Balancing Efficacy With Toxicity Among the Agents for HCC

Balancing Efficacy With Toxicity Among the Agents for HCC
Catherine Frenette, MD

Published Online:Nov 29, 2018

Catherine Frenette, MD: The 2 groups of lenvatinib [Lenvima] versus sorafenib [Nexavar] in the REFLECT trial were not stratified by AFP [alpha-fetoprotein] level. They were also not stratified by their underlying cause of liver disease. The patients in the lenvatinib group did have a slightly higher AFP than the patients in the sorafenib group. This may actually have resulted in a favorable imbalance in the positive for sorafenib. Additionally, hepatitis C patients were more frequent in the sorafenib group as compared with the lenvatinib group. This may have given a benefit to sorafenib. The reason for this discussion is that we recall, in the SHARP trial, when they broke out a subgroup of patients who were treated with sorafenib and had hepatitis C, had quite a longer median survival. In the SHARP trial, the overall survival [OS] in the subgroup was 10.7 months. In the hepatitis C–treated population with sorafenib, there may have been a longer OS than would have been seen in patients who were stratified for that risk factor.....

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https://www.targetedonc.com/case-based-peer-perspectives/hepatocellular-carcinoma/frenette-unresectable-hcc/balancing-efficacy-with-toxicity-among-the-agents-for-hcc

Liver Cancer Treatment Paradigm Undergoing Major Overhaul

Liver Cancer Treatment Paradigm Undergoing Major Overhaul

Christine Lehmann, MA

Published Online: Oct 15,2018

Until recently, few systemic therapies had been approved for the treatment of patients with liver cancer, as few agents could demonstrate significant benefit over placebo. Sorafenib (Nexavar) was the first systemic therapy that extended median overall survival (OS) over placebo by nearly 3 months (10.7 versus 7.9 months),1 and, in December 2007, it became the first systemic therapy approved by the FDA for patients with unresectable hepatocellular carcinoma (HCC).

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https://www.targetedonc.com/publications/targeted-therapy-news/2018/oct-2018/liver-cancer-treatment-paradigm-undergoing-major-overhaul

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SIRT is better tolerated than sorafenib, but doesn't increase overall survival in HCC

Meeting Updates
Updates On This Blog

SIRT is better tolerated than sorafenib, but doesn't increase overall survival in HCC
           

ILC 2017: Selective internal radiation therapy (SIRT) also resulted in tumor response rates of 19 percent versus 11.6 percent in the sorafenib group

April 22, 2017, Amsterdam, The Netherlands: Results of the SARAH trial presented today demonstrate that SIRT resulted in median overall survival (OS) of 8.0 months compared to 9.9 months with sorafenib (p=0.179), in patients with locally advanced and inoperable hepatocellular carcinoma (HCC). The trial, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, further demonstrated that the cumulative incidence of radiologic progression in the liver as the first event was significantly lower in the SIRT group compared to the sorafenib group (p=0.014), and the response rate was significantly higher in the SIRT group compared to the sorafenib group (19.0% vs 11.6%, p=0.042). Both the side-effect profile and quality of life scores were significantly better over time in the SIRT group compared to the sorafenib group (p=0.005).

Liver cancer, or HCC, is the second most common cause of cancer-related deaths worldwide.1,2 HCC represents more than 90% of primary liver cancers and is a major global health problem.3 The prognosis for patients with advanced liver cancer is poor,2 and the multikinase inhibitor, sorafenib, is the only approved first-line systemic treatment.3 If patients are not tolerant or have contraindications for sorafenib therapy, there is currently no standard of care and patients lack effective treatment options.3 SIRT with yttrium-90 (Y-90) resin microspheres has shown promising anti-tumour results with a safe profile; further trials are needed to establish this treatment as a viable option for patients.3

"Patients with advanced or inoperable hepatocellular carcinoma have a poor prognosis, often with underlying cirrhosis, and the treatment option currently available, sorafenib, has a high level of toxicity. As cohort studies have demonstrated the efficacy of SIRT with Y-90 resin microspheres, we set out to compare the efficacy of this treatment versus the current standard of care," said Prof Valérie Vilgrain, Hôpital Beaujon Service de Radiologie, Paris, France, and lead author of the study.

"While SIRT demonstrated significantly reduced side effects, better quality of life, higher response rates and more effectively controlled tumour progression in the liver, the overall survival of patients was not higher than in the sorafenib group. Nonetheless, this study provides evidence that SIRT may be a better-tolerated alternative for managing this complex and difficult-to-treat disease, deserving further evaluation."

