Maeve Lowery, MD, on a Novel Bifunctional Antibody in Advanced Hepatocellular Carcinoma

This presentation by Dr. Shu and colleagues reports results of a phase II study in the first-line treatment of locally advanced or metastatic hepatocellular carcinoma. Thankfully, this is an area where we've seen tremendous progress over the last five years, with several new drug approvals following a long period where we were dependent on single-agent tyrosine kinase inhibitor therapy. With the advent of combination therapies with immune checkpoint blockade, we've seen more durable tumor responses, median overall survival approaching two years, and three-year overall survival rates of greater than 30%. With FDA and EMA approval of atezolizumab and bevacizumab, pembrolizumab and durvalumab, and approval in China of pembrolizumab and revaciramib, pending perhaps approval soon for ipilimumab and nivolumab, now replacing single-agent tyrosine kinase inhibitors in the first-line setting. It's become clear that combination therapy is required to elicit benefit in this setting when single-agent immune checkpoint blockade is insufficient. And so double treatment combining PD-1 inhibition with anti-VEGF, dual-immune checkpoint blockade, or even combination with tyrosine kinase inhibitors produces early and durable responses across several studies. And of course, we observe the patients who have a radiographic response to treatment are more likely to have a sustained benefit to treatment. And so in this context the stage is set for sporing triplet regimens in this context of new checkpoint blockade in combination with tyrosine kinase inhibitors and anti-VEGF therapy. But of course, increasing treatment comes with increasing toxicity. And in particular, combined inhibition of both PD-1 and CTLA-4 can lead to an increase in immune-related adverse events as compared to anti-PD-1 therapy alone. And of course, the severity of immune-related adverse events is more associated with the delta CTLA-4 inhibition than PD-1 inhibition. And so in this context, the compound discussed in the study presented by Dr. Shu and colleagues is a compound which is a bifunctional antibody, the compound QL1706. So it's a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1, produced together in a fixed ratio of 2:1. Importantly, the anti-CTLA-4 antibodies engineered have a shorter elimination half-life, thereby reducing its exposure and potentially lowering the risk of immune-related adverse events. And this makes it attractive for combining with other agents. The study that was presented here was an adaptive open-label, phase II/III study, and a phase II component is what we saw presented. It was essentially an adaptive study design that facilitates arm selection based on surrogate endpoints showing early efficacy signal, and also facilitates combination of data from the phase II component with data from the phase III component. This study enrolled 120 patients with locally advanced or metastatic HCC across four arms, a control arm of sintilimab and bevacizumab, QL1706 plus chemotherapy, that's with CAPOX chemotherapy, QL1706 with CAPOX and bevacizumab, and one arm of QL1706 and bevacizumab alone. Importantly, within this patient population, almost 30% were intermediate stage and the majority had Child Pugh A disease. So well-preserved liver function, perhaps not reflecting the population that we see outside of China in Europe or in the United States with underlying cirrhosis and coexisting liver disease in medical conditions. Looking at the initial activity results that were presented at ESMO, we see numerically higher response rate and all the QL1706 containing arms with early responses compared to control and response rate approaching 35, 36% in those arms compared to 20% in the control arm. Also, numerically higher median progression-free survival, and six-month progression-free survival in the QL1706 containing arms, small numbers of course, but overall the cross-trial comparison to other first-line residents showed encouraging response rates and PFS data in the QL1706 containing data. Treatment related AEs were similar in all arms, perhaps more treatment delayed in the QL1706 containing arms, but we didn't see presented were results of immune-related adverse events and the frequency of those. So we're not sure yet as a signal or reduced toxicity using this antibody bifunctional antibody as compared to a new checkpoint inhibitor blockade. So overall, in summary, I would say we see from the QL1706 compound. Evaluating this phase two study, we see encouraging response rate and median progression-free survival in all QL1706-containing arms. Based on improvement in six-month progression-free survival and disease control rate, the investigators chose the arm containing chemotherapy with bevacizumab and QL1706, to move forward to evaluation versus control arm in a phase three randomized study. It is unclear how relevant these results may be to a patient population with more underlying liver dysfunction. Also, unclear that chemotherapy is required or warranted in this setting, and certainly our ability of majority of our patients to tolerate chemotherapy in a triplet regimen certainly may be questionable in this setting. However, as a move toward evaluating triplet combinations in this context, it's certainly possible that bifunctional antibodies may facilitate this with less toxicity.