750PA phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL

Abstract Background The efficacy of TACE is secondary to its dual ischaemic and cytotoxic effect, which promotes immunogenic tumor cell death. TACE may prime adaptive immunity and facilitate pembrolizumab (pembro; anti-PD1) in promoting tumour immune rejection and improve outcome in HCC. We designed this phase Ib study to evaluate safety, preliminary activity of TACE+pembrolizumab and explore mechanisms of efficacy. Methods Up to 32 patients (pts) with intermediate-stage HCC were planned to receive up to 2 rounds of conventional TACE followed by pembro 200mg q3w 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety with dose-limiting toxicities emerging from the combination being evaluated over a 21-days window from commencement of pembro. Secondary endpoints included PFS rates q12w. We explored tumour and host determinants of response in tissue, blood and stool samples to confirm the bioactivity of the combination. Results In cohort 1 (n=6) patients were all of BCLC-B stage, 83% males, 16% HCV-positive, 50% ECOG PS 0, median age 62 years. Child-Pugh (CP) was A in 5 and B7 in 1pt. Median tumour size was 4cm, and median number of lesions was 2. All-grade adverse events potentially related to treatment (tx) occurred in 50% of pts including diarrhoea (n=1, G3), skin rash (n=2, G2), infusion reaction (n=1, G2) and adrenal insufficiency (n=1, G2). Pembro yielded no synergistic toxicity with TACE and no DLTs were reported. At data cut-off, tx was ongoing for 3 pts with a median duration of tx of 2.8 months. Of the 4 radiologically evaluable patients, 3 had stable disease on pembro, 1 had progressive disease. Cause of withdrawal included disease progression/death (n=2) and worsening liver failure in the CP B7pt, non tx-related (n=1). Updated data from an expanded pt cohort will be shown and efficacy data will be correlated with T-cell responses to recognized tumor-associated antigens, tumour-infiltrating lymphocyte profiling and stool bacterial metagenomics. Conclusions The TACE+pembro combination had a tolerable safety profile with no evidence of synergistic toxicity. Alongside emerging efficacy data, this encourages the clinical development of the combination in CP A pts. Clinical trial identification NCT03397654. Legal entity responsible for the study Imperial College London. Funding Merck Sharp & Dohme. Disclosure D.J. Pinato: Research grant / Funding (self), Funder of the clinical study presented: MSD; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): ViiV Healthcare; Honoraria (self), Travel / Accommodation / Expenses: Bayer. All other authors have declared no conflicts of interest.