The SARAH trial was a randomised, controlled, open-label, multicentre investigator initiated Phase 3 trial. Patients with locally advanced or inoperable HCC, who did not respond to other treatments or had two failed rounds of transarterial chemoembolisation, were randomised to SIRT with Y-90 resin microspheres, or oral sorafenib 400 mg twice daily. The primary endpoint of the study was OS and secondary endpoints included progression-free survival (PFS), time to radiological progression at any site and in the liver as the first event, tumour response, quality of life, and safety and toxicity.

There were 459 patients from 25 French clinical centres included in the study, 237 of whom received SIRT. Median PFS was 4.1 months and 3.7 months in the SIRT and sorafenib groups, respectively (p=0.765). Cumulative incidence of radiological progression at any site did not differ in either group (p=0.256). Overall, there were 1,297 and 2,837 treatment-related adverse events (AEs) including 230 and 411 grade ?3, in the SIRT and sorafenib groups, respectively. The number of patients with at least one treatment-related adverse event was 173 (76.5%) and 203 (94.0%), (p<0.001), including 92 (40.7%) and 136 (63.0%) grade ?3 adverse events, (p<0.001), in the SIRT and sorafenib groups, respectively. Quality of life, assessed using the Global Health Status scale of the EORTC QLQ-C30 questionnaire, was significantly better in patients who received SIRT compared to the sorafenib group (p=0.005), an advantage that tended to increase with time (p=0.045).

"The SARAH trial is the first reported randomised controlled trial evaluating the survival benefit of SIRT in locally advanced HCC compared to sorafenib. SIRT was found to be safe, but regrettably the study failed meet the primary endpoint and SIRT did not show an overall survival superior to sorafenib. Further trials are needed to establish this treatment as a viable option for patients," said Prof Alejandro Forner, BCLC group, Liver Unit, Hospital Clinic Barcelona, Spain and EASL Governing Board Member.

Yttrium-90 resin microspheres
Y-90 resin microspheres are miniscule radioactive 'beads' that are used in SIRT. They contain the radioactive component yttrium-90. These microspheres are injected in huge quantities into the liver tumours, where they become stuck in the small blood vessels that are in and around the tumours. The microspheres then emit high doses of radiation, which enable doctors to deliver up to 40 times more radiation to the liver tumours than would be possible using standard radiation therapy, all while sparing surrounding healthy tissue.4

About The International Liver Congress™
This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 - 23, at the RAI Amsterdam, Amsterdam, The Netherlands.

About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European Association with international influence, with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Onsite location reference
Session title: General session III and award ceremony II
Time, date and location of session: 10:00 - 12:00, Saturday 22 April, Hall 5
Presenter: Valérie Vilgrain, France
Abstract: SARAH: a randomised controlled trial comparing efficacy and safety of selective internal radiation therapy (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma (GS012), 10:00 - 10:15

Author disclosures
Speaker fees: Guerbet, SIRTEX, Supersonic, Toshiba. SIRTEX: Funding of SARAH trial. Guerbet: Study Investigator.

References
1 World Health Organization. Cancer. Available from: http://www.who.int/mediacentre/factsheets/fs297/en/. Last accessed: April 2017.
2 World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Last accessed: April 2017.
3 EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943.
4 Sirtex Medical Liminted. About SIR-Spheres microspheres. Available from: http://www.sirtex.com/us/patients/about-sir-spheres-microspheres/. Last accessed: April 2017.

Sorafenib benefit dependent on hepatitis status in patients with HCC

Sorafenib benefit dependent on hepatitis status in patients with HCC

February 19, 2017

Sorafenib improved OS among patients with hepatocellular carcinoma who were hepatitis C positive but hepatitis B negative, suggesting that the beneficial effects of sorafenib may be based on hepatitis status, according to results of a meta-analysis.

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Of Interest

MicroRNA-125a-5p is a downstream effector of sorafenib in its antiproliferative activity toward human hepatocellular carcinoma cells.

Article ID: 669739
Released: 17-Feb-2017 3:05 PM EST
Source Newsroom: Sbarro Health Research Organization (SHRO)

Sorafenib is a multikinase inhibitor with specific activity against Raf kinase and several receptor tyrosine kinases. The addition of sorafenib to hepatocellular carcinoma cells increased cellular expression of miR-125a. Upregulation of this miRNA inhibited cell proliferation and induced cell cycle arrest by targeting c-Raf, part of the ERK pathway that is involved in cell proliferation and sirtuin-7, (SIRT-7) a NAD(+)-dependent deacetylase that inhibits transcriptional activation of the cell cycle inhibitor p21. Therefore, sorafenib inhibits Raf activity and upregulates miR125 that, in turn, targets c-Raf and SIRT7; this dual inhibition of Raf activity and expression together with p21-dependent cycle arrest coherently combine to explain the antiproliferative activity of the drug.

