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Latest Evidence in Melanoma
A Call to Action: Identifying and Addressing Practice Gaps in the Management of Melanoma Based on the Latest Evidence

Released: May 03, 2023

Hussein Tawbi
Hussein Tawbi, MD, PhD
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Key Takeaways
  • A survey of healthcare professionals revealed gaps in their knowledge and practice in managing patients with melanoma.
  • Most patients with advanced BRAF-mutated melanoma should receive immunotherapy prior to targeted therapy.
  • Recent evidence supports the addition of neoadjuvant immunotherapy for patients with resectable stage III melanoma.
  • To learn more about optimal management of patients with melanoma, please visit the Clinical Care Options website often as this educational program unfolds

In this commentary, Hussein Tawbi, MD, PhD, discusses findings from a recent survey conducted by Clinical Care Options to assess awareness and preference of treatment strategies for melanoma among a global audience of healthcare professionals (HCPs). The survey’s respondents revealed a lack of familiarity with the latest evidence supporting optimal treatment approaches in melanoma despite commonly encountering patients with melanoma in the clinic.

Key Finding 1: Selection of First‑line Therapy for Metastatic BRAF V600E/K Melanoma
One of the most challenging decisions in the first‑line setting has been the choice between targeted therapy and immunotherapy for patients with BRAF-mutated metastatic melanoma. The latest clinical evidence from the phase III DREAMseq trial supports the use of immunotherapy first, followed by targeted therapy upon progression or recurrence. However, approximately one third of HCP survey respondents selected a BRAF/MEK inhibitor combination for patients with newly diagnosed BRAF V600‒mutant melanoma.

The phase III DREAMseq trial compared first-line nivolumab/ipilimumab followed by dabrafenib/trametinib vs dabrafenib/trametinib followed by nivolumab/ipilimumab in patients with stage III/IV melanoma and BRAF V600 mutations. The study ended early because of significant improvement in the 2-year overall survival (OS) rate in patients receiving immunotherapy first vs those receiving first-line BRAF-targeted therapy (71.8% vs 51.5%, respectively). These results have driven clinical practice, and it is now very uncommon for me to start with BRAF-targeted therapy in this patient population. I do order BRAF mutation testing, but I do not wait for those results before starting patients on combination immunotherapy based on these data.

My Thoughts on Choosing Between First-line Immunotherapy Combinations
The next question is which first-line immunotherapy to use. My preferred first‑line therapy for patients with metastatic melanoma is almost always combination immunotherapy. Just as I rarely use BRAF/MEK inhibitors in the first‑line setting, it is now exceedingly rare for me to use single‑agent nivolumab in the first line.

The nivolumab/ipilimumab combination is approved based on improved OS in the phase III CheckMate 067 trial vs single-agent ipilimumab for first-line treatment of advanced melanoma. Nivolumab/ipilimumab is a very effective regimen with durable, high responses but fairly high toxicity. The combination of nivolumab plus relatlimab, an anti‒LAG-3 antibody, is also an approved option based on the phase III RELATIVITY-047 trial, which demonstrated a significantly improved median progression-free survival (PFS) of 10.2 months with nivolumab/relatlimab vs 4.6 months with nivolumab (HR: 0.78; 95% CI: 0.6-0.9) in patients with stage III/IV melanoma. A numerical but not statistically significant improvement in median OS (not reached vs 34.1 months) was observed. Patients were stratified by PD‑L1 and LAG‑3 expression, BRAF status, and disease stage, and in every subgroup examined for OS and PFS, nivolumab/relatlimab was favored vs nivolumab. Overall response rate (ORR) was 43.1% with nivolumab/relatlimab vs 32.6% with nivolumab. LAG-3 expression and testing are not required for the use of relatlimab. In my opinion, the added benefit of combining nivolumab and relatlimab is not at the expense of added toxicity, which we see with nivolumab/ipilimumab.

The decision regarding which immunotherapy combination to use is not driven by any head-to-head evidence, but rather is informed by a comparison of the existing clinical trial data and clinical experience. The nivolumab/ipilimumab and nivolumab/relatlimab combinations both are more effective than single-agent immunotherapy. For clinical outcomes, the efficacy of nivolumab/relatlimab seems comparable to nivolumab/ipilimumab in terms of PFS, but I think it is unfair to compare the OS data between CheckMate 067 and RELATIVITY‑047 because of the difference in length of follow‑up between the trials.

The investigator-assessed ORR for nivolumab/ipilimumab was 58% in CheckMate 067, which is higher than the 43% ORR by blinded independent central review for nivolumab/relatlimab in RELATIVITY‑047. It is unclear whether this is a substantial difference, but it is one of the reasons I could justify using the more toxic combination of nivolumab/ipilimumab when it is important for the patient to get an immediate response. If a quick response is not urgent, then a less-toxic, comparably effective regimen is appropriate. In my practice, it is an approximately 50/50 split of patients receiving one of these immunotherapy combinations. Of note, nivolumab/ipilimumab is the clear choice for patients with brain metastases based on the phase II CheckMate 204 trial, which showed that nivolumab/ipilimumab had excellent activity and durable response in the brain, with an intracranial ORR of 53.5%. There is a lack of data on nivolumab/relatlimab for brain metastases; a clinical trial to address this question is underway (NCT05704647).

