This trial is trying to address a problem that we have every day in metastatic melanoma, it’s what can we do once patients have progressed on a standard of care treatment with anti-PD-L1 given in monotherapy or in combination with anti-CTLA-4. Because we have very limited options, therapeutic options, in this situation and also there are no really approved treatments for this indication. This is the main objective that this trial aims to address. Also because this position happens because patients become resistant to immunotherapy and resistance is multifactorial so in order to test this hypothesis this study uses two agents, lenvatinib that is a tyrosine kinase inhibitor, plus anti-PD-1, in this case pembrolizumab, to try to address this clinical problem.
What methods did you use?
The most important thing in this trial has been the definition of failure to anti-PD-1 because it is an area of unmet medical need and there are many trials around. In this trial this definition was very stringent – patients had to receive at least two doses of an anti-PD-1 based therapy; progression to anti-PD-1 had to be while they were on treatment or within twelve weeks of the last dose. Patients could have received monotherapy anti-PD-1 or a combination of anti-PD-1 combined with some other agent and anti-CTLA-4 plus anti-PD-1 was included, these patients were allowed. In addition, this progression had to be confirmed according to immune related RECIST criteria. That means that we need two radiological assessments to confirm progression that are separated, that are performed at least four weeks apart. All this has been evaluated and confirmed by an external radiological independent committee.
What were the results?
That was a phase II open label study, international multicentre from several countries. More or less 103 patients were included and the primary endpoint of the study was objective response rate that was assessed according to RECIST 1.1 criteria and in addition was evaluated by an independent radiological review committee. For the total population the objective response rate was 21.4% and in the subgroup analysis came an observation – it has been that the patients who progress on a combination of anti-CTLA-4 plus anti-PD-1 had a higher response rate, that was 31%. That was in a small subset of patients but these results come from the subpopulations, from the subgroup analysis, for objective response rate. But it’s interesting and it’s something that you look to explore further.
What adverse events did you see?
Approximately treatment related adverse events, the ones that we considered grade 3 plus, so more severe in nature, were about 45% but most of these adverse events were managed by dose interruptions and also with dose modifications. It was 8% of patients who had to stop in a definitive manner treatment because of treatment related adverse events. But the majority of them all these adverse events could be managed by these two managements that I mentioned.
What are you concluding from the results?
They are very interesting and encouraging because in this trial especially there was no limit on the number of previous systemic therapies, there was no limit on the type or in the sequence because in some trials new combinations need to be tested at determined time points. But in this trial all treatments were allowed so patients were pre-treated, heavily pre-treated. You have seen 61% of the patients had received two or more lines of prior systemic therapies and 20% of the patients four or more lines of prior systemic therapies plus a population of patients, if you look at the patient characteristics, it was enriched with poor prognostic features. So to get for that whole population a 21% objective response rate that has been assessed by an independent committee, I think this is encouraging and also it’s very interesting that this central analysis has come out in this sub-population of patients that have been treated with anti-CTLA-4 and anti-PD-1 that have progressed on this particular combination.
What’s next for the trial?
This is on the table now, what is going to be next, probably maybe to explore this population of patients. Also to wait because that was LEAP-004, that was assessing the activity or the efficacy of lenvatinib plus pembrolizumab in patients who progressed on anti-PD-1 based therapy. But now we have a phase III trial, LEAP-003, that is running in first line treatment also for patients with metastatic melanoma and that is comparing pembrolizumab monotherapy versus pembrolizumab plus lenvatinib. With all these results from the first line phase III trial and what has come out from these phase IIs, it has to be seen or decided where to go next.