Newswise — Treatment options for liver cancer are often limited and almost exclusively involve transplantation if possible, or local chemoembolization and radiofrequency ablation. Medical treatments for more advanced stages have been explored during recent decades, but only the drug sorafenib, a small molecule multi-kinase inhibitor, has shown promising results and been approved for use by international medical agencies. Unfortunately, only 25% of patients respond to sorafenib treatment, so researchers have endeavored to understand its mechanism of action and discover a way to boost its effectiveness.

A recent study, published in the journal Journal of Cellular Physiology, describes further scientific insight into the involvement of a small non coding RNA, miR-125a, in the anti-cancer effects of sorafenib in the treatment of liver cancer, or hepatocellular carcinoma. These results are interesting as miRNAs have multiple available intracellular targets and could contribute to the amplification of the effects of sorafenib.

The link between small kinase inhibitors such as sorafenib, and the existing molecular pathways that govern cell proliferation such as miR-125a, may be useful to potentiate the anticancer activity of sorafenib. Clinical applications of this knowledge might seek to identify and increase the number of liver cancer patients that respond positively to the drug.

The study includes work done by Prof. Michele Caraglia and Aniello Russo, of the University of Campania “L. Vanvitelli” in Naples, and Caserta, Italy, in collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.

“Sorafenib is still the only drug indicated in the treatment of hepatocellular carcinoma, which highlights the difficulty in the medical treatment of liver cancer,” says Prof. Antonio Giordano. “Sorafenib is effective because it acts upon multiple intracellular targets and interferes with both cancer proliferation and tumor blood supply. However, its activity is limited to only 25% of patients that are sensitive to its effects. This strongly pushes the researchers to define the mechanism of action of the drug,” Giordano concludes.

“MicroRNAs can act as either cancer-fighting tumor suppressors, or as cancer-causing oncogenes,” says Professor Michele Caraglia. "We have found that the expression of miR-125a is strongly involved in the mechanism of action of sorafenib and its ability to regulate cancer cell proliferation. These findings suggest the possible use in the future of miR125a in combination with sorafenib in order to potentiate the anti-cancer activity of the drug,” Caraglia concludes.

The study results open a new scenario of intervention in the treatment of hepatocellular carcinoma in which small molecules such as sorafenib can be used in association to nucleic acids such as miR-125a. The latter could be administered to patients systemically encapsulated in novel drug delivery options such as nanocarriers. Researchers plan to further study the in vivo efficacy of these strategies to increase treatment options for this difficult form of cancer.

Citations
Potenza N, Mosca N, Zappavigna S, Castiello F, Panella M, Ferri C, Vanacore D, Giordano A, Stiuso P, Caraglia M, Russo A. MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells. J Cell Physiol. 2016 Dec 16. doi: 10.1002/jcp.25744.

Meta-analysis/Effect of sorafenib for advanced liver cancer dependent on patients’ hepatitis status

Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials

The following article summary is provided by HealthDay News, abstract and discussion is available below or view the original report published in the Journal of Clinical Oncology.

Summary

Sorafenib Effect on HCC Survival Depends on Hepatitis Status
For patients with advanced unresectable hepatocellular carcinoma, the effect of sorafenib on overall survival is dependent on patients' hepatitis status, according to a meta-analysis published online Jan. 3 in the Journal of Clinical Oncology.

Richard Jackson, from the Liverpool Cancer Trials Unit in the United Kingdom, and colleagues undertook an individual patient data meta-analysis of three prospective randomized trials in which sorafenib was the control arm. Data were included for 1,643 patients with advanced unresectable hepatocellular carcinoma who received sorafenib.

The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, respectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.

"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib."

One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.

Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials

Richard Jackson, Eftychia-Eirini Psarelli, Sarah Berhane, Harun Khan, and Philip Johnson

Abstract

Purpose
Following the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib has become the standard of care for patients with advanced unresectable hepatocellular carcinoma, but the relation between survival advantage and disease etiology remains unclear. To address this, we undertook an individual patient data meta-analysis of three large prospective randomized trials in which sorafenib was the control arm.

