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KEYNOTE-240 and HIMALAYA Trials in Advanced HCC

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

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