LBA4 - Low-dose stereotactic body radiotherapy prior to pre-operative cemiplimab for patients with resectable hepatocellular carcinoma

Background

Immune checkpoint inhibitors (ICIs) are the standard of care for advanced hepatocellular carcinoma (HCC). Small trials in HCC and other tumours have evaluated the addition of stereotactic body radiotherapy (SBRT) to induce immunogenic cell death and augment ICI activity. Early-stage HCC is often surgically resected but recurrence occurs in ∼70% of patients. We previously presented the first study of perioperative ICI using cemiplimab in resectable HCC and showed ≥50% necrosis in 35% of patients after 2 doses of cemiplimab. Here we present the first trial to investigate low-dose SBRT prior to ICIs in patients with early-stage HCC.

Methods

In this single-arm, open-label phase 2 trial (NCT03916627), adults with resectable HCC tumours received SBRT (8Gy x3 fractions), then 2 cycles of neoadjuvant cemiplimab 350 mg every 3 weeks before surgical resection and 8 cycles of adjuvant cemiplimab. The primary endpoint was significant tumour necrosis (STN; >70% necrosis of the resected tumour). Secondary endpoints included overall response rate, incidence of adverse events (AEs) and change in lymphocyte infiltration. Patients had pre-treatment biopsies and serial blood collection during treatment for exploratory analyses, including multiplex immunohistochemistry and single-cell proteomic and transcriptomic analysis. Data cutoff was 15 Sep 2023; surgical results obtained from 1 patient after the data cutoff are included.

Results

20 patients were enrolled from Dec 2021 to Aug 2023: median age was 65 years, 80% were male, 50% were Asian, and 85% had a history of viral hepatitis. Of 16 patients who underwent surgical resection 3 (19%) achieved STN, 2 (13%) of which had complete tumour necrosis; in total, 6 (38%) had ≥50% tumour necrosis. Most common AEs were anaemia (35%), elevated transaminases (30%) and hyperglycemia (30%). No Grade ≥3 treatment-related AEs occurred during neoadjuvant therapy.

Conclusions

This is the first clinical trial to report efficacy of SBRT + ICIs in patients with resectable HCC. Pathologic response rates were similar to those observed with cemiplimab alone. Planned deep tissue and blood analyses will be used to define the immunodynamic effects of this combination compared to cemiplimab alone.

Clinical trial identification

NCT03916627.

Editorial acknowledgement

Editorial writing support was provided by Jenna Lee, MSc, of Prime, Knutsford, UK.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

T.U. Marron: Financial Interests, Personal, Advisory Board: Rockefeller University, Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, Glenmark, Simcere, Surface, NGMbio, DBV Technologies, Arcus, Astellas; Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, Merck, Boehringer Ingelheim. P. Tabrizian: Financial Interests, Personal, Advisory Board: Bayer, AstraZeneca, Boston scientific. B. Taouli: Financial Interests, Personal, Research Funding: Bayer, Guerbet, Takeda, Regeneron Pharmaceuticals, Inc., Helio Genomics, Siemens, Echosens; Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer, Guerbet, Ascelia, WorldCare Clinical. E. Kim: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Eisai-Merck, Boston Scientific, Ethicon. K. Garcia-Reyes: Financial Interests, Personal, Advisory Board: Boston Scientific, Cook Medical, TeleFlex, AstraZeneca, Neuwave. M.I. Fiel: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck Pharmaceuticals. S. Ward: Financial Interests, Personal, Other, Salary support from a grant: Boehringer Ingelheim, Ltd; Financial Interests, Personal, Other, Part of a research consensus panel: AstraZeneca. P. Thanigaimani,Y. Hao, I. Lowy, E.A. Miller, T.S. Uldrick: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Merad: Financial Interests, Personal, Advisory Board: Compugen, Myeloid Therapeutics, Morphic Therapeutic, Asher Bio, Dren Bio, Nirogy, Oncoresponse, Owkin, Larkspur, Pionyr, OSE, Genenta; Financial Interests, Institutional, Funding: Regeneron, Boehringer Ingelheim. All other authors have declared no conflicts of interest.