Recent Breakthroughs in Melanoma Treatment: What Patients Need to Know

Table of Contents

• Introduction: A Decade of Transformation
• Melanoma Staging: Improved Precision
• Molecular Features of Melanoma
• Surgical Treatment: Less Invasive Approaches
• Checkpoint Immunotherapy: Revolutionizing Treatment
• Targeted Therapy for BRAF Mutations
• Other Targeted Therapies
• Adjuvant Therapy After Surgery
• Conclusions and Future Directions
• Source Information

Introduction: A Decade of Transformation

Melanoma rates continue to increase worldwide, but the landscape of treatment has undergone a remarkable transformation. Over the past 10 years, the lethality of advanced melanoma has significantly decreased thanks to major scientific breakthroughs.

Research insights from melanoma studies have led to a deeper understanding of how the immune system can fight cancer, establishing immunotherapy as one of the main approaches to cancer treatment. Back in 2004, no systemic therapies for melanoma had been shown to provide a survival benefit. Now, patients have at least four immunotherapy regimens and three targeted therapy regimens that significantly increase overall survival and disease-free survival.

This article reviews the recent advances in melanoma treatment, including changes in how melanoma is staged, improvements in surgical management, and groundbreaking developments in systemic therapy for both high-risk and advanced melanoma.

Melanoma Staging: Improved Precision

The current eighth edition of the American Joint Committee on Cancer (AJCC-8) melanoma staging system represents a significant advancement in precision medicine. This system is based on data from more than 46,000 patients treated with contemporary surgical methods, including sentinel lymph-node biopsy.

The staging system maintains the traditional tumor-node-metastasis (TNM) categories but incorporates interactions between these categories to determine final stages more accurately. The inclusion of sentinel-node status has greatly improved prognostic information because it allows doctors to better distinguish between node-negative and node-positive disease.

Features of the primary melanoma site, including depth of invasion, extent of ulceration (skin breakdown), and mitotic rate (how quickly cells are dividing), can be used to estimate the risk of nodal metastasis. Future staging systems are being developed that won't require complete lymph-node dissection, since current standard practice avoids this procedure in most patients due to its invasive nature.

Molecular Features of Melanoma

Molecular analysis has become increasingly important in melanoma management, though the current AJCC-8 staging system doesn't yet include molecular characterization. Retrospective evaluations of gene-expression profiling have shown promise in improving prognostic determinations and estimating the probability of finding a positive sentinel node.

Gene-expression profiling signatures may help doctors select patients for sentinel-node biopsy or for adjuvant systemic therapy, though additional prospective evaluation is needed to validate this approach. Molecular evaluation also reveals that melanoma has one of the highest mutational burdens among solid tumors.

This high mutational burden is hypothesized to serve as a source of neoantigens for host immune responses and may predict response to immunotherapy. While most mutations in melanoma are "passenger" mutations that don't drive cancer growth, several "driver" mutations can be targeted by drugs and have revolutionized treatment.

Approximately 50% of melanomas have BRAF mutations, which lead to constant activation of cell signaling pathways. This discovery has made BRAF the main target of currently approved targeted therapies. The other genomic subtypes include mutated RAS (approximately 28% of cases), mutated NF1 (approximately 14%), and triple wild type (no mutations in these three genes).

BRAF testing should be performed in patients with stage III or IV melanoma at the time of diagnosis to determine if they might benefit from targeted therapies.

Surgical Treatment: Less Invasive Approaches

More than 90% of patients with melanoma have localized or regional disease, and the primary treatment for these patients remains surgical. Current standard surgical approaches are markedly less invasive and associated with lower morbidity than previous approaches, yet they maintain equivalent or superior accuracy and effectiveness.

Historical approaches to surgical treatment were radical, involving excision of 5-centimeter margins at the primary tumor site and elective prophylactic removal of regional lymph nodes. Questions about the necessity of such extensive surgery led to prospective randomized clinical trials examining less radical procedures.

