by Dr. Christian Posch

To date, state-of-the-art melanoma treatment includes checkpoint inhibition and targeted kinase inhibition. While we have seen a dramatic improvement of progression-free and overall survival, up to 50% of patients still do not benefit from modern melanoma treatment.¹ This is due to primary resistance (patients initially not responding to treatment) and secondary resistance (patients with initial response to treatment who develop disease recurrence over time). Additionally, adverse events (AEs) – including severe ones – may challenge the health of patients. Thus, we need new drugs harnessing novel targets which ideally have a favourable toxicity profile. At EADV 2021, Dr Livingstone presented data on four new drugs.

First, relatlimab, a LAG-3 targeting antibody. LAG-3 is a co-inhibitory immune checkpoint that is often co-expressed with other immune checkpoint molecules like PD-1.² This trial, called Relativity, showed that a LAG-3+PD-1 combination resulted in superior progression-free survival (PFS) compared to PD-1 monotherapy: at 12 months, PFS for the combination was 47.7% compared to 36.0% for PD-1 monotherapy (HR 0.75; P=0.0055). Interesting to note is that the curves separate very early, at first assessment and stay separated. After Month 3, curves show similar trajectories, suggesting that primary resistance is addressed with the combination of LAG-3+PD-1 treatment. The combination treatment caused more severe treatment-related AEs; however, indirectly comparing AEs of relatlimab+nivolumab to the combination of ipilimumab+nivolomab reveals an improved safety profile for LAG-3+PD-1 treatment. There is great hope that this new combination will be available for the treatment of melanoma patients soon pending regulatory approval.  

Second, Lenvatinib – a multi-kinase inhibitor blocking several pro-angiogenic targets including VEGF, FGFR, and PDGFR – was tested to help shift a pro-tumorigenic tumour microenvironment to an immune stimulatory state. Lenvatinib was given in combination with the PD-1 antibody pembrolizumab.³ This trial was conducted in heavily pre-treated patients, all with confirmed progression on previous checkpoint inhibitor treatment including PD-1, PD-L1, and CTLA4+PD-1 therapy. The objective response rate was 21.4%, with a disease control rate of 66% and a median duration of response of 8.3 months. The median overall survival was 14 months. Response to combined lenvatinib+pembrolizumab treatment was independent of primary or secondary resistance to previous checkpoint inhibition. AEs were common, and 60% of patients had to interrupt treatment or reduce dosing at least once. Typical AEs were hypertension, diarrhoea, and nausea among others. Since the drug has already been approved in other diseases, there is hope that lenvatinib will become available for patients with otherwise limited treatment options.

Third, lifileucel, which is an adoptive T-cell therapy using autologous tumour infiltrating lymphocytes (TILs). This concept is nothing new; however, the improved process time of 22 days is a major improvement.⁴ First data are available from 60 patients and show an objective response rate of 36.4% and a disease control rate of 80.3%. To date, the median duration of response has not been reached. The main limitation of TIL treatment is very high rates of severe AEs: 97% of patients had any grade 3/4 AEs, mainly thrombocytopenia, chills, anaemia, pyrexia, and neutropenia. The need for myeloablation and systemic IL-2 stimulation post-TIL infusion limits the use of TIL treatment to specialised centres, and patients that are fit enough to withstand treatment related AEs. Currently, lifileucel is being used only in clinical trials.

Last but not least, tebentafusp, a bispecific molecule targeting TCR and CD3 domains. With this approach, it is hoped that CD3+ cells are being dragged towards tumour cells. Thus far, tebentafusp has been investigated in cutaneous and uveal melanoma with quite promising results in uveal melanoma, a melanoma entity with very limited effective treatment options. Response rates for tebentafusp were only slightly superior to investigator choice with a HR of 0.73; however, overall survival (OS) was markedly better in the tebentafusp group (HR 0.51). These data suggests that secondary resistance is, at least in part, addressed by this new molecule. Tebentafusp is also the first drug to show better OS in uveal melanoma patients.⁵

 

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References:

1. Michielin O, Atkins MB, Koon HB, et al. Evolving impact of long-term survival results on metastatic melanoma treatment. J Immunother Cancer 2020;8;e000948.
2. LAG3-PD-1 Combo Impresses in Melanoma. Cancer Discov 2021;11;1605–6.
3. Mo DC, Luo PH, Huang SX, et al. Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. Int Immunopharmacol 2021;91;107281.
4. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol 2021;39;2656–66.
5. Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med 2021;385;1196–206.