Rachna T. Shroff, MD, MS, FASCO on Advanced Hepatocellular Carcinoma: Anlotinib Plus Penpulimab vs Sorafenib

I'm excited to discuss the results from the phase III APOLLO Study that was presented this year in Barcelona at ESMO 2024. This was a study done entirely in China that looked at a combination of a tyrosine kinase inhibitor with an anti-PD1 agent in hepatocellular carcinoma. We know that liver cancer is a very common cause of cancer globally, and in China in particular, half of the prevalence of mortality is associated with hepatitis B infection. So this study looked at penpulimab, which is a humanized anti-PD1 monoclonal antibody, in combination with anlotinib, which is a multi-targeting tyrosine kinase inhibitor that affects VEGF as well as PDGFR, FGFR and CKIP. Primary studies done initially looked at anlotinib alone in HCC and demonstrated some efficacy, and so this combination of anlotinib and penpulimab was investigated in this large randomized phase III trial against sorafenib in newly diagnosed advanced hepatocellular carcinoma. The study involved 648 patients randomized two-to-one to receive the VEGF tyrosine kinase inhibitor and anti-PD1 agents versus sorafenib in the standard dosing. This is primarily for the typical things that we see with HCC, advanced disease, BCLC stage B and Child Pugh Class A, but even including up to B, less than or equal to seven. Patients were stratified for things like macrovascular invasion and extra hepatic spread as well as AFP level, and there was dual primary endpoints of progression-free survival by RECIST and overall survival. The study was enrolled quickly and as I mentioned, entirely in China with 433 patients in the investigational arm versus 216 patients in the sorafenib arm. Importantly, 84.3% of patients with the investigational arm, in addition to 83.8% of patients with the sorafenib arm, had cirrhosis related to a hepatitis B etiology. There was a small percentage that had hepatitis C as well. When you look at the primary end point, the primary end point was statistically improved progression-free survival with a median PFS with anlotinib and penpulimab of 6.9 months versus 2.8 months with sorafenib with a hazard ratio of 0.3. Similarly, the overall survival dual primary end point had an improvement in median OS of 16.5 months with the investigational arm versus 13.2 months with sorafenib, again, with a statistically significant improvement and a hazard ratio of 0.69. The investigators, importantly, looked at a number of subgroup analyses and the forest plot demonstrated in general favorability of the TKI plus anti-PD1 combination in both PFS and overall survival. When we look at safety, importantly, treatment-related adverse events, grade 3 or greater, were relatively balanced between sorafenib and anlotinib and penpulimab with about 50% of patients having grade 3 or greater treatment-related adverse events. A smaller number of these treatment-emergent adverse events led to dose reductions in the TKI and anti-PD1, however. The most common treatment-related adverse events were really things focused on hypertension, for instance, but even that with the grade 3 or higher was really only 17% in the investigational arm. Then, of course, there were some hematologic toxicities as well. Importantly, and slightly surprisingly, there was not a significant incidence of immune-related adverse events with, literally, less than 5% seen in terms of the typical immune-mediated adverse events that we think of, including pneumonitis, enterocolitis, hypothyroidism, myositis and neuropathy. It's important to note that a number of patients went on to receive subsequent anti-cancer therapies in an investigational arm that was around 35.8% and closer to 45% in the sorafenib arm. A lot of these patients went on to receive anti-angiogenic treatments and PD-L1 inhibitors, which could, of course, obscure the median overall survival data. So the authors concluded that the APOLLO Study met its endpoints of improvements in median progression-free survival and overall survival with the combination of anlotinib and penpulimab, compared to sorafenib, and that it was a relatively well-tolerated agent. This is absolutely fair to say, and I think is an interesting study that combines the idea of dual therapy in HCC, which we have investigated for some time. But at least here in the United States, we have not seen benefits from the combination of tyrosine kinase inhibitors with anti-PD-1s with both the negative LEAP-002 study that looked at lenvatinib and pembrolizumab versus lenvatinib, and the COSMIC-312 study that looked at cabozantinib and atezolizumab versus sorafenib. Interestingly, however, the CARES-310 study, which again was done predominantly in Asia, compared camrelizumab and rivoceranib, again, another TKI and anti-PD1 versus sorafenib, and there, there was an impressive median overall survival of 22.1 months. So I think that this is absolutely an important study that was positive and that demonstrated the potential for combining a TKI and immunotherapy. Surprisingly, a little bit better tolerated, for instance, in terms of side effects than what we saw in CARES-310. But again, this is a study that was done entirely in China with a predominantly hepatitis B etiology population. So the generalizability of this and whether or not this is something that we will be able to implement more globally remains to be seen.