Safety margins for primary tumor excision have been progressively narrowed based on clinical trial evidence:

• For thin melanomas (<2 mm): Margins reduced from 2 cm to 1 cm
• For intermediate-thickness melanomas (1 to 4 mm): 2-cm margins established as safe
• For thicker melanomas (>2 mm): 2-cm margins shown to be safe

The ongoing Melanoma Margins Trial II (MelMarT-II) is comparing 1-cm margins with 2-cm margins for melanomas that are stage T2b or higher to determine whether further narrowing of excision margins is safe.

Elective lymph-node dissection (removal of regional lymph nodes in patients with no clinically detectable regional metastases) has been replaced by sentinel lymph-node biopsy. This approach involves removing only nodes receiving direct lymphatic drainage, which avoids full dissection in the majority of patients.

This change reduces morbidity, including lymphedema (swelling due to fluid retention), and improves staging accuracy. Initially, all patients found to have metastases on sentinel-node biopsy underwent completion lymph-node dissection, but two major trials showed the safety of nodal observation instead.

Current practice involves wide excisions with 1- or 2-cm margins depending on tumor thickness, with lymphatic mapping and sentinel-node biopsy. Most patients with sentinel-node metastases can choose nodal observation with regular ultrasounds rather than completion nodal dissection.

This change in practice hasn't increased the risk of uncontrolled local or regional recurrence and has substantially reduced the number of patients undergoing extensive surgery. Future improvements may involve better predictive models incorporating clinical variables and molecular markers to select patients who need sentinel-node biopsy.

Checkpoint Immunotherapy: Revolutionizing Treatment

The paradigm-changing advances in cancer immunotherapy involve inhibitory receptors or checkpoints, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) protein. The researchers who pioneered this work, Dr. Allison and Dr. Honjo, earned a Nobel Prize for their achievements.

Translation of their basic science insights has changed the standard of care for melanoma and many solid tumors. CTLA-4 acts as a negative regulator of T-cell activation in lymphoid tissues, while the PD-1 pathway promotes T-cell tolerization and is a marker of T-cell exhaustion in chronically inflamed tissues, including tumors.

The outcome for patients with advanced melanoma has been transformed with combined checkpoint antibody therapy. Ipilimumab combined with nivolumab has been associated with a 53% response rate and is now the standard of care for immunotherapy in most patients with advanced melanoma.

In just three years, therapy for advanced melanoma changed dramatically:

• From ipilimumab monotherapy with a 10% response rate and incremental survival benefit
• To checkpoint combination therapy with more than 50% response rate and significant survival benefit
• Approximately 10% of patients require no further melanoma therapy after treatment

Checkpoint immunotherapy can induce regression of melanoma in any organ, including the brain. The combination of ipilimumab and nivolumab induced an intracranial response (complete or partial regression or stable brain metastases for at least 6 months) in 57% of patients with brain metastases measuring up to 3 cm.

The objective response at other visceral sites was 56%. Immune-mediated side effects are increased with checkpoint combinations, but these can be managed with dose delays, steroids (glucocorticoids), and anti-tumor necrosis factor antibodies.

Although checkpoint blockade improves survival in most patients, only a minority experience complete remission or cure. Resistance mechanisms can develop through JAK1/2 cytokine signaling pathway mutations or decreased beta-2 microglobulin expression, which reduce immune recognition of cancer cells.

The remarkable success of combination checkpoint therapy has transformed melanoma treatment, but questions remain about the best sequence of immunotherapy and targeted therapy in patients with BRAF-mutated melanoma.

Targeted Therapy for BRAF Mutations

In 2011, vemurafenib became the first BRAF-targeted therapy approved by the FDA for melanoma treatment based on a 48% response rate and a 63% reduction in the risk of death compared with dacarbazine chemotherapy.

Although the initial response to vemurafenib was rapid and clinically meaningful, progression-free survival was only 5.3 months due to rapid development of resistance. Combined BRAF and MEK inhibition addresses this resistance mechanism and is now the standard of care for targeted therapy in patients with melanoma.

Treatment combinations show significantly improved outcomes:

• Dabrafenib and trametinib
• Vemurafenib and cobimetinib
• Encorafenib and binimetinib

These combinations are associated with prolonged progression-free and overall survival compared with BRAF inhibitor monotherapy, with response rates exceeding 60% and complete response rates of 10-18%.

