Ablation Reboots the Response in Advanced Hepatocellular Carcinoma With Stable or Atypical Response During PD-1 Therapy: A Proof-of-Concept Study

Abstract

Background: The anti-programmed cell death protein-1 (PD-1) inhibitor is one of the second-line therapies for advanced hepatocellular carcinoma (HCC) after sorafenib failure. The goal of this study is to evaluate the feasibility and safety of ablation on the tumor in patients with advanced HCC who had stable disease or atypical response during single anti-PD-1 therapy after sorafenib failure. Atypical response defined as mixed responses in different lesions of the same individual (e.g., active or stable lesions mixed with progressive lesions). Patients and Methods: This proof-of-concept clinical trial enrolled 50 patients treated with an anti-PD-1 inhibitor of nivolumab or pembrolizumab monotherapy between July 2015 and Nov 2017. Thirty-three cases with stable disease or atypical response to anti-PD-1 inhibitor received subtotal thermal ablation. The safety and the response of ablation during anti-PD-1 therapy were evaluated. The survival was estimated by the Kaplan-Meier curve. Results: Of all 50 patients treated with anti-PD-1 therapy, the rate of response, stable disease, atypical and typical progression were 10% (n = 5), 42% (n = 21) 32% (n = 16), and 12% (n = 6), respectively. Additional ablation improved efficacy with tolerable toxicity, and the response rate was increased from 10 to 24% (12/50). The median time to progression, progression-free survival, and overall survival was 6.1 months (95%CI, 2.6-11.2), 5 months (95%CI, 2.9-7.1), and 16.9 months (95%CI, 7.7-26.1), respectively. Conclusions: This proof-of-concept trial suggested that additional ablation may increase the objective response rate with tolerated toxicity and achieved a relatively better median survival, in advanced HCC patients who had stable or atypical progressive diseases during anti-PD-1 therapy, which may provide a potentially promising strategy to treat advanced HCC. Trial registration number: ClinicalTrials.gov identifier: NCT03939975.

Keywords: anti-PD-1 mAbs; hepatocellular carcinoma; nivolumab; pembrolizumab; thermal ablation.

Copyright © 2020 Lyu, Kong, Li, Mu, Deng, Chen, He, Lai, Li, Tang, Lin and Zhao.

Figures

Figure 1

Study profile flow. CR, complete response; HCC, hepatocellular carcinoma; PD-1, programmed cell death protein-1; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2

Swimmer's plot shows the time of response, time of ablation, the survival of patients treated with an anti-PD-1 inhibitor in the combination of thermal ablation or anti-PD-1 monotherapy, post-discontinuation of anti-PD-1 treatment survival, and current status. Assessed in a total of 50 patients. PD-1, programmed cell death protein-1.

Figure 3

Data of a participant treated with an anti-PD-1 inhibitor in the combination of subtotal thermal ablation. The patient had a diagnosis of recurrent intrahepatic tumors with tumor thrombus invading both inferior vena cava and right atrium, and multiple lung metastases. After receiving 14.3 weeks of anti-PD-1 inhibitor of pembrolizumab, an atypical progression was assessed on image examination on October 8, 2016 (time of 0) as that intrahepatic tumors (Lesion 1, 2, and 3; yellow arrow), vascular invasions (no showing), and part of the lung lesions progressed (a representative example as Lesion 4; yellow arrow), but the other part of lung metastases (representative examples as Lesion 5, 6, and 7; yellow arrow) regressed. Two progressive lesions (Lesion 1 and Lesion 2) in the liver was selected for subtotal thermal ablation (red arrows), and consequently, the leaving intrahepatic tumor (Lesion 3) disappeared, and all the lung metastases regressed due to the combination of pembrolizumab and ablation therapy. Stable disease was recorded on December 1, 2016 (7.7 weeks), and a partial response was achieved on June 14, 2017 (35.6 weeks). Pembrolizumab infusion was lasted for 17.8 months and discontinued because of more than 12 months of ongoing disease control. At last follow-up, the patient was still alive with a progression-free survival of 21.4 months and overall survival of 32.6 months. (A) The Images of seven lesions at baseline, response assessment to anti-PD-1 monotherapy, ablation procedure, and post-ablation assessment. (B) Dynamic changes in the size of the seven lesions before and after thermal ablation (red lighting). (C) The dynamic curve of the serum AFP level before and after thermal ablation (red lighting). AFP, alfa-fetoprotein; PD-1, programmed cell death protein-1.

Figure 4

Clinical events of a participant who treated with a continuous anti-PD-1 inhibitor of pembrolizumab in the combination of multiple sessions of thermal ablation. The patient was enrolled due to progressive lung metastases to sorafenib and had an atypical response (stable lesions with progressive lesions) to pembrolizumab monotherapy after 6 months of anti-PD-1 inhibitor initiated. Then the first subtotal ablation (red lighting) was performed, and the size of two targeted lesions (Lesion 1 and 2) shrunk obviously after 2.5 months of ablation. The duration of response of Lesion 1 and Lesion 2 since the first ablation was 14.9 months and 23.8 months, respectively. Lesion 1 (yellow lighting) and Lesion 2 (blue lighting) were ultimately ablated due to tumor progression. The fourth session of ablation (green lighting) was done for a new tumor (Lesion 3), which occurred at 28.6 months from baseline. A total of 33 doses of pembrolizumab was infused with a duration of 32.4 months. At date cutoff, the patient had a complete response to anti-PD-1 inhibitor in the combination of ablation, with a level of serum alfa-fetoprotein in the normal range, and progression-free survival of 41.6 months. (A) The middle panel shows the timeline of treatments, including pembrolizumab (black rhombus) and ablation (lightning). Upper panels show CT images of three representative lesions at baseline, course of treatment, and last follow-up since initiation of the pembrolizumab. The lower panel shows CT images of the four sessions of ablation. CR, complete response; PD-1, programmed cell death protein-1; PD, progressive disease; PR, partial response; SD, stable disease. (B) The dynamic curve of the serum AFP level. AFP, alfa-fetoprotein.