LEAP-004 is a phase II clinical trial that evaluates the efficacy of the combination of an anti-PD-1, in this case pembrolizumab, in combination with lenvatinib that is a multi-tyrosine kinase inhibitor in patients with metastatic melanoma who have progressed on a prior therapy based on anti-PD-1 immune checkpoint inhibitor.
What was the methodology used in the study?
This is a phase II trial, a single-arm study. It’s an international study, and has included 103 patients and is the largest trial in this setting, in patients with advanced melanoma that assessed the efficacy of the combination of pembrolizumab plus lenvatinib in patients who have progressed to prior anti-PD-1 based therapy.
What were your findings?
The primary objective of the study has been objective response rate, that has been assessed by an independent radiological committee. In this update objective response rate is 21.4% and the median follow-up is 15.3 months. In this update there has been an increase, one partial response has gone to complete response and one progressive disease has gone to unstable disease. Again, in patients who responded, in responders, the median duration of response has increased from 6.3 months to 8.3 months. Something that we have observed is that we can see responses across all different clinical characteristics of these patients, and independently of the prior therapy to which this patient had been exposed.
The thing that has been assessed in this study is response rate according to the definition of primary resistance and secondary resistance that has been used in this particular study. In LEAP-004 primary resistance is defined as including those patients who have had as a best response to prior anti-PD-1 of progressive disease or stable disease in the metastatic setting. Secondary resistance includes those patients who responded to prior anti-PD-1 therapy but later on they progressed. Within this trial 60% of the patients fulfilled the category of primary resistance and the rest fulfilled the definition of secondary resistance. One interesting observation is that the response rate is the same in the context of primary resistance, 22.6%, and secondary resistance, 22.7%. That means that this combination can have activity in both settings. Although still we don’t know which are the particular mechanisms that are involved in this tumour or microenvironment resistance to anti-PD-1.
In this update the safety profile remains the same, has not changed. Approximately 45% of the patients experienced Grade 3-5 treatment related toxicities and in the type of toxicities the pattern follows the type of toxicities that usually are associated with this type of multi-tyrosine kinase inhibitors, with no new safety signals.
What is next for this trial?
I think one of the interesting points of this trial is that we have a very well-defined definition of failure to anti-PD-1; that failure or progression to anti-PD-1 has been confirmed independently by an external review committee; that the response rate to this combination of pembrolizumab plus lenvatinib has been assessed not only by the investigators but also by this independent radiological review committee; that the patients that have been included in this trial, this group of patients is quite heterogeneous, because approximately 58% of the patients had received two or more lines of prior therapy so this is a tough-to-treat group of melanoma patients; and that objective response rate is 21.4%. For further or for future development also there is an additional trial, that is the LEAP-003 trial, that is assessing the efficacy of this combination in first line treatment, in first line therapy, in patients with advanced or metastatic melanoma. Once we have the results, in addition to the results of LEAP-004, that will decide which one is the future of this combination in this setting of failure to anti-PD-1 based therapy in patients with metastatic melanoma.
