Insights From: Arndt Vogel, MD, Hannover Medical School; Oliver Waidmann, MD, Goethe-Universitat Frankfurt am Main
Oliver Waidmann, MD: The METIV trial investigated tivantinib, which is a MET inhibitor, in patients with HCC and previous treatment with sorafenib. The study was quite interesting because it was a biomarker-driven study. We had the biopsy, we had tested for MET, and only in patients with high MET expression was the treatment with tivantinib started. It was placebo controlled, so it was 2:1. Even though it was a biomarker-driven study, the study was negative, so there was no improvement in overall survival. I think there are some critical points concerning the study. I think there was 1 critical point. Within the study, they had to decrease the study amount of the drug because they had severe side effects, which they didn’t expect. So, neutropenia was a problem. And the second point: I think it wasn’t very good to do the biomarker testing, it wasn’t standardized. You could do the biomarker testing from really old biopsies, which had been from before the start of first-line treatment or really fresh biopsies. Maybe this is biased to the study results, but in the end, it was not active. And we also saw it in gastric cancer. We had also MET inhibition with antibodies, all small molecules, and there was no improvement in overall survival in patients with gastric cancer. So, just targeting MET without targeting other kinases, it’s probably not the best way to go.
Arndt Vogel, MD: In second-line treatment, we now have 1 drug available that has shown efficacy after failure of sorafenib. The trial was a very well-conducted trial with very specific inclusion and exclusion criteria. And one of the inclusion criteria was that patients needed to progress on sorafenib and they were required to tolerate sorafenib for at least 4 weeks. So, patients who did not tolerate sorafenib were not candidates for this trial, indicating that we now have a really specific population of patients who use and tolerate tyrosine kinase inhibitors and also, very importantly, have a good liver function—because only Child-Pugh A patients were included—so that they were able to participate in this trial.
When patients fulfill these requirements, they have a really very good prognosis for success with the treatment of regorafenib. Median overall survival was increased by almost 3 months, which I think is a very good result in HCC in second-line treatment, and it was clearly a positive trial. This is very good news, and from my own impression, if you really stick to the inclusion and exclusion criteria from the clinical trial, also in clinical practice, regorafenib can be very well tolerated by our patients. So, we have used regorafenib in colorectal cancer, and it was really sometimes very difficult to manage all these side effects. But my impression in HCC was that patients who tolerate sorafenib also tolerate regorafenib. Also, in the trial, there was, of course, also quite a number of side effects that occurred. But in daily life, my experience is that regorafenib is very well tolerated, and we also see responses with regorafenib after sorafenib. So, I think it’s a very active drug and a drug that we clearly can use in these patients who reflect the patients who have been included in the clinical trial.
The concern, and the highest unmet need, is that most patients who get to second-line therapy are no longer Child-Pugh A. And this brings me back to the point that we really need to monitor liver function during our treatment. So, we can use all these local therapies, but we need to carefully monitor liver function. We need to see that we do not harm the liver and that we stop the treatment once we see a decline in liver function. For first-line, we most likely will have 2 options available in the near future. And then, again, we should not continue with treatment beyond radiologic progression, for example, because now we have effective drugs in second-line. So, I think the management of HCC will change with the approval and most likely the approval of the drugs that have been positive, tested in these recent phase III trials.