PW: What does it mean for patients with advanced HCC to now have another medication option, after so many years with limited options?
GK: On one level, there are more treatments, that are better. On another level, because we have more treatments now, you can tailor some of these treatments for patients. For example, do we use atezolizumab for everyone? No, we only use that for patients who are Child’s Pugh A, have low risk of bleeding, have cleared endoscopy, and have no MI, hypertension, etc. But what if they have significant esophageal varices but are Child’s Pugh A? It used to be that we would use Lenvatinib, a TKI, or PD1 monotherapy.
But with results of the Himalaya study, why not do dual therapy and get more bang for your buck? Because we have more options, patients don’t necessarily need to just funnel between one and two options. Patients with good liver function could be prescribed dual immune checkpoint inhibitor therapy and get more benefit versus just one.
I think the myriad of treatments we have right now allows us to more specifically optimize treatment for a patient with a specific situation.
Did the availability of another option for this patient population open the door for more options that are in the pipeline and showing promise?
Promise is a tricky word. I think it’s, it’s deeper than just saying “this drug plus this drug make a rational combination.” It might look theoretically promising, but in the real world, trying to get a clinical trial to, demonstrate something comes with so many factors that come into play. There are many novel treatment strategies in the works, but the first line treatment setting has developed so rapidly, I think a lot of companies are waiting for the dust to settle before figuring out what space would benefit most from clinical investigations of novel therapies.
Results of the IMbrave-150 study update in 2021 helped establish AB therapy as a first-line option for patients with advanced HCC. How did the study results differ from those of Himalaya?
Himalaya had positive overall survival results and negative progression-free survival results. IMbrave-150 was positive for both, but that’s partly because atezolizumab itself is a drug that when you give it, you know you’re going to see something. It takes time for a CTLA-4 inhibitor to work, so you might only see the benefits on the tail end; when you look at the curves with AB therapy, they separate early. With Himalaya, they separate late. But Himalaya did demonstrate 3-year survival, which I don’t think any trial in HCC has ever shown with first reports.
It’s really intriguing, and it harkens back to whether the treatment is additive or synergistic, but I do think there is still some preference for oncologists to use AB therapy because of the early separation of the curves to prevent an early dropout. The VEGF pathway is a valid target in HCC. Bevacizumab, sorafenib, and lenvatinib all target that pathway, but it’s not immunotherapy. There’s something to be said about getting patients benefits/response by treating that pathway in addition to immunotherapy.
Some treatments are purely immunotherapy, but what if the HCC you’re treating is a completely immune-cold tumor? There are no ways to find that out before starting treatment. If I’m treating a patient with HCC with immunotherapy only and their tumor is cold, nothing is going to work and that tumor will grow quickly. On the other hand, AB therapy includes immunotherapy but the real backbone is really atezolizumab. But by adding bevacizumab, the concept is to make the tumor microenvironment less immunosuppressive so that atezolizumab can work better and normalize the blood flow into the liver tumor so immune cells can get there. But even without that strategy, atezolizumab itself does something. That’s a treatment strategy that covers two bases.
What’s unique about the study and its participants?
It allowed patients with high-risk HCC who typically have a poor prognosis, which is patients with significant vascular involvement. These are not the type of patients who typically are included in most other HCC studies, but the researchers were still able to show clinical benefits despite the risks involved with this high-risk patient population.
What do the results add to the initial IMbrave-150 study, published in 2020 in N Engl J Med?
When the IMbrave-150 study came out, everyone got really excited, because it was the first thing to beat sorafenib. The question was whether it could maintain the response rate. And it was able to do that. I think that puts the mind of patients and oncologists better at ease.
The other “c” word being thrown around now is cure (the other being cancer). We don’t really use the cure word in situations like advanced HCC, but I’ve heard people use it. We typically say someone is cured with no recurrence for 5 years off treatment. I have seen a few patients with HCC off treatment for about 2 years and nothing’s growing. We’ve never encountered this before. These patients with very robust and durable long-term outcomes exist.