Sequencing Therapy for Metastatic Melanoma
Unfortunately, many of our patients experience disease progression and need second‑line therapy, but sequencing therapy remains difficult. It is unclear whether the efficacy of immunotherapy regimens changes based on prior treatments received. In the second line, there are limited conclusive data guiding treatment. The only randomized study in this setting is the phase II SWOG S1616 trial, which compared nivolumab/ipilimumab vs ipilimumab alone in patients with advanced melanoma who had progressed while receiving anti‒PD-1/PD-L1 therapy. Nivolumab/ipilimumab improved median PFS and ORR vs ipilimumab alone, so nivolumab/ipilimumab should be considered in the second line for patients who progressed on anti‒PD-1/PD-L1 therapy. Nivolumab/relatlimab appears less effective in the second line following immunotherapy. In the phase I/IIa RELATIVITY-020 trial part D, patients with advanced melanoma who had progressed while receiving 1 or more anti‒PD-1/PD-L1 therapies had an ORR of 9.2% to 12% with nivolumab/relatlimab.

Key Finding 2: Knowledge of Tumor-Infiltrating Lymphocyte (TIL) Therapy
TIL therapy is a novel approach that currently is not approved by any regulatory agency—but it is one that we hope will become available to our patients. Not surprisingly, 39% of survey respondents indicated that they were unfamiliar with TIL therapy, and HCPs will need education to incorporate this therapy into clinical practice once approved.

Generating TIL therapy is a more complicated process than typical cancer treatments and takes several weeks, and the process continues to be refined and shortened. The patient must undergo a lymphodepletion regimen, followed by TIL infusion and high‑dose IL‑2 therapy. The major benefit of TIL therapy has been durable responses after a single infusion. In the phase III M14TIL trial, patients with stage IV melanoma—the majority of whom were refractory to anti‒PD-1 therapy—were randomized 1:1 to receive TIL therapy or ipilimumab. Patients receiving TILs had superior median PFS (7.2 months vs 3.1 months; HR: 0.50; 95% CI: 0.35-0.72; P <.001), ORR, and median OS compared with patients receiving ipilimumab. A single‑arm phase II trial of lifileucel TIL therapy also showed excellent results in a heavily pretreated patient population with stage III/IV melanoma, all of whom had received prior anti‒PD-1/PD-L1 therapy. The ORR was 31%, with the median duration of response not yet reached.

Key Finding 3: Role of Neoadjuvant and Adjuvant Therapy
One quarter of HCPs surveyed indicated that they “rarely” or “never” consider neoadjuvant immunotherapy for patients with high-risk, node-positive stage IIIB/C/D resectable melanoma. I think all of our patients with high‑risk resected melanoma should be considered for adjuvant therapy, and there is mounting evidence in favor of neoadjuvant immunotherapy. The randomized phase II S1801 trial examined pembrolizumab as adjuvant therapy with or without neoadjuvant pembrolizumab in patients with resectable stage III/IV melanoma. Patients receiving both neoadjuvant and adjuvant pembrolizumab had significantly longer event‑free survival (P =.004) compared with patients receiving adjuvant pembrolizumab alone. Consideration of neoadjuvant immunotherapy is appropriate now that we have practice‑changing randomized evidence that clearly shows it to be superior to surgery followed by adjuvant therapy alone. 

Selecting Neoadjuvant Immunotherapy
Although the S1801 trial clearly showed that neoadjuvant plus adjuvant therapy is better than adjuvant therapy alone, a single‑agent anti‒PD‑1 drug is not necessarily the best neoadjuvant regimen. It is safe and effective, but we have other options that are just as safe and more effective. A phase II trial (NCT02519322) examined nivolumab/relatlimab as both neoadjuvant and adjuvant therapy in patients with stage III/IV melanoma. Dual neoadjuvant and adjuvant therapy achieved a very high response rate (57% pathologic complete response [pCR], 70% overall pathologic response), with no grade 3/4 immune-related adverse events during the neoadjuvant period.

Randomized evidence from the phase II PRADO and OpACIN-neo trials showed that low-dose ipilimumab (1 mg/kg) plus nivolumab for 2 cycles prior to surgery results in a pCR of 49% to 57%, with approximately 20% of patients experiencing grade 3/4 adverse events. Because nivolumab/relatlimab has a pCR rate similar to nivolumab/ipilimumab, I tend to use the former more consistently in my practice.

In a pooled analysis published in early 2021 from all of the trials on neoadjuvant immunotherapy or BRAF/MEK-targeted therapy conducted to that point, it was shown that pCR correlated with excellent relapse survival. Thus, inducing a higher pCR is something worth aiming for. For this reason, I think that although the results with single‑agent anti‒PD‑1 neoadjuvant therapy are excellent, a combination immunotherapy could reach the goal of trying to induce the highest possible rate of pCR with the lowest toxicity.

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