Updates in Frontline Treatment of Metastatic Liver Cancer - Episode 6
Richard S. Finn, MD: In the last 2 years, we’ve seen an incredible amount of approvals in liver cancer. In front line, we initially had just sorafenib, and then lenvatinib was approved; in late May, ATEZO (atezolizumab)/BEV (bevacizumab) was approved. In second line, we’ve had approval for regorafenib; from a phase 3 study, cabozantinib was approved in second line based on phase 3 data, both those studies versus placebo. We have phase 3 data with ramucirumab, the VEGF (vascular endothelial growth factor) receptor monoclonal antibody for patients who have an elevated AFP (α-fetoprotein), and that study was versus placebo. Three approved agents after sorafenib in the second-line setting.
Based on accelerated approval, we have both pembrolizumab and nivolumab approved for second line. Recently, we saw nivolumab and ipilimumab approved for second line based on accelerated and approval mechanisms. That’s an incredible amount of new options for us to use for our patients, and I think that will eventually lead to improved survival, even beyond what we’re seeing in recent datasets. With all that data in the past, there’s also a huge amount of data coming up in the future. At ASCO (American Society of Clinical Oncology annual meeting), we saw some very interesting updated data on the combination of CTLA4 (cytotoxic T-lymphocyte-associated protein 4) and PD-L1 (programmed death-ligand 1) inhibition with tremelimumab and durvalumab. Rich, can you walk us through that dataset, presented by Katie Kelley?
Richard Kim, MD: Sure. As you mentioned, this was a trial, and it actually had 4 arms. One is a combination of using 2 different doses of DURVA and TREME, 1 using high dose of CTLA4, and the other 2 arms are of a single agent of activity of TREME alone and DURVA alone. The winner in this sort of pick-the-winner kind of trial was a high dose of TREME with a standard dose of DURVA, with response rate up to 28%. It’s interesting that the problem with combining PD-1 (programmed cell death protein 1) and PD-L1 with CTLA4 is the toxicity. We know that, as a single agent with either PD-1 or PD-L1, the response rate seems to be hovering around 15% to 20%. When you add in another I/O (immuno-oncology), such as a CTLA4, the efficacy seems to be a bit better, but at what cost? That was a concern, especially if you use a high dose of CTLA4.
This trial showed that the winner was a high dose of CTLA4 with TREME. This was exact response that we saw when you combined (ipilimumab) and nivolumab in CheckMate040 study. In a similar study, they also used a different dose and scheduling of the combination. In the winner of that study, the response rate seems to be very similar in all 3 arms. The one that had the longest OS (overall survival) benefit was the combination of high dose IPI with a standard dose of (nivolumab), the winner. For whatever it’s worth, there are 2 studies telling us that if you combine I/O to I/O, including PD-L1 and PD-1 plus CTLA4, the higher dose of CTLA4 seems to benefit the most when you combine, despite the toxicity, which is a concern.
Transcript Edited for Clarity