Mutation Testing and Adjuvant Systemic Therapy in Cutaneous Melanoma

According to Dr. Anthony J. Olszanski, the most significant updates to the treatment of cutaneous melanoma include the recently published results of MSLT-II, which demonstrated that ultrasound-guided follow-up can be performed rather than a complete lymph node dissection, improving morbidity in patients with sentinel node metastases while not adversely affecting survival. In the adjuvant setting, the PD-1 inhibitors nivolumab and pembrolizumab are now FDA-approved, in addition to dabrafenib and trametinib, for patients with BRAF mutations.

Abstract

According to Dr. Anthony J. Olszanski, the most significant updates to the treatment of cutaneous melanoma include the recently published results of MSLT-II, which demonstrated that ultrasound-guided follow-up can be performed rather than a complete lymph node dissection, improving morbidity in patients with sentinel node metastases while not adversely affecting survival. In the adjuvant setting, the PD-1 inhibitors nivolumab and pembrolizumab are now FDA-approved, in addition to dabrafenib and trametinib, for patients with BRAF mutations.

Patients with stage III melanoma are at high risk for disease recurrence, but adjuvant therapy—including targeted therapy and immunotherapy—may prevent or delay relapse, according to Anthony J. Olszanski, MD, RPh, Associate Professor and Vice Chair, Department of Hematology/Oncology, Fox Chase Cancer Center. At the NCCN 2019 Annual Conference, Dr. Olszanski discussed recent treatment advances in cutaneous melanoma and, in particular, what clinicians should add to their armamentarium in the adjuvant setting.

New TNM Staging

AJCC recently released updates to their staging criteria for melanoma in the 8th edition.1 AJCC uses the TNM system, a staging methodology based on primary tumor (T), regional lymph node (N), and distant metastasis (M).

“T” relates to the thickness of the primary tumor and presence of ulceration. “It's important to understand what the thickness is, but also whether or not it's ulcerated,” Dr. Olszanski said. “That's actually an important prognostic criterion when we're looking at patients with melanoma because it can upstage them.”

“N” refers to the number of tumor-involved regional lymph nodes and presence of in-transit, satellite, or microsatellite metastases. These can be clinically detected (ie, identified by clinical, radiographic, or ultrasound examination) or clinically occult (ie, identified microscopically by sentinel node [SLN] biopsy). “Examination can determine whether lymph nodes are palpable or not, so the physical examination still has a role here,” he noted.

“M” staging is based on whether the melanoma has metastasized to distant organs. An M1a classification describes distant metastasis to skin or soft tissue, including muscle and/or nonregional lymph nodes. M1b describes distant metastasis to lungs ± M1a sites of disease. M1c describes metastasis to additional organs, but no longer includes central nervous system (CNS) metastasis; a new M1d designation includes distant CNS metastasis ± other distant sites of disease.

Compared with the AJCC 7th edition, the proportion of patients with a diagnosis of stage III disease based on the 8th edition has increased, from approximately 10% to >20%.2 “That's going to impact a large number of patients,” he noted.

In addition, there is a new category in stage III disease: stage IIID. According to Dr. Olszanski, survival in this group is “miserable.” Compared with patients with stage IIIA disease, >75% of patients with stage IIID disease will have died at 10 years. “Stage IIIA melanoma is still a potentially deadly disease, but these categories really [help us to] prognosticate a lot better for patients,” he said.

Surgical Management

After a melanoma diagnosis, patients often undergo SLN biopsy to determine whether the disease has spread beyond the primary tumor or local tissues. In the MSLT-I trial, SLN biopsy did not impact overall survival (OS) compared with nodal observation.3 “So, a SLN biopsy does not help patients live longer. But that doesn't mean we shouldn't do it, because it is extremely important prognostically,” Dr. Olszanski said. “In fact, a positive SLN is the single strongest predictor of disease recurrence or death from melanoma.”

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous Melanoma state that patients with stage IB (T1b) disease that is <0.8 mm thick with ulceration, or 0.8 to 1.0 mm thick ± ulceration, should be considered for SLN biopsy. Patients with stage IB (T2a) or stage II disease (>1 mm thick, any feature, N0), should also be offered SLN biopsy.

