECOG-ACRIN EA6134 [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 356154.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Berk-Krauss J, Stein JA, Weber J, et al. New systematic therapies and trends in cutaneous melanoma deaths among US whites, 1986–2016. Am J Public Health 2020;110:731733.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Disclosures: Dr. Boland has disclosed receiving grant/research support from InterVenn Biosciences, Olink Proteomics, Palleon Pharmaceuticals, and Takeda Pharmaceuticals North America, Inc.; and serving as a scientific advisor for Ankyra Therapeutics, InterVenn Biosciences, Iovance Pharmaceuticals, Merck & Co., Inc., Nektar Therapeutics, and Novartis Pharmaceuticals Corporation.

Correspondence: Genevieve Boland, MD, PhD, Massachusetts General Hospital, 55 Fruit Street, Jackson 9, Boston, MA 02114. Email: gmboland@mgh.harvard.edu
  • View in gallery

    Adjuvant therapy in stage III–IV melanoma.

    Abbreviations: D/T, dabrafenib + trametinib; DMFS, distant metastasis–free survival; HR, hazard ratio; Ipi, ipilimumab; Nivo, nivolumab; NR, not reached; Pembro, pembrolizumab; RFS, relapse-free survival.

  • View in gallery

    Recent neoadjuvant studies.

    Abbreviations: Ipi, ipilimumab; Nivo, nivolumab.

    Slide courtesy of Roda N. Amaria, MD, The University of Texas MD Anderson Cancer Center.

  • 1.

    Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual, 8th edition. New York, NY: Springer Cham; 2017.

  • 2.

    Morton DL, Thompson FJ, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599609.

  • 3.

    Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:22112222.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 2008;26:527534.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ugurel S, Röhmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer 2017;83:247257.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:18241835.

  • 7.

    Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:643654.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial [published online March 31, 2022]. Lancet, doi: 10.1016/S0140-6736(22)00562-1

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017;377:18131823.

  • 10.

    Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:16551661.

  • 11.

    Rozeman EA, Reijers ILM, Hoefsmit EP, et al. Twenty-four months RFS and updated toxicity data from OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant ipilimumab and nivolumab in stage III melanoma [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 10015.

    • Search Google Scholar
    • Export Citation
  • 12.

    Blank CU, Reijers ILM, Pennington T, et al. First safety and efficacy results of PRADO: a phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in resectable stage III melanoma [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 10002.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Long GV, Hodi S, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047) [abstract]. J Clin Oncol 2022;40(Suppl):Abstract 360385.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq: a phase III trial—ECOG-ACRIN EA6134 [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 356154.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Berk-Krauss J, Stein JA, Weber J, et al. New systematic therapies and trends in cutaneous melanoma deaths among US whites, 1986–2016. Am J Public Health 2020;110:731733.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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