Updates in Frontline Treatment of Metastatic Liver Cancer - Episode 7
Richard S. Finn, MD: The durvalumab/tremelimumab combination is being evaluated in the HIMALAYA study versus sorafenib, and since the study completed accrual, we’re waiting for the efficacy readout. At the same time, as I mentioned a few minutes ago, nivolumab and ipilimumab got accelerated approval in second line, based on 1 of the arms of the ever-expanding CheckMate040 study, which was a phase 1b/2 study. There, response rates were around 30% plus or minus, but in that study, 50% of patients needed steroids to manage their adverse events. Needless to say, it appears to be very active, and that regimen is in a front-line study, the CheckMate 9DW versus frontline TKI (tyrosine kinase inhibitor). There are other things going on as well, other combinations, like lenvatinib and pembrolizumab. That has very provocative data. There was an update at ASCO. Rich, did you see that data presented by Andy Zhu?
Richard Kim, MD: Dr Zhu presented data. This was a combination of a TKI plus a PD-1, and the LEAP-002 study was presented. It had about 100 patients in this study. One thing you notice was that the response rate seemed to be a little higher than the typical combination of I/O–I/O. It was hovering around close to 40%. The median overall survival was hovering around 22 months. There’s a rationale for combining TKIs and I/O. The fact that a TKI will change the microenvironment of the tumor and allowing the immune system to kick in allows the I/Os to work better.
Based on the data that was seen at ASCO, the combination of TKI and I/O could be another combination that’s in the works. There is a phase 3 study going on right now that is comparing the combination of lenvatinib-pembrolizumab versus lenvatinib alone. From what the data suggest, we’re expecting it to be positive, but we have to wait for the final numbers to come out. This will add another weapon that we could use on these patients. atezolizumab/bevacizumab was approved so far. As you mentioned, Rich, there are a lot of front-line combination studies that are going on right now, and we’re waiting for the results. Maybe by next year, there will be 2 other combinations approved for first line.
Richard S. Finn, MD: That would be a good problem to have for our patients. The more options available, the better outcomes will be. Again, pembrolizumab and lenvatinib was evaluated in the LEAP-002 study, which, like HIMALAYA, has completed accrual; we’re waiting for results. That regimen got a breakthrough therapy designation from the FDA. As we combine things, we generally start to see more adverse effects. Again, with the pembrolizumab/lenvatinib dataset, we see adverse effects for both, similar to IMbrave150, where we don’t tend to see synergy with the adverse effect profile of these 2 combinations.
At the same time, cabozantinib is approved in second line and is being evaluated with atezolizumab in a phase 3 study, the COSMIC-312 study. At this point, we don’t have a lot of early phase data to evaluate that specific combination. At ASCO, we saw some data with a new TKI, donafenib. This was studied first with sorafenib, mostly in China. Rich, given that this is a drug we’re not familiar with in the United States, can you comment about that dataset?
Richard Kim, MD: The drug called donafenib is a TKI that’s molecularly very similar to sorafenib and regorafenib. It is a drug that blocks the VEGF and the RAF1 pathways and seems to be more potent than sorafenib. This was a trial done in China. The trial was a phase 2/3, nonsuperiority, randomized study comparing donafenib and sorafenib, and the primary endpoint of the study was overall survival. This drug showed there was a benefit of overall survival of close to 2 months, with 10 to 12 months favoring the arm of donafenib over sorafenib. There are 2 messages to take away from the trial. One is that this is the first TKI that has shown OS (overall survival) benefit of sorafenib. As you mentioned, lenvatinib was a noninferior study, so that’s important.
The second thing we must point out is that, because it was done in China with the bulk of the patients, 80% of the patients in both arms had hepatitis B. Why is that important? We know that sorafenib works much better in patients with hepatitis C. That has been shown. Therefore, because the trial was done mostly in China with mostly hepatitis B patients, the efficacy of sorafenib is probably a little inferior than some of the other phase 3 studies we’ve seen. Maybe that has something to do with it. Regardless, this is another TKI that has been studied in the first-line setting that has shown OS benefit...sorafenib, so that’s the significance. Unfortunately, this trial was done in China, so that drug will not be available in the United States. Maybe in the future it may come out with a combination in other studies.
Richard S. Finn, MD: It reflects the global interest in this disease, given that it’s one of the leading causes of death worldwide. The incidence continues to rise.
Transcript Edited for Clarity