Anthony El-Khoueiry, MD, Norris Comprehensive Cancer Center at University of Southern California, Los Angeles, California, discusses the results of the phase 2 study evaluating the activity of regorafenib plus pembrolizumab among patient with advanced hepatocellular carcinoma who had progressed on 1 prior immune checkpoint inhibitor regimen.

This combination showed modest activity in this patient population, and, Dr El-Khoueiry stated, “The standard and second-line regiment continues to be an unmet need, and additional studies are needed.”

Transcript:

Hi, I’m Anthony El-Khoueiry. I’m an Associate Professor of Medicine at the USC Norris Comprehensive Cancer Center.

I’m happy to share with you the results of the phase two study of pembrolizumab and regorafenib in advanced [hepatocellular carcinoma] HCC patients who have received prior immunotherapy. The importance of this abstract that I’ve presented at ASCO 2024 is that it is exploring second-line treatment in HCC after first-line immunotherapy. As we all know, the standard-of-care treatment in the first line includes immunotherapy combinations such as atezolizumab-bevacizumab or durvalumab-tremelimumab.

The second-line treatment has remained largely empiric, and we have been using tyrosine kinase inhibitors that had been previously evaluated either as first-line treatments and were displaced now to second line or as second-line treatments post-sorafenib. There is really an unmet need to develop prospective data. Based on the immunomodulatory effect of regorafenib, we had performed a phase 1b study of pembrolizumab and regorafenib in first-line HCC and observed a response rate of 31%.

This study again is looking at that same combination of pembrolizumab-regorafenib but in the second line. It was a prospective phase 2 study across 8 countries. The primary objective was response rate that’s centrally assessed. The design had 2 cohorts: cohort 1 consisted of patients who received atezolizumab-bevacizumab as their first-line treatment, and cohort 2 patients had received any prior immunotherapy combination or single-agent immune checkpoint inhibitor, but not a atezolizumab-bevacizumab. 

The target response rate was 35% with an assumed historical response rate of 20%. The study had a pilot phase and then an expansion phase. In the pilot, if we observed 8 or more responses out of 26, we would proceed to the expansion phase. Now, the target response rate was not reached, the assumptions were not reached, but the accrual still went on. We didn’t hold accrual for the interim analysis. That’s why you see 68 patients were recruited to cohort 1 and 27 patients to cohort 2.

Now, on to the results. What did we see? The objective response rate by RECIST v1.1 in cohort 1, which is post–atezolizumab-bevacizumab, was 5.9%, so almost 6%. And in cohort 2, which is post any [immunotherapy] IO, a single agent or combination, it was 11%. Incidentally, in cohort 2, 8 out of the 27 patients had received single-agent immune checkpoint inhibitor as their first-line therapy. The disease control rate in cohort 1, post–atezolizumab-bevacizumab was 54%, and in cohort 2 was 74%. The PFS in cohort 1 was 2.8 months and in cohort 2 was 4 months.

At first look you may think, okay, so in cohort 2 patients seem to be doing a bit better, but 2 things to be cautious about: one, the cohorts were not designed to be compared to each other. Second, when we look at the baseline characteristics, in cohort 2, there were more patients with ECOG 0, more patients with BCLC stage B, and fewer patients with extra-hepatic metastases or macrovascular invasion. So, generally a more favorable patient population. 

As far as safety, there were no new safety signals. It is what we expect to see with pembrolizumab or regorafenib or the combination as it was previously investigated. The incidence of immune-related adverse events was 22%, even though these patients had already received prior immunotherapy and continued on pembrolizumab. This is as far as the clinical part of the study. 

We had an extensive biomarker plan that included tissue and blood. In this presentation, we focused on 4 paired biopsy samples, so pre- and on-treatment biopsy samples, all were from non-responders, but some intriguing things emerged. When we look at biomarkers related to regorafenib, in the 4 biopsy samples, we see a decrease in macrophage expression by looking at CD163, which is a marker of suppressive macrophages like M2 macrophages, and we see a decrease in angiogenesis signatures — the expected effects of regorafenib. In contrast, we did not see signs of T-cell activation. We did not see an increase in interferon signature or in CXCL10. Also, the combination did not alter the [regulatory T-cells] Tregs or the T-[cell] exhaustion signature in these patients. To put that in context, in the atezolizumab-bevacizumab phase 1b study, which was immunotherapy-naïve patients, there was a decrease in Tregs in responders versus non-responders.

Lastly, we did an exploratory analysis, where we looked at the baseline immune microenvironment of patients from this current study, which is post-IO, and looked at the patients who had gotten pembrolizumab-regorafenib as first-line therapy who were treatment-naïve. And it became clear, comparing across these 2 studies, that in our current trial, which is post-IO, there was up-regulation of T-regulatory lymphocytes and T-cell exhaustion signature was more prominent, indicative again of an immune-suppressive environment. These things have been associated with immune checkpoint inhibitor resistance. Even though it’s an exploratory analysis, it’s quite intriguing and worthwhile of a further follow-up.

In short at this point, the combination of PD-1TKI with pembrolizumab-regorafenib had modest activity after first-line immunotherapy in HCC. The standard treatment in the second line continues to be an unmet need and additional studies are needed. Thank you.

Source:

El-Khoueiry, Kim T-Y, Blank J-F, et al. International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI). Presented at the 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL. Abstract #4007