ASCO 2015

Nivolumab shows highly promising activity in advanced liver cancer in early-stage trial

Dr Anthony El-Khoueiry - University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA

Now hepatocellular carcinoma could, from what you’ve been saying, have a potential new treatment on the way. Can you tell me what it is you were trying to do in this study you’ve just reported?

I presented the interim results of an on-going phase I/II study of the anti-PD1 antibody nivolumab in patients with advanced hepatocellular carcinoma. The presentation focussed on the results of the dose escalation phase and a few patients from the ongoing expansion phase of the study. Overall we were able to look at safety in 47 patients by the time of the interim analysis and we showed that the majority of the adverse events were mild in nature, were grade 1 and 2.

Now, this disease, these patients with advanced hepatocellular carcinoma would have been candidates for sorafenib, for instance, in the past.

68% of the patients enrolled into the study had prior sorafenib treatment but the eligibility allowed patients who had not had prior sorafenib if they refused to have sorafenib as treatment. The challenge with sorafenib is that it’s the only approved systemic therapy for advanced hepatocellular carcinoma and the median survival is less than 11 months overall.

So could you give me a comparison between the historical data from sorafenib and what you actually got treating patients with hepatocellular carcinoma with nivolumab?

Sure. Just to put things in context, the objective response rate with sorafenib is 2-3%. The response rate that we saw in this trial in 42 patients is 19% with two patients having complete responses. The other important part is the durability of the responses in the patients with stable disease. So 7 out of 8 responses lasted 9 months or longer. 48% of patients had stable disease and the range is up to 17 months.

Now these drugs are very different, they’re both targeting molecular mechanisms. What is the difference, in fact?

They’re actually quite different. Sorafenib is what we call a tyrosine kinase inhibitor that has multiple targets, one of the most important ones being vascular endothelial growth factor receptor 2, PDGF, the Ras and Raf molecules. The nivolumab anti-PD1 therapy is intended, again, to enhance T-cell activity against the tumour by releasing the PD1 immune inhibition that happens when PD1 and PDL1 communicate between the tumour cell and the T-cell.

So why is it that releasing the body’s natural abilities to fight cancer is more effective, apparently, in your study?

There are many potential reasons. These are preliminary results in a small number of patients. We are looking to validate these findings in the expansion phase. But there is a sound rationale for evaluating immunotherapy and anti-PD1 therapy in liver cancer. This is an inflammation associated cancer, both hepatitis B and C, which are frequent causes of liver cancer, have been associated with higher PD1 expression. Also up-regulation of PD1 and the ligand PDL1 has been associated with worse prognosis in hepatocellular carcinoma. So there is a sound rationale for why this could succeed.

Now clinically where do you think this is going because it is only 47 patients, it’s not a large number. Is there a strong enough signal for you to be holding out clinical promise?

The study is built in a way that after the dose escalation we have a large expansion of 200 patients, 50 per cohort, to validate the promising response and survival that we are seeing in this initial small group of patients. If the signal that we are seeing is validated then this could open the door to a potentially novel therapy in this cancer, in larger trials of course.

You’re not saying yet then. But what should doctors then be making of the data we have, these very interesting data we have, so far?

We have a responsibility as a community of healthcare providers to ensure that even promising therapies are well studied, that we’ve established the safety and efficacy. So I would encourage doctors to really refer and encourage patients to participate in trials to validate the promise of immunotherapy in liver cancer.

And finally, what is this telling us about immunotherapy in some of these tumours we might not have thought about using it in before?

This is telling us that there is broad potential for immunotherapy across tumour types. We will still have challenges down the road because not every patient will get a cure from immunotherapy even though responses have an end to them. So our challenge will be to find biomarkers to better select the patients and to combine immunotherapies together to make the impact even more profound.