Is TGF-β the New Kid on the Block for Nexavar Failures? Or is it More of the Same?

Clinically speaking, hepatocellular carcinoma (HCC) is a particularly challenging disease. Surgery remains the only curative strategy for patients with HCC, however not all patients are eligible for surgery. The approval of Nexavar® (sorafenib, Bayer/Onyx/Amgen) revolutionized HCC, providing a targeted therapy option for patients with HCC and an advance over de facto standard doxorubicin. The enthusiasm for Nexavar is dampened by the fact that not all patients may be eligible for Nexavar treatment due to poor liver function, and options remain limited for patients whose disease progresses. Since the introduction of Nexavar, other targeted therapies have attempted to carve a place in the HCC treatment landscape, either as frontline agents or in the relapsed setting, only to be met with failure.

Recent pivotal trial failures include: Sutent® (sunitinib, Pfizer) in comparison with Nexavar in first-line;1 brivanib compared with Nexavar in first-line2 and in Nexavar-refractory patients;3 and most recently Afinitor® (everolimus, Novartis) failed to demonstrate efficacy in Nexavar-refractory HCC patients.4 Despite multiple failures, there is a long list of agents that are currently in active clinical development either in Phase II or Phase III trials, with most agents aiming for the Nexavar-refractory population. Agents currently in pivotal trials in Nexavar-refractory patients include ADI-PEG20 (Polaris Group), Cometriq® (cabozantinib, Exelixis), ramucirumab (Eli Lilly), and Stivarga® (regorafenib, Onyx/Amgen), as well as tivantinib (Arqule/Daiichi Sankyo) that is being studied in a subpopulation of patients with MET overexpression.

Into this matrix enters LY2157299, a novel transforming growth factor-beta receptor 1 (TGF-β1) kinase inhibitor that Eli Lily is developing in HCC. Elevated TGF-β1signaling promotes liver fibrosis and progression to HCC; hence targeting TGF-β signaling has been proposed as a unique approach in HCC treatment. While limited data is available with LY2157299, this agent prevented HCC cancer cell migration on extracellular matrix substrates in cell culture studies.5 Given the potential importance of this pathway in HCC and some preliminary evidence that inhibition of this pathway can inhibit certain processes in HCC, Eli Lilly is evaluating this compound in an ongoing Phase II study. The trial is evaluating LY2157299 in patients ineligible for Nexavar therapy or who have progressed on Nexavar. While the trial is still recruiting, interim results were presented6 at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium on Friday, January 17, 2014. The study accrued 109 patients who were randomized to two arms: Arm A LY2157299 at 160 mg/day and Arm B LY2157299 at 300 mg/day. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β, and e-cadherin). Serum AFP was used as a surrogate marker for clinical efficacy and patients in whom AFP levels decreased greater than 20% compared to baseline were considered “AFP responders.” Of the eligible patients accrued, about 80% were Nexavar-pretreated and 50% had AFP levels greater than 400 ng/ml at baseline. The median TTP was 12.0 weeks in Nexavar-refractory patients (90% CI: 6.6-12.6) and 18.3 weeks in Nexavar-naïve patients (90% CI: 6.6-42.4). About one-quarter of the patients achieved more than a 20% decrease in AFP levels and were categorized as AFP-responders. The drug was very well-tolerated, with the most common grade 3/4 toxicities being neutropenia (2.7%) and fatigue (1.8%). Perhaps the most exciting piece of data from this study was the increase in median OS in the AFP responder population compared to AFP-non-responders (93.1 weeks versus 29.6 weeks; p=0.00006). In contrast, median OS in the entire population was 8.3 mos (36 weeks). Given that Nexavar achieves an OS of about 10 months and given that not all patients can tolerate Nexavar, this appears to be a niche positioning opportunity for Eli Lilly.

Although this study is very promising, there are a couple of caveats. Key amongst them is the use of AFP as a biomarker. Decreases in AFP levels have been shown to be clinically useful in monitoring tumor response in HCC patients; however, AFP detection is also known to be a poorly reliable marker, particularly in small tumors.7 This may present a challenge in metastatic disease or on small tumors that progress very slowly. Whether AFP is the most appropriate biomarker to use in this context and whether this is an appropriate biomarker to support approval down the line is not known – all biomarkers approved to-date focus on patient selection based on baseline presence of the biomarker; this would pave new ground as a biomarker of response post-therapy, and perhaps would be more useful in guiding decisions of whether to continue treating patients with the drug as opposed to guiding decisions of whether to initiate therapy with the drug. In addition, whether the inhibitor is truly inhibiting the TGF-βpathway is not known, as downstream targets such as phosphor-Smads have not yet been evaluated. The phosphorylation of Smad protein plays an important role in TGF-β signaling and activates a nuclear transduction protein.

So where does LY2157299 stand in terms of novel agents in HCC? Clearly, it is too early to determine how this compound will fit into the overall picture of HCC therapy. The table below provides a preview of the clinical efficacy of LY2157299 in comparison to the key agents in development in Nexavar-refractory patients.

Table 1: Efficacy Outcomes in Nexavar-pretreated HCC

In favor of LY2157299 are its manageable toxicity profile and the fact that it targets a novel pathway. However, the demonstrated efficacy benefit in the general population is not striking compared to the other agents currently in development in the same population. The OS and TTP observed with LY2157299 in AFP responders are particularly intriguing; however, whether the test is appropriate or whether AFP level is an appropriate marker for response remains a concern. While the study is promising, we will have to wait until the data mature and see how this plays out in a larger Phase III trial.


  1. Cheng et. al., J Clin Oncol,. 31(32): 4067-4075, 2013
  2. Johnson et al., J Clin Oncol, 31(28): 3517-3524, 2013.
  3. Llovet et. al., J Clin Oncol,31(28):3509-16, 2013.
  4. Zhu et al.. Abstract 172, ASCO GI 2014.
  5. Duturi et. al. PLOS One 27;8(6):e67109 2013
  6. Faivre, Abstract LBA 173, ASCO GI 2014
  7. Farinati et. al., Am J Gastroenterol, 101(3):524-32, 2006
  8. Bruix et al., Eur J Canc, 49(16): 3412-3419, 2013
  9. Verslype, Abstract 4007, ASCO 2012

By Neesha Suvarna, PhD, Consultant, Kantar Health and Len Kusdra, Analyst, Kantar Health

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