OBR: What did the IMbrave 050 trial examine, and what were some of your main findings?
Pierce Chow, MBBS, MMed, FRCS(E), PhD: The IMbrave 050 trial addresses one of the major unmet clinical needs in primary liver cancer or hepatocellular carcinoma, which we also call HCC. Of the common cancers, HCC stands out because after surgical resection or ablation, there is currently no adjuvant therapy available. So this is where this is very different from other cancers like colorectal cancer or breast cancer or lung cancer where, after surgical resection, you always have adjuvant therapy to reduce recurrence. And as you can imagine, recurrences in liver cancer after surgical resection and ablation tends to be high because of that. And this is the unmet need that the trial addresses.
So we found that the use of atezolizumab and bevacizumab decreases the rates of recurrence and also increases recurrence-free survival, which is very important because in liver cancer, as in many other solid cancers, the longer it takes for the patient to get a recurrence, the better the eventual outcomes and survival will be. So it addresses this very important need, and I'm very glad it's a positive trial.
OBR: What were the study’s endpoints, and what were the results?
Dr. Chow: The primary endpoint is recurrence-free survival. And here we see a very clear difference in recurrent-free survival between patients treated with atezolizumab and bevacizumab versus active surveillance, which is until this point in time, the standard of care. We see that in patients treated with atezolizumab and bevacizumab, the median recurrence-free survival, well, the 12-month recurrence-free survival was 78% versus 65%. So that's a big gap. And more importantly, the hazard ratio was 0.73 with a very, very good P value of 0.012. So it was definitely a positive trial in that sense.
But because the data was arrived at or the trial met is primary endpoint at the first interim analysis, the overall data is still relatively immature, and we were not able to assess overall survival because the data is just too short. So that is one of the main limitations of the study, and we will need to follow-up with the patients for a longer period of time, in order to get some of these secondary endpoints. But anyway, we planned the whole trial to run for five years, so we'll eventually gather the data.
OBR: How did the duration of the combination treatment compare with the previous IMBrave150 trial?
Dr. Chow: The duration of treatment for the [IMbrave]050 was actually very much longer than the previous [IMbrave]150. For atezolizumab, it was 11.1 months, and for bevacizumab it was 11 months. And this was much longer than that in the 150 where it was 7.6 [months] and 6.9 [months]. But the interesting thing is that, in spite of the much longer duration of treatment, we do not see an increase in the number of adverse events [AEs], which is actually very good for the patients because patients on adjuvant therapy, they're essentially well, the cancer has been taken out of them or ablated. And for these people, AEs will not be so acceptable. And we are glad to see that the patients tolerated AEs, if any, and a lot of them have very long duration of therapy.
OBR: What were some of the common adverse events, and how did you manage them?
Dr. Chow: The adverse events were as expected for the drug. And if you compare the group of patients treated with atezolizumab versus the group of patients treated with just active surveillance, the major adverse events that were seen, which was higher in the treatment group, was number one, proteinuria. That is to say the presence of protein in the urine. Second was hypertension, an increase in blood pressure. Third was a decrease in platelets, which is a component of the blood that helps clotting. And then there was also derangements of liver function tests. So these were the major adverse events that were seen more in the treatment group rather than the observation group.
OBR: How does this trial attempt to address the worse outcomes seen in patients with HCC, compared with patients who have other solid-tumor cancers?
Dr. Chow: Of course, patients with HCC tend to do badly because there was no adjuvant therapy. So currently, because we have succeeded in reducing recurrence rates and improving recurrence-free survival, there is an expectation that further down the line as we follow up the data, we will see that impact in the overall survival. But at this moment, we can't say, of course, there are other factors at play.
For example, in this trial, patients on the active surveillance arm as they develop recurrence, which they will, they're permitted to cross over to the atezolizumab and bevacizumab arm. So because of that, it might not be very easy to see differences in overall survival. But those are secondary endpoints. The primary endpoint doesn't change, that is recurrence-free survival. And for that, we already have positive data. But the expectation from what we understand of liver cancer is that the later the patients develop a recurrence, the better their overall outcomes will be. And we don't expect this to be different for patients within this trial.
OBR: What further research do you feel is needed regarding adjuvant treatments in HCC?
Dr. Chow: I think for adjuvant treatment for HCC, there are a couple of other studies also running at the same time, but the first one to reach a positive conclusion was the IMbrave 050. Certainly, we will look forward to the results of the other trials to see whether different combinations of therapies can work just as well. Here, of course, as you realize there are two drugs working together.
Other than this, I think in the future it might be worthwhile to see whether there's a new role for neoadjuvant therapy, which is to say that rather than giving the drugs after surgical resection, for example, you might want to give it upfront before surgical resection and then go for surgical resection, and then you continue that after afterwards. Because in other cancers, for example, melanoma, it has been shown to be useful this way. So these are things that we can investigate in the near future, as we have a positive adjuvant therapy now.