After a diagnosis of stage III disease based on SLN biopsy, the previous version of the NCCN Guidelines stated that these patients should undergo complete lymph node dissection (CLND). “’The questions we had to ask were, ‘Is that something we should be doing?’” said Dr. Olszanski, “and, ‘Does it have a mortality benefit’?” According to results from the MSLT-II trial,4 which randomized almost 2,000 patients to CLND or nodal observation, the answer is “No, [CLND] does not provide a survival benefit.”

Improved Morbidity With Ultrasound Follow-Up

“Results of MSLT-II demonstrated that we don’t necessarily have to do a CLND; we can perform an ultrasound-guided follow-up for these patients, which may help reduce morbidity,” he said.

In patients with SLN metastases, those who underwent CLND (n=824) had no improvement in melanoma-specific survival compared with those monitored by nodal ultrasonography for the first 5 years (n=931).4 CLND did decrease nodal recurrence compared with observation, but it also caused lymphedema, a major quality-of-life issue, in almost a quarter of patients. Based on these results, Dr. Olszanski stated that, “ultrasound observation is reasonable. But, let me point out, this is only in patients with microscopic disease. If patients have clinically positive nodes, meaning that you felt them, or they have in-transit disease, we would think that CLND is still the most reasonable option.”

Despite surgical resection, patients with stage III disease remain at high risk for recurrence. For patients with stage III disease and clinically positive nodes who are at extremely high risk for local recurrence, radiation therapy can be considered as part of planned adjuvant treatment, according to the NCCN Guidelines. “That’s really one of the only times we consider radiation therapy in the treatment of melanoma,” he noted.

Systemic/Targeted Adjuvant Therapy

Therapy for the treatment of melanoma has changed drastically since 2011, when immunotherapy and targeted therapy agents entered the treatment landscape and improvements in OS were observed for patients with metastatic disease. Use of these agents as systemic adjuvant therapy should be strongly considered in patients with high-risk resectable melanoma, because it reduces the risk of relapse and mortality by targeting residual micrometastatic disease, he said (Figure 1).

Figure 1.
Figure 1.

Considerations for adjuvant therapy in high-risk resectable melanoma.

Abbreviations: CLND, complete lymph node dissection; SLN, sentinel lymph node; SLNB, sentinel lymph node biopsy; WLE, wide local excision.

Data from Francken AB, Accortt NA, Shaw HM, et al. Follow-up schedules after treatment for malignant melanoma. Br J Surg 2008;95:1401–1407; Romano E, Scordo M, Dusza SW, et al. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 2010;28:3042–3047; and Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. Version 1.2019. Available at NCCN.org.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 5.5; 10.6004/jnccn.2019.5019

Approximately half of all melanomas harbor a BRAF mutation; most commonly, these mutations are activating BRAF V600E or V600K mutations (only ∼8% of BRAF mutations are non-V600E/K). The second most common genomic alteration in melanoma is NRAS, occurring in approximately 28% of patients.5 Understanding the disease pathogenesis is extremely important to understanding treatment strategies, Dr. Olszanski warned, pointing out that giving an inhibitor to a patient who does not have that mutation may harm them.

“What’s really amazing to me about BRAF is that it occurs early on,” he said. BRAF (and NRAS) driver mutations are seen even in benign nevi.6 “This is why we think that younger patients are more likely to be BRAF-positive—because they haven’t had a lot of chronic skin damage.” Recommendations put forth by the European Association of Dermato Oncology (EADO), ESMO, and NCCN are fairly consistent, and all recommend early BRAF mutation testing in high-risk patients with melanoma.

NCCN recommends BRAF testing for patients with stage III disease at high risk for recurrence and for whom future BRAF-directed therapy may be an option. According to Dr. Olszanski, the ESMO guidelines suggest that patients with stage IIC disease, who are at higher risk of recurrence than those with stage IIIA disease, can also be considered for testing.

