START-FIT: TACE + RT + avelumab promising as conversion therapy for locally advanced unresectable HCC

START-FIT, a prospective, single-arm, phase II trial, has found sequential transarterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT) followed by anti–PD-L1 treatment with avelumab to be a promising strategy for making patients with locally advanced unresectable hepatocellular carcinoma (HCC) amenable to curative treatment.

According to the latest Hong Kong Cancer Registry data, approximately 1,700 new cases of HCC are diagnosed in the territory every year. [https://www3.ha.org.hk/cancereg/topten.html] While surgical resection with or without liver transplantation represents a curative treatment option for early-stage disease, only 20–40 percent of newly diagnosed HCC patients are eligible for surgery. [Curr Oncol 2022;29:8802-8813] The START-FIT research team focused on the remaining majority of inoperable cases in the hope of developing a new treatment strategy that would improve their chances of cure.

The trial enrolled 33 adult patients (male, 97 percent) with locally advanced HCC not suitable for curative treatment from two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, a Child-Pugh liver function score of A5–B7, tumour size of ≥5 cm, a maximum of three tumour lesions, and adequate hepatic, renal and bone marrow functions. Participants received TACE on day 1, followed by SBRT (27.5–40.0 Gy in five fractions) on day 28, while avelumab (10 mg/kg) was administered 14 days after SBRT and every 2 weeks thereafter. [Lancet Gastroenterol Hepatol 2023;8:169-178]

The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial response for ≥2 months and could undergo curative treatment (ie, resection, radiofrequency ablation, or transplantation), as analyzed by intention to treat.

At a median follow-up of 17.2 months, 18 patients (55 percent) were deemed amenable to curative treatment. Of these, four patients received curative treatment (resection or radiofrequency ablation), and 14 patients had a radiological complete response and opted for close surveillance.

A third of patients in the trial experienced grade ≥3 treatment-related adverse events (TRAEs). The most common grade ≥3 TRAE were transient increases in alanine aminotransferase or aspartate aminotransferase following TACE, which occurred in 5 patients (15 percent). Five patients developed grade ≥3 immune-related adverse events, namely, hepatitis in three patients and dermatitis in two patients.

“To our knowledge, START-FIT is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable HCC, and it yielded promising results,” wrote the researchers.

“The approach we used involves three modalities and provides a definite treatment schedule. Most patients should have an idea of treatment efficacy within 6 months of starting it, enabling better planning for themselves and their family,” said START-FIT study lead, Professor Albert Chan of the Department of Surgery, University of Hong Kong. “Now the team is looking forward to expanding treatment coverage to more patients, especially those with poor liver function, to help shrink the tumour and thus increase their chances of satisfying the criteria for liver transplantation. We are also seeking ways to improve the efficacy of immunotherapy, from single agent to double agents, in order to enhance treatment results.”