At this meeting we presented data from the LEAP-002 study which was a large multinational phase III
study evaluating the combination of lenvatinib and pembrolizumab to lenvatinib and placebo in
patients with advanced liver cancer in the first line setting. This study grew out of a phase Ib study
where we initially evaluated lenvatinib and pembrolizumab in combination in about 100 patients and
saw significant activity – objective response rates of 36% and a median survival of over 21 months.
As it stands now, lenvatinib is globally approved in the frontline setting as a single agent;
pembrolizumab, a PD-1 inhibitor is approved in the United States in second line and there is scientific
rationale to combine these two agents together and the phase Ib study gave us clinical rationale to go
ahead with a large phase III study.

In this phase III study just under 800 patients were randomised 1:1 to receive lenvatinib and
pembrolizumab or lenvatinib and placebo. Like most studies in advanced liver cancer we accrued
patients who had well compensated liver disease, [inaudible], they were good performance status, had
no prior treatment. Importantly, patients with main portal vein invasion were excluded. They were
stratified using the common prognostic factors – region, elevated AFP, ECOG performance status,
presence or absence of high risk features such as macrovascular invasion or extrahepatic spread.
The study had dual primary endpoints of overall survival and progression free survival by independent
review.

When we looked at the analysis that was presented at ESMO, so the final analysis for overall survival,
we saw that the treatment arm of pembrolizumab and lenvatinib performed as expected. We saw a
median survival of over 21 months; we saw an objective response rate of 25%; we saw a PFS of over
8 months. However, the control arm performed much better than expected – the control arm gave us
a median survival of 19 months as compared to the benchmark in the REFLECT study, the pivotal
study that got lenvatinib approved, overall survival in that study was 13.5 months. So in this new era
of liver cancer where we have many drugs available at progression we’re seeing, to some degree, a
change in the natural history and that lenvatinib is providing 5-6 months longer survival as a single
agent in the frontline setting than it did in the pivotal REFLECT study.

So unfortunately this is a negative study. When we look at the other endpoint of PFS, the hazard ratio
is 0.86 but it did not reach statistical significance but, like in other immuno-oncology studies we see a
tail to the curve where over time, like at a two-year benchmark, 16% of patients in the treatment arm
still had not progressed as compared to 9% in the control arm. Objective responses were higher with
the combination, as mentioned – 25% versus about 17% - and the safety was consistent with
everything we know about these drugs. The combination did not increase the frequency or intensity of
adverse events. Most of the adverse events looked like those that we see with lenvatinib and immune
related adverse events were generally low grade and less than 10% of patients needed steroids.
So, in conclusion, we demonstrated the activity of lenvatinib pembrolizumab. It was not statistically
better than lenvatinib alone in terms of overall survival or PFS. The safety has been established.
Really, the activity of lenvatinib alone has improved over time and reaffirms its position as an
important agent for patients with advanced liver cancer in the frontline setting. The regimen is still
being evaluated in another phase III study which we’re hopeful will show benefit and that is the LEAP-
012 study of lenvatinib pembrolizumab plus chemoembolization versus chemoembolization or
placebo in patients with intermediate stage liver cancer.

Moving forward, lenvatinib pembrolizumab does serve as a backbone for future drug development,
even though it won’t get regulatory approval based on this study; I don’t anticipate that because it did
not meet its endpoints. But it did show a significant activity in liver cancer and the other takeaway is
just reassuring the activity of lenvatinib as a very active TKI in this space.