In the randomized COMBI-AD trial, combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib demonstrated exciting results in the adjuvant setting: relapse-free survival was significantly increased in patients with fully resected stage III disease (based on AJCC 7th edition) with a BRAF V600E/K mutation.7

Adjuvant Immunotherapy

The addition of immunotherapy to the treatment paradigm has dramatically impacted survival in patients with melanoma. CTLA-4 and PD-1/PD-L1 immune checkpoints are negative regulators of T-cell immune function. PD-L1 binds to PD-1 and inhibits T-cell killing of the tumor cell, but blocking PD-1/PD-L1 with checkpoint inhibitors allows for T-cell engagement. Anti–CTLA-4 therapy works in a very similar fashion by allowing T cells to remain activated and fight the cancer cells.

The CTLA-4 inhibitor ipilimumab demonstrated an OS benefit versus placebo in patients with fully resected stage III disease in the EORTC 18071 trial.8 “That is important,” Dr. Olszanski said. “Not only do we have an OS benefit in the metastatic setting, but we now have an OS benefit in patients at risk for disease recurrence in the stage III setting.”

But PD-1 inhibition outperformed CTLA-4 inhibition in the CheckMate 238 trial.9 In patients with high-risk disease (stage IIIB, IIIC, or IV resected), adjuvant nivolumab resulted in higher rates of recurrence-free survival than ipilimumab: 70% versus 60% (hazard ratio, 0.65; P<.001). “We now know that PD-1 inhibition is more effective from a relapse-free survival standpoint.” As a result, NCCN has incorporated nivolumab and pembrolizumab into the adjuvant treatment guidelines for stage III cutaneous melanoma.

“This is a fascinating time to care for patients with cancer. Not only are we improving survival, but we’re improving the disease control rate so that we can produce durable responses,” said Dr. Olszanski. “I have patients I treated 10 years ago with immunotherapy who are not on treatment anymore. They had brain metastases at diagnosis, and they’re alive today. Explain that to me. Or don’t! I’ll just take it for what it is, and it is amazing.”

Disclosures: Dr. Olszanski has disclosed that he received honoraria from Alkermes, Array, EMD Serono, Iovance, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc.

References

  • 1.

    Gershenwald JEScolyer RAHess KR Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:472492.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Balch CMGershenwald JESoong SJ Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:61996206.

  • 3.

    Morton DLThompson JFCochran AJ Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599609.

  • 4.

    Faries MBThompson JFCochran AJ Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:22112222.

  • 5.

    Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 2015;161:16811696.

  • 6.

    Omholt KPlatz AKanter L NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003;9:64836488.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Hauschild ADummer RSchadendorf D Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma [published online October 22, 2018]. J Clin Oncol doi: 10.1200/JCO.18.01219

    • Search Google Scholar
    • Export Citation
  • 8.

    Eggermont AMChiarion-Sileni VGrob JJ Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522530.

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

    Weber JMandala MDel Vecchio M Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:18241835.

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Correspondence: Anthony J. Olszanski, MD, RPh, Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Email: anthony.olszanski@fccc.edu

Article Sections

Figures

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    Considerations for adjuvant therapy in high-risk resectable melanoma.

    Abbreviations: CLND, complete lymph node dissection; SLN, sentinel lymph node; SLNB, sentinel lymph node biopsy; WLE, wide local excision.

    Data from Francken AB, Accortt NA, Shaw HM, et al. Follow-up schedules after treatment for malignant melanoma. Br J Surg 2008;95:1401–1407; Romano E, Scordo M, Dusza SW, et al. Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 2010;28:3042–3047; and Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. Version 1.2019. Available at NCCN.org.

References

  • 1.

    Gershenwald JEScolyer RAHess KR Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:472492.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Balch CMGershenwald JESoong SJ Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:61996206.

  • 3.

    Morton DLThompson JFCochran AJ Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599609.

  • 4.

    Faries MBThompson JFCochran AJ Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:22112222.

  • 5.

    Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 2015;161:16811696.

  • 6.

    Omholt KPlatz AKanter L NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 2003;9:64836488.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Hauschild ADummer RSchadendorf D Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma [published online October 22, 2018]. J Clin Oncol doi: 10.1200/JCO.18.01219

    • Search Google Scholar
    • Export Citation
  • 8.

    Eggermont AMChiarion-Sileni VGrob JJ Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522530.

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

    Weber JMandala MDel Vecchio M Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:18241835.

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