Transcript:
Tanios Bekaii-Saab, MD: Anthony, we heard at ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] the results from HIMALAYA. Can you tell us what the study design was and the results?

Anthony El-Khoueiry, MD: Yes, absolutely. HIMALAYA was intended to examine the concept of I/O–I/O [immuno-oncology] combinations. It looked at the combination of anti–PD-L1 durvalumab with anti-CTL4 tremelimumab. Tremelimumab was given in this study as 1 loading dose based on preclinical evidence that 1 loading dose could find the immune microenvironment, and continuation of durvalumab single agent. This loading dose of tremelimumab was a higher dose than normal: 300 mg compared with the traditional dose of 75 mg.

The study had 3 arms and 2 comparisons. One comparison was this stride regimen, which is 1 dose of tremelimumab and a continuation of durvalumab, compared with sorafenib in the control arm. There was another arm of durvalumab single agent also compared with sorafenib. There was no formal statistical comparison of the double I/O tremelimumab-durvalumab with durvalumab. A fourth arm, which people may see on the design that was closed early, examined a different schedule of the T75+D, meaning tremelimumab 75 mg, 4 doses, and continue with durvalumab alone. That was the design.

The primary end point was overall survival looking for superiority of stride, tremelimumab-durvalumab to sorafenib. That was a secondary end point of noninferiority of durvalumab to sorafenib. The study was positive as designed. The median overall survival for the STRIDE regimen was superior to sorafenib in the range of 16 months for the combo vs around 13 months for sorafenib. That superiority end point was met for the combination. Then for durvalumab vs sorafenib, the noninferiority end point was met as well. This was based on a phase 1b study called Study 22, where the response rate was close to 30%, in the high 20%. In this trial, the response rate with the combination was 20%, and there was no difference in PFS [progression-free survival] with the stride regimen vs sorafenib.

Tanios Bekaii-Saab, MD: Even at the median, they may have looked a little worse.

Anthony El-Khoueiry, MD: Not statistically.

Tanios Bekaii-Saab, MD: Understood. Those curves flipped a little.

Anthony El-Khoueiry, MD: Some of the strengths of this trial are that it’s the largest randomized phase 3 study in first-line HCC [hepatocellular carcinoma]. It’s mature with long follow-up, so for the first time we’re seeing 36-month OS [overall survival] rates. At 36 months, the combination was superior to sorafenib. Those curves diverged and stayed separate for a long time. We now have 2 positive phase 3 studies in first line, so those are 2 options to choose from. I know the discussion is going to be, how do we choose? I don’t know if you want me to comment on that.

Tanios Bekaii-Saab, MD: Not yet. We’ll get to that. I want to understand a little more, and we’ll get to the choices. This study excluded main portal venous thrombosis, VP4. In your viewpoint, what would the implication be? Because the other studies have not. What are the implications of this exclusion in terms of trying to put this study in perspective?

Anthony El-Khoueiry, MD: That’s a valid question. In the REFLECT study, VP4 was also excluded. IMbrave150 did not exclude these patients. We’ve seen a complete response, so checkpoint inhibitors are effective in this patient population. In HIMALAYA, as you pointed out, these patients excluded the question, what does it mean to understand these data? Patients with VP4 have the worst prognosis, which could lead to the question, does this lead to a longer or medium overall survival than either arm? It doesn’t appear so in the sorafenib arm. That was good for the study. Median overall survival wasn’t very long, not 15.5 months as in the COSMIC study; it’s more like 13 months. It was a positive study in contrast to the CheckMate 459 study, which was negative with similar overall survival data. It doesn’t appear that excluding these patients with a worse prognosis led to a significantly longer survival, which we’ve learned for sorafenib.

The other question is, what does it mean for the bleeding risk? With respect to bevacizumab, we were scared about bleeding from varices, and we recommended endoscopy in patients with portal hypertension. Patients with VP4 tend to have varices, and they’re at risk for bleeding. Can we compare the bleeding risk in the HIMALAYA study with the other studies? Probably not. In HIMALAYA, there were no severe bleeding events in either arm, or in the sorafenib arm, which we’ve observed in the REFLECT study. What does it mean for bleeding? With the dual-checkpoint inhibition, we would not expect bleeding risk anyway. I don’t understand why they were excluded. In the REFLECT study, it was a decision by the Japanese society, as I understand, because they don’t want to treat patients with a TKI [tyrosine kinase inhibitor] if they have a VP4. The specific reason to exclude them here, I don’t know.

Tanios Bekaii-Saab, MD: It’s a bit obscure.

Transcript edited for clarity.