2021: The Year of Advances in Unresectable HCC? - Episode 11

KEYNOTE-240 and HIMALAYA Trials in Advanced HCC

March 31, 2021
Amit Singal, MD, UT Southwestern Medical Center

Masatoshi Kudo, MD, PhD, Kindai University

Stephan L. Chan, MD, The Chinese University of Hong Kong

A review of currently available ongoing data for unresectable HCC (hepatocellular carcinoma), including data from the HIMALAYA trial.

Masatoshi Kudo, MD, PhD: Unfortunately, in the pembrolizumab study, KEYNOTE-240, after sorafenib, pembrolizumab as a second-line agent was negative, but the OS [overall survival] benefit was shown in the Kaplan-Meier curve. The P value was 0.02-something but statistically negative. Because of KEYNOTE-240, there are coprimary end points, PFS [progression free survival], and OS [overall survival]. It consumed the LFR [local failure rate], and there were 2 interim analyses, so 2 allocated LFR to these interim analyses. In the final analysis, P value should be under .01-something. Statistically, the pembrolizumab study was negative, but clinically, apparently pembrolizumab is a benefit for OS compared with placebo. It was not approved because it is statistically negative, but it was clinically meaningful.

The HIMALAYA study is a durvalumab-tremelimumab combination trial, and the phase 3 trial is ongoing. There is a phase 1/2 study that’s called Study 22. There is comparison between 4 arms: high-dose tremelimumab, 300 mg, plus durvalumab; durvalumab alone; tremelimumab alone; and tremelimumab 75 mg plus durvalumab. The high-dose tremelimumab plus durvalumab shows a very good clinical outcome. Response rate is 24% compared with other 3 arms. All 3 are less than 20%. OS is longest in the tremelimumab 300 mg and durvalumab arm. That is around 18 months. In the pharmacokinetic study, high-dose tremelimumab plus durvalumab arm increase the CD8-positive cells in the proliferative as compared with the other 3 arms. The HIMALAYA study improved high-dose tremelimumab; tremelimumab 300 mg plus durvalumab is compared with sorafenib. That’s the HIMALAYA trial.

The other trial, the nivolumab-ipilimumab trial, is also PD-1 antibody plus CTLA4 antibody. This is a very important finding similar to durvalumab-tremelimumab combination therapy. High-dose ipilimumab and high-dose CTLA4 antibody show the best outcome. Response rate is around 30%, and OS is 22 months. It’s longest among the other arms. There are 3 arms: nivolumab 1 mg, ipilimumab 3 mg—that’s a high-dose IPI group; nivolumab 3 mg, ipilimumab 1 mg/kg; and I forgot the dosing, but for nivolumab and ipilimumab, high-dose ipilimumab group showed the best benefit, best outcome. Those regimens have adopted the phase 3 trial, nivolumab-ipilimumab trial.

The dose CTLA4 plus PD-1 or PD-L1 antibody show a similar trend, like high-dose priming with CTLA4 antibody, induce the CD8-positive cell and then induce a very good outcome. We expect the results of phase 3 studies.

Transcript Edited for Clarity