Peter Galle, MD: Ramucirumab has been tested in 2 phase 3 trials: REACH and REACH2. It started with the REACH trial, assessing the efficacy and safety of ramucirumab in second line following sorafenib in a nonselect group of patients, and here it did not reach statistical significance. There was a trend, and in a subgroup analysis, it became apparent that among those patients with high alpha-fetoprotein [AFP]—high meaning above 400 ng/mL—there was an improved overall survival compared with placebo.

This was then taken by Eli Lilly and Company as rationale to go into a select group of patients in the second line, and it was indeed required or the inclusion criteria included patients with AFP above 400 ng/mL. This was a positive trial, with a hazard ratio of 0.71. It’s not a dramatic absolute difference; it was a little more than 1 month. But in the pooled analysis, where all the patients positive for high AFP from the REACH trial combined with the REACH2 trial were assessed, it was coming down to a difference of about 3 months absolute number, which we have gotten used to more or less with respect to other therapies.

What sticks out here in terms of assessment of ramucirumab is very good tolerability. Although it’s an infusional regime, it requires the patient to come into the hospital, but that’s basically the only burden which ramucirumab is imposing. It was indeed, in clinical practice, very well tolerated. We do see those adverse effects, which we have been seeing in past use of antiangiogenic agents, such as hypertension, proteinuria. But overall it’s very simple: Patients on ramucirumab tolerate the therapy quite well.

What is relevant to point out is that we’ve always been asking for a biomarker-based therapy. Indeed, the ramucirumab trial REACH2 is the first 1 where we had gotten rid of the all-comer inclusion, which was basing inclusion on the biomarker.

The results of the REACH trial, as we talk about second-line treatment with respect to our situation, are quite comparable. All these trials were in the range of roughly 0.7, meaning a 30% reduction of the likelihood to die. That is, in fact, comparable to regorafenib and cabozantinib.

Kate Kelley, MD: The REACH and REACH2 trials are very important, both as a clinical option for patient care, but also as a model for the directions we’d like to go in hepatocellular carcinoma [HCC] by establishing the first biomarker-defined patient population for a drug. In the REACH trial, the overall population did not achieve a statistically significant benefit from ramucirumab, but the subgroup analysis for patients with elevated alpha-fetoprotein across a range of levels, with a cut point of 400 ng/mL, determined to be the optimal cut point, did show a significant benefit from ramucirumab. That prompted the development of the first successful biomarker-enriched and biomarker-selected trial of REACH2.

REACH2 required alpha-fetoprotein greater than 400 ng/mL for eligibility and, as we know, determined a statistically significant survival benefit and secondary end point benefit for ramucirumab in the high alpha-fetoprotein population over placebo. There is biological rationale for this. We know that alpha-fetoprotein expression is higher in patients with HCC tumors dependent on VEGF pathway signaling and angiogenesis. Thus, there is rationale for the drug having a disproportionate benefit in patients with high AFP and dependency on VEGF. On the other hand, how to place ramucirumab in the expanding treatment landscape will, I think, require additional studies in the future.

Transcript Edited for Clarity