Insights From: R. Kate Kelley, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Josep Llovet, MD, PhD, Icahn School of Medicine at Mount Sinai; Masatoshi Kudo, MD, PhD, Kindai University; Arndt Vogel, MD, PhD, Hannover Medical School
Joseph Llovet, MD, PhD: I think that the field is moving to combinations. Certainly, if the patient is responding to checkpoint inhibitors, the response is outstanding, and the median survivals that have been published in second- and first-line settings based on the phase II data with median survivals beyond 20 months with nivolumab. So these are very good survival rates, but the patients who achieve stable disease or, needless to say, progressive disease certainly have primary resistance to checkpoint inhibitors.
So now there is a trend in almost all the trials to combine TKIs [tyrosine kinase inhibitors] with checkpoint inhibitors in order to boost the immunity in this percentage of population, the 60%, 70%, or 80%—particularly those with immune exclusion—who are completely silent from the immune system. To boost immunity there, there certainly are a lot of efforts. We’re seeing combinations with lenvatinib/pembrolizumab, regorafenib/pembrolizumab/nivolumab. We’re seeing bevacizumab/atezolizumab in combination. All these efforts may be able to rescue some of the patients who are certainly not responding to checkpoint inhibitors into responders or switching cold tumors to hot tumors. So what’s your take in this combination?
R. Kate Kelley, MD: I’m eagerly watching those trials, as well, and also the addition of the checkpoint inhibitor combination with the CTLA-4 plus PD-1 or PD-L1 inhibitors to that list, such as the durvalumab plus tremelimumab combination or the nivolumab plus ipilimumab combinations, which are all eagerly awaited. I guess one of the questions from the scientific side or with respect to tumor biology is—of course it will take clinical data to tell us: Which is the best strategy for which type of patient? But we also have the combinations of liver-directed therapy plus checkpoint inhibition with the idea of will that better create immune infiltration or convert a tumor from cold to hot. Do you have a thought about those combinations on the horizon?
Joseph Llovet, MD, PhD: Yes. But certainly, I would say that in advanced HCC, the field will be dominated by the combinations for the next 5 years. There are preliminary studies suggesting that these TKIs may be able to increase the CD8 cells, infiltrate into the tumors, and decrease the Tregs [regulatory T cells]. These are the 2 main mechanisms that are out there. In terms of locoregional therapies boosting the immunity, there are a few studies, phase II, small, short studies. But also the release antigens may also enhance the immunity there. But how I envision the field of intermediate HCC improving is trying to move the combinations already in advanced disease to intermediate disease on top of chemoembolization or head-to-head even. This is how I envision it.
Masatoshi Kudo, MD, PhD: The checkpoint inhibitor monotherapy response rate is just less than 20%. But recently combinations with immunotherapy are in ongoing trials, such as lenvatinib plus pembrolizumab, which was presented at ASCO [the American Society of Clinical Oncology Annual Meeting] last year, and the response rate was 43% in 26 patients, and the response is durable. And also, at the same meeting, the atezolizumab plus bevacizumab data were presented. But at that time, the response rate was very high, 65%, but at the ESMO [European Society for Medical Oncology] meeting, the response rate was up to 32%. But still relatively high, and the response is durable.
So those checkpoint inhibitors plus TKI or anti-VEGF antibody are promising. Another promising agent combination is PD-1 or PD-L1 antibody plus CTLA-4 antibody, like nivolumab plus ipilimumab. Another PD-1, PD-L1 plus CTLA-4 combination is durvalumab plus tremelimumab. This durvalumab/tremelimumab combination is also in a phase III trial ongoing. And the atezolizumab/bevacizumab combination is also in a phase III trial; IMbrave150 is ongoing. So those are very promising. Response rate is very high, and the responses are durable.
Arndt Vogel, MD, PhD: The IMbrave150 trial is a very interesting study, which looked at the efficacy of the antiangiogenic drug bevacizumab and the immunotherapy agent atezolizumab. So basically the combination of immunotherapy and antiangiogenesis. And there are some preclinical data that suggest synergy. So there was a clear rationale to use these drugs in our patients. And we have seen the first clinical outcome data at ASCO. It was a very, very strong signal with a response rate of 60%, which was really remarkably high. At ESMO we got an update with more patients. The response rate dropped to 34%, which, however, is still higher compared with what we have seen before.
So far there are only 70 or 80 patients included. So we have to be careful, but the first initial signal is strong and is in line with other drugs we have for other combinations we have seen for TKI and immunotherapy: lenvatinib with pembrolizumab for example, for which the first data have been reported. And similarly, we have a response rate of 37%. So I think at the moment, there’s a clear indication, as we have seen it in other tumor types, that when we combine immunotherapy with TKIs, or with antiangiogenic drug, we might have more efficacy. It’s not yet clear whether it’s additive or synergistic efficacy. But it very much looks like we will go to combination therapies in the future.