Dual Checkpoint Blockade/Ablation Regimens Show Intriguing Activity in Advanced HCC

Rebecca Wetzel, DO

Combining durvalumab (Imfinzi) and tremelimumab plus transcatheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) was found to be both efficacious and safe as a treatment for patients with advanced hepatocellular carcinoma (HCC), according to results of a pilot study presented during the 2021 International Liver Cancer Association Conference.¹

Results showed that the median progression-free survival (PFS) and overall survival (OS) with TACE plus the PD-L1/CTLA-4–inhibitor regimen was 7.4 months and 20.5 months, respectively. For those treated with RFA plus immunotherapy, the median PFS was 4.3 months and the median OS was 16.5 months.

For those who received the combination of durvalumab/tremelimumab and ablation, the median PFS was 4.4 months and the median OS was 13.6 months. The median PFS and OS was 4.9 months and 19.2 months, respectively, for patients who received combination immunotherapy alone.

“This data demonstrates safety and efficacy of combined checkpoint inhibition in patients with advanced hepatocellular carcinoma,” Rebecca Wetzel, DO, a hematology oncology attending at Walter Reed National Military Medical Center, said in a virtual presentation during the meeting. “The addition of ablative therapies may improve patient outcomes, and may represent a therapeutic approach for patients unable to receive a [VEGF] inhibitor.”

Checkpoint inhibitors have demonstrated encouraging outcomes in HCC, and improved efficacy with single-agent PD-1/PD-L1 inhibitors by augmenting immune responses through ablative procedures. However, the impact of the ablation modalities, TACE or RFA, in combination with dual checkpoint inhibitors durvalumab and tremelimumab has not been evaluated.

In the pilot study, investigators enrolled 30 patients with advanced or unresectable HCC who progressed on, refused, or were intolerant to sorafenib (Nexavar). Patients needed to have disease that was deemed technically amenable to TACE or RFA, with at least 2 measurable lesions; other requirements included a Child Pugh score of A/B7 if liver cirrhosis was present, Barcelona Clinic Liver Cancer (BCLC) stage B or C, and an ECOG performance status of 0 or 1.

Tremelimumab was given intravenously (IV) at 75 mg on day 1 every 4 weeks for 4 doses, and durvalumab was administered intravenously at 1500 mg on day 1 for 4 weeks until progressive disease. TACE or RFA was given on day 36.

The primary end point was 6-month progression-free survival (PFS) rate; secondary outcome measures were safety and feasibility of the combination regimen.

The median age was 64 years (range, 19-81) and 57% of patients had locally advanced disease. Seventy-three percent had BCLC stage C disease, 53% had hepatitis C, and 17% had hepatitis B. Thirty percent of patients were treated with sorafenib; 86% of patients had BCLC stage C disease and planned for RFA and 71% had BCLC stage C disease and planned for TACE.

Nine patients received immunotherapy alone, 21 were assigned to TACE or RFA; 7 patients each were treated with TACE plus durvalumab/tremelimumab and RFA plus the immunotherapy combination.

Regarding safety, grade 3/4 adverse events were reported in the forms of lymphopenia (43%), increased aspartate aminotransferase (43%), increased amylase (33%), and anemia (30%).

Investigators concluded that the addition of ablative therapies may improve patient outcomes, and the combination could represent a therapeutic option for those with HCC who have a contraindication to VEGF inhibition.

Further studies are necessary to identify patient subsets who are most likely to respond to these interventions, they added.

Another immunotherapy combination is currently indicated in the frontline setting for patients with advanced HCC. In May 2020, the FDA approved the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for patients with unresectable or metastatic HCC who have not received prior systemic therapy based on primary findings from IMbrave150 study. Here, results showed that the regimen led to reductions in the risk of disease progression or death (HR, 0.59) and death (HR, 0.58).²

References

1. Wetzel R, Monge C, Xie C, et al. A pilot study of the combination of immune checkpoint inhibition with ablation in subjects with hepatocellular carcinoma; an evaluation of trans-arterial chemoembolization (TACE) and radiofrequency ablation (RFA). Presented at: 2021 International Liver Cancer Association Conference; September 2-5, 2021; virtual. Abstract P36.
2. FDA Approves Genentech’s Tecentriq in Combination With Avastin for People With the Most Common Form of Liver Cancer. Published May 29, 2020. https://bit.ly/2Aneztc. Accessed September 3, 2021.