Looking forward to further combinations and approaches for frontline and second-line therapy in advanced, unresectable hepatocellular carcinoma.
Richard S. Finn, MD: When we look at clinical trial options, there is a lot of activity in the frontline setting. Many of these have completed accrual, and these include phase 3 studies still looking at TKIs [tyrosine kinase inhibitors] as the comparator, such as the combination of lenvatinib and pembrolizumab, which a large phase 1b expansion study was published in JCO [Journal of Clinical Oncology] [in 2020], which again shows response rates of 36%. However, we are waiting for phase 3 data from a randomized study: the LEAP002 study. There is a lot of interest in IO [immune-oncology]/IO or a PD-1 and CTLA-4 combination, such as the combination of ipilimumab and nivolumab, which was approved on accelerated approval mechanisms in second-line liver cancer [in 2020]. This data set was published in JAMA [Journal of the American Medical Association] Oncology in 2020 as well, and that is now being compared to sorafenib in the frontline setting or lenvatinib. There is also the HIMALAYA study, which is looking at PD-L1 inhibition with durvalumab vs CTLA-4 inhibition with tremelimumab. The HIMALAYA study has completed accrual, and we are waiting for events and a readout. Also ongoing is the atezolizumab study in combination with cabozantinib, the VEGF, MET, AXL inhibitor approved in the second-line setting, looking at a combination with PD-L1 inhibition.
The next phase of frontline studies is just getting going. Some of them are working on an atezolizumab/bevacizumab backbone and adding a new mechanism of action. There will be a little pause as we wait for the current phase 3 studies to read out, and as we look for new mechanisms and new targets to put forward in the frontline setting. There is an interest now in second- and third-line settings, moving cellular-based therapies into clinical development. This is also an exciting area, such as CAR T [chimeric antigen receptor T cell] or T-cell modified approaches. However, it will be some time before we get these into the standard of care.
At the end of the day for physicians out in the community, it is important that you work with your colleagues if possible in a multidisciplinary tumor board-type of approach, but I know that this is not always feasible. Certainly, for hepatologists and medical oncologists, even if patients are receiving locoregional treatment, you need to be involved in your patients’ care and follow-up. No longer can we just do locoregional treatment until patients have clinical progression or decompensate. We have new drugs in the frontline setting as well as a host of drugs in second- and third-line settings that have shown to improve survival, and it is important that we transition patients appropriately when they haveradiographic progression, before they have clinical progression. In that way, we can maximize the sequence of treatment, which should include clinical trials that, at the end of the day, are pushing the survival of patients with advanced liver cancer.
If we look at where we were in 2008, the median survival in the control arm from the SHARP study was about 8 months. We made an incremental step forward with sorafenib in survival from the SHARP study of about 11 months. However, we have now looked at data of integrating new drugs into the treatment of advanced liver cancer, and using the sequence of TKIs, we have shown, for example, with sorafenib to regorafenib in the context of a phase 3 study, that survival can be out to 26 months. As the data mature from the IMbrave150 study, we will continue to see improvements in survival for our patients. It is still not curative, but we need to continue to push forward for the benefit of our patients and work together as a team to make this happen.
Transcript edited for clarity.