Revisiting Data from Phase III Trial Failures in HCC


Josep M. Llovet, MD (Spain/USA)

After the sorafenib approval, more than 300 clinical trials testing 60 novel compounds have been conducted in HCC patients. Few of these trials were aimed at regulatory approval, the so-called pivotal trials. Unfortunately all of them have failed to show survivals benefits. In the early stage seeting, the heat trial comparing radiofrequency vs radiofrequency+ doxorubicin missed the primary end-point survival. Similarly 4 drugs failed in first-line advanced HCC (sunitinib, brivanib, linifanib and erlotinib) or second-line after progression to sorafenib therapy (brivanib). In some cases, the trials were stopped due to futility or toxicity (sunitinib, linifanib) but in others the study did not reached the primary –end point for superiority (sorafenib+erlotinib vs sorafenib; brivanib vs placebo in 2nd line) or non-inferiority (brivanib vs sorafenib in first line). The reasons for failure are heterogeneous and include liver toxicity (leading to liver faliure), problems in trial design, and lack of efficacy. Nonetheless, a new wave of studies are coming and can eb classified in 2 types: ones targeting all comers (everolimus, ramucirumab or regorafenib vs placebo in 2n line) and others favoring trial selection based upon potential oncogenic addition (refametinib in Ras+ patients) or trial enrichment based on pathway activation (tivantinib in MET+).