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At the recently concluded 25th World Congress of Dermatology 2023, Parkway Cancer Centre’s Dr Richard Quek, Senior Consultant, Medical Oncology, was invited to speak on the state-of-the-art treatment for metastatic melanoma with emphasis on the growing body of literature on the neoadjuvant approaches in melanoma.

Over the last decade, advances in melanoma treatment have substantially improved patient survival. These treatments include immune checkpoint inhibitors and targeted therapy.

Within the field of immunotherapy, checkpoint inhibitors – such as anti-CTLA4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab) and anti-PDL-1 (atezolizumab) – have all been approved for standard use. While in the field of BRAF-targeted therapy, doublet therapies such as dabrafenib/trametinib, encorafenib/binimetinib and vemurafenib/cobimetinib were added to the armamentarium in BRAF-mutated melanomas.

For years, the big questions faced by clinicians and patients alike were firstly, what is the optimal front-line option in patients with BRAF-mutated melanomas; is it immunotherapy or targeted therapy? The second big question was, should we use single agent immunotherapy (anti-PD-1 or PDL-1) or dual immunotherapy (anti-CTLA-4 plus anti-PD-1) in patients we opt to treat with immunotherapy?

Patients with BRAF mutation positive advanced melanoma

For patients with advanced melanoma, oncologists will firstly assess the tumour BRAF mutation status and stratify patients into BRAF mutations positive vs negative disease. If the tumour is BRAF mutation positive, both immunotherapy or targeted therapy are approved standard options. The treating oncologists will have to decide on whether to proceed with either an upfront immunotherapy or targeted therapy approach.

The recently published DREAMseq study¹ – a phase III randomised study conducted to determine which initial treatment or treatment sequence produced the best results in patients with advanced BRAF mutation positive melanoma, helped answer the first question.

In the trial, the patients had BRAF-mutated melanoma and were randomised into two groups:

The first group of patients started treatment with dual immunotherapy, consisting of both Nivolumab (NIVO) and Ipilimumab (IPI), monoclonal antibodies that work to activate the immune system by targeting both the PD-1 and CTLA-4 protein receptors respectively. At the time of cancer worsening, patients will then switch over to BRAF-MEK inhibitor combinations – in this case, dabrafenib and trametinib.

The other group of patients started treatment in the reverse order. They started with a BRAF-targeting strategy using dabrafenib and trametinib. At the time of cancer worsening, they switched over to immunotherapy using the same 2 immunotherapy drugs of NIVO and IPI.

At the study’s conclusion, the 2-year overall survival data strongly favoured the strategy with starting patients on treatment with immunotherapy (IPI and NIVO) before switching over to BRAF-targeting therapy at time of cancer progression. Additionally, the overall response rate (proportion of patients whose cancer shrink in size) was significantly higher at the time of switch over in the first group of patients.

As such, Dr Quek emphasised that for patients with advanced BRAF-mutation positive melanoma, in absence of contraindications, the optimal treatment approach would be dual immunotherapy with NIVO and IPI first, keeping BRAF-targeting agents in reserve.

Patients with BRAF mutation negative advanced melanoma

As for patients whose tumours are BRAF mutation negative, BRAF-targeting therapy is not an option.

The recurring clinical question oncologists faced was whether to start with single agent immunotherapy or dual agent immunotherapy. In other words, oncologists needed to decide whether to use one or two immunotherapy drugs upfront. From the information we had to date then, two drugs gave a better chance of shrinking the tumour but came at the expense of more frequent and more serious side effects. Additionally, we were uncertain if using 2 immunotherapy agents at the same time prolonged survival of patients to justify the expense of greater side effects.

To shed more light on this clinical dilemma, Dr Quek cited the updated Checkmate 067 study², which demonstrated the impressive overall survival rate of using combined IPI and NIVO together, as compared to using either IPI or NIVO alone. The median survival duration of patients with advanced metastatic melanoma treated with 2 immunotherapy agents (IPI and NIVO) was approximately 6 years as compared to 3 years when treated with NIVO alone. These survival figures were hugely impressive in a patient population with very poor prognosis. Just a decade ago, these same patients had no effective treatment and whose survival was less than a year. This data validates the strength of using dual agent immuno-oncology.

However, serious treatment-related toxicities of using both IPI and NIVO are significant, at the rate of 59% as compared to 21%, when only NIVO is used. Thankfully, these days, treating oncologists are more aware of such immune-related side effects, able to recognise them earlier, and better equipped to manage them appropriately.

New drugs in Melanoma: Combined RELATLIMAB (RELA) AND NIVOLUMAB (NIVO)

Relatlimab (RELA) – an anti-LAG-3 checkpoint inhibitor – has recently been approved by the United States Food and Drug Administration (U.S. FDA) and Health Science Authority (HSA) Singapore for use in combination with Nivolumab (NIVO) in patients with advanced melanoma.

LAG3 and PD-1 are distinct immune checkpoints, often expressed on tumour-infiltrating lymphocytes (TILs) – a form of immune cell therapy. The two checkpoints contribute to tumour-mediated T-cell exhaustion, which prevents optimal control of infection and tumours.

In preclinical models, LAG-3 and PD-1 inhibitors demonstrated synergistic anti-tumour activity³, including durable, objective responses in patients with relapsed or refractory melanoma.

In a large international phase 3 study, Relativity-047⁴, the use of combined RELA and NIVO demonstrated superior progression-free survival (PFS) – time from random assignment in a clinical trial to disease progression or death from any cause – to NIVO alone. The two inhibitors also demonstrated a manageable safety profile on top of showing a numerically improved overall survival and tumour objective response rate – an important assessment of the tumour burden which demonstrates the efficacy of a treatment. Notably, serious side effects occurred in less than 20% of patients treated with RELA and NIVO. This compares favourably to the approximately 60% seen in the current standard of IPI and NIVO.

While data is not available to guide the choice between the front line options of IPI and NIVO versus RELA and NIVO, Dr Quek posits that if the patient is relatively young and has a good performance status, IPI and NIVO – the current standard with good long-term survival data – is a preferred option. While older patients, with a poorer performance status or do not have easy access to a medical facility (should complications occur), may be more suited for RELA and NIVO instead.

As of now, treatment-related toxicities play a significant part in choosing the appropriate treatment. However, we hope that in time to come, more matured data becomes available to allow a proper comparison between the two front-line immunotherapy treatment strategies.

What’s next for patients with advanced melanoma?

Over the past decade, there have been several significant advances made in the systemic treatment for advanced melanoma, including BRAF-targeted therapy, dual agent immune-oncology with IPI and NIVO.

Now, with the novel addition of RELA, we have another potent treatment strategy in melanoma. The low toxicities of RELA and NIVO propel both patients and oncologists alike onto a more hopeful path as we await future possibilities in the treatment of advanced melanoma.

¹ Atkins M.B., et al. Journal of Clinical Oncology, 2023.
² Wolchok J.D., et al. ASCO 2021.
³ Woo S-R, et al. Cancer Res 2012.
⁴ Tawbi, et al. N Engl J Med 2022.