Recent research shows that combining atezolizumab (anti-PD-L1 immunotherapy) with vemurafenib and cobimetinib improves progression-free survival compared with combined targeted therapy alone. BRAF plus MEK targeted therapy can achieve disease control that lasts for years, though acquired resistance remains a limitation.

In community practice, targeted therapy is usually offered as first-line treatment to symptomatic patients with high tumor burden, since the response may be more rapid than with immunotherapy. Most patients with advanced, BRAF-mutated melanoma ultimately receive both targeted therapy and immunotherapy.

Other Targeted Therapies

Mutations of the KIT gene are typically found in specific melanoma subtypes:

• Mucosal melanomas: 39% frequency
• Acral melanomas (on palms, soles, nail beds): 36% frequency
• Chronically sun-damaged skin: 28% frequency

These mutations activate intracellular signaling pathways. Tyrosine kinase inhibitors such as imatinib have activity in KIT-mutated melanomas, with a 53% response rate and progression-free survival of 3.9 months. However, imatinib doesn't work against melanomas with KIT amplification.

Anti-PD-1 checkpoint immunotherapy has activity in mucosal melanoma with a 20% response rate. When combined with anti-CTLA-4 immunotherapy, the response rate increases to 37%, with median progression-free survival of 6 months.

Other driver mutations may give rise to targeted agents for specific subgroups of melanoma patients in the future, expanding treatment options for those with less common mutation profiles.

Adjuvant Therapy After Surgery

Adjuvant therapy refers to additional treatment given after primary surgery to reduce the risk of cancer returning. Several options have shown significant benefits for patients with high-risk melanoma.

PD-1 blockade with nivolumab or pembrolizumab has become a standard adjuvant treatment for resected stage III melanoma. The CheckMate 238 trial showed significantly longer recurrence-free survival with nivolumab than with ipilimumab.

Similarly, the KEYNOTE-054 trial showed that pembrolizumab significantly prolonged recurrence-free survival compared with placebo in patients with resected stage III melanoma. At 3.5 years, the recurrence-free survival rate was 59.8% in the pembrolizumab group versus 41.4% in the placebo group.

For patients with BRAF-mutated melanoma, the COMBI-AD trial evaluated adjuvant dabrafenib plus trametinib in patients with resected stage III melanoma. The trial showed a 53% lower probability of recurrence and a 43% lower risk of death with combination therapy than with placebo.

Five-year follow-up showed that 52% of patients remained recurrence-free in the combination therapy group, compared with 36% in the placebo group. Combined BRAF and MEK inhibition is now a standard adjuvant treatment option for stage III BRAF-mutated melanomas.

Both PD-1 blockade and combined BRAF and MEK inhibition have clear benefits in resected stage IIIB, IIIC, and stage IV melanomas. While no head-to-head comparisons exist between these two approaches, both represent significant advances in preventing melanoma recurrence.

Conclusions and Future Directions

The treatment landscape for melanoma has undergone a revolution in the past decade, moving from a time when no systemic therapies provided survival benefits to having multiple effective options. The integration of immunotherapy and targeted therapy has transformed outcomes for patients with advanced disease.

Surgical approaches have become less invasive while maintaining effectiveness, and staging systems have improved in precision. The development of checkpoint immunotherapy and BRAF-targeted therapies has provided new hope for patients who previously had limited options.

Despite these advances, challenges remain. The probability of cure for advanced melanoma, while improved, remains low for many patients. Researchers continue to work on understanding resistance mechanisms and developing strategies to overcome them.

Future directions include optimizing treatment sequences, developing better biomarkers to predict treatment response and side effects, and expanding effective treatments to melanoma subtypes that have proved less responsive to current therapies, such as mucosal and uveal melanomas.

The progress in melanoma treatment serves as a model for cancer therapy development overall, demonstrating how basic science insights can be translated into clinical practice to dramatically improve patient outcomes.

Source Information

Original Article Title: Recent Advances in the Treatment of Melanoma

Authors: Brendan D. Curti, M.D., and Mark B. Faries, M.D.

Publication: The New England Journal of Medicine, June 10, 2021

DOI: 10.1056/NEJMra2034861

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine and preserves all significant findings, data points, and clinical implications from the original scientific publication.