ILCA Symposium 3: Novel Opportunities of Treatment in HCC
Chairs: Josep M. Llovet, MD (Spain/USA) and Riccardo Lencioni, MD (Italy)
Current Phase I and II with Systemic Drugs
Ronnie Poon, MD, PhD (China)
Novel Approaches for Interventional Treatment
Riccardo Lencioni, MD (Italy)
Interventional treatments play a key role in the management of hepatocellular carcinoma (HCC). Image-guided radiofrequency ablation (RFA) is recommended in patients with early-stage HCC when surgical options are precluded. Novel thermal and non-thermal techniques for tumour ablation – including microwave ablation and irreversible electroporation – seem to be able to overcome the limitations of RFA and warrant further clinical investigation. The development of lysolipid thermally sensitive liposomes, a unique technology with a novel mechanism of action that delivers high concentrations of drug in a region targeted with the application of localised heat, is being studied in combination with heat-based local treatments with the goal to expand the effective treatment zone. Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage HCC. Embolic, drug-eluting microspheres seem to offer advantages over conventional regimens owing to the ability to release the drug in a controlled and sustained fashion. The available data for radioembolization with yttrium-90 suggests that this is a potential new option for patients with HCC that should be investigated in the setting of randomised trials. Despite the advances and refinements in loco-regional approaches, the long-term survival of patients managed with interventional techniques is not fully satisfactory, mainly because of the high rates of tumour recurrence. The recent addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between loco-regional and systemic treatments. The outcomes of these trials are eagerly awaited, as they have the potential to revolutionise the treatment of HCC.
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+).
Targeted Therapies: What Can we Learn from Other Cancers?
Jean-Luc Raoul, MD, PhD (France)
The demonstration of efficacy of trastuzumab in breast cancer and of imatinib in GIST more than 20 years ago was the first signal of a new revolution confirming that same pathological neoplasms can be extremely different molecularly. Currently these progresses are particularly obvious in breast, lung, colon cancers and melanoma. In breast cancers, previous therapeutic algorithms have been changed and are based exclusively on tumour expression of hormones and of HER2. In non small cell lung cancers, cancers with EGFR mutations (15% of the cases) and ALK translocations (5% of the cases) respond to EGFR TKIs (gefitinib and erlotinib) or to ALK TKI (crizotinib) and it is expected that in the near future most (?) of these patients can have a specific therapy guided by tumour genotyping. In advanced melanoma, activating mutation in BRAF are present in about 50% of the cases and in such cases the use of BRAF inhibitor improves outcome. In metastatic colorectal cancers, targeting EGFR in KRAS wt patients significantly improves response rate and survival. Currently some trials are comparing therapy based on tumour molecular profiling vs. conventional treatment in all solid tumours refractory to usual treatments. This new generation of biopsy-driven clinical trials will require the development early phases focused on the development of predictive biomarkers. In parallel another major progress is represented by non-invasive liquid biopsy allowing to study genomic evolution before and under treatment by sequencing tumour DNA into plasma. Preliminary results have shown that increase in plasma of mutant alleles is associated with emergence of therapy resistances, likely due to expansion of a resistant subclone.