Methods
Of a total of 3,256 patients, 1,643 (50%) who received sorafenib were available. The primary end point was overall survival (OS). A Bayesian hierarchical approach for individual patient data meta-analyses was applied using a piecewise exponential model. Results are presented in terms of hazard ratios comparing sorafenib with alternative therapies according to hepatitis C virus (HCV) or hepatitis B virus (HBV) status.

Results
Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for “other” treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.

Conclusion
There is consistent evidence that the effect of sorafenib on OS is dependent on patients’ hepatitis status. There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib. There was no evidence of any improvement in OS attributable to sorafenib for patients positive for HBV and negative for HCV.

Discussion Only
View full text article online here or download PDF.  

We have carried out an IPD meta-analysis of three phase III RCTs that demonstrates that the effect of sorafenib compared with other treatments for patients with aHCC cannot be considered independent of a patient’s HBV and HCV status. For patients who were HBV positive and HCV negative, there was no evidence of any positive effect on OS due to sorafenib, with the HR in this subgroup favoring the comparator, although this was not statistically significant. This patient group comprises 51% of all patients included in the analysis. There was, however, a significant positive effect of sorafenib in the group of patients who were HCV positive and HBV negative (n = 628; 22%). For all remaining patients, there was a trend supporting the use of sorafenib, but this was not statistically significant.

Our analysis extends the previous aggregate meta-analysis, which, although lacking the ability of IPD analyses to investigate treatment effects within patient subgroups, did involve additional trials to ours (the SHARP4 and Asia-Pacific region5 studies) and concluded that sorafenib might provide more survival benefits to patients positive for HCV. IPD meta-analyses are the gold standard and allow us to analyze trial data that may be more mature than the published results, ensure consistency of analytical techniques across the data sources, and further allow for the inspection of subgroup effects and treatment interactions, which would not be possible using an aggregate meta-analytical approach. Still, the results reported here represent secondary analyses of trial subgroup effects and the evidence provided is not as strong as a RCT, which specifically would look at the effect of sorafenib within each hepatitis subgroup.

The subgroup analysis of the SHARP trial showed that patients positive for HCV had a superior median OS of 14 months compared with 7.4 months in the placebo-treated group, and this benefit was also seen in terms of time to tumor progression (7.6 v 2.8 months) and disease control rate (44.2% v 29.6%).6 As noted by Bruix et al,6 the SHARP trial was not randomized relative to etiology and, therefore, the resulting subgroups were at risk for imbalance. Nonetheless, inspection of the data provided in this subgroup analysis shows that there were a significant number of patients within the HCV-positive subgroup (n = 167; 86 receiving sorafenib and 81 receiving placebo), and that the treated and the placebo groups were, in fact, well balanced with respect to region, age, sex, Child-Pugh class, macrovascular invasion/extrahepatic spread, ECOG PS, and disease stage. These observations, combined with the present detailed IPD meta-analysis and the previous aggregated meta-analysis, support the contention that the impact of sorafenib is largely confined to the patients who are HCV positive. Because the overall benefit of sorafenib in the SHARP study was only 2.8 months compared with placebo, and we found little significant overall effect of sorafenib in the analyses presented here, there is insufficient evidence to support the absolute benefit of sorafenib outside patients positive for HCV. We considered the possibility that ethnicity might be a confounding factor (because HCV and HBV are more prevalent in Western and Eastern populations, respectively), but our analysis did not support this contention. Treatment before trial entry, which may be less intense in Western (and, hence, HCV-positive) populations may also be a confounding factor, but we had insufficient data to exclude this possibility.

There is evidence of genetic diversity22-25 in HCC that can be linked to specific etiologic factors22,26 and may permit identification of specific targets for therapy. The reasons for differential response to sorafenib according to etiology remain unclear. Although some in vitro data have suggested that sorafenib inhibits HCV viral replication directly, this has not been borne out in the clinical setting.7,27 There is evidence of Wnt-pathway dysregulation in about 50% of HCC cases. Of the two major activating classes (CTNNB1 and Wnt-TGFβ), the former appears to be related to HCV infection and activity is modulated by sorafenib in a xenograft model.13,24,28 HCV has also been shown to upregulate C-RAF,29 a known sorafenib target, and Braconi et al30 have shown that HCV proteins can modulate the expression of microRNAs and thereby influence the sensitivity of HCC cells to sorafenib.

Irrespective of the mechanism, our data suggest that in future trials in aHCC, particularly where sorafenib is the control arm, there should be stratification according to etiology. Etiologic differences have already been considered as factors in the interpretation of clinical trials. In the trial of adjuvant sorafenib after surgical resection or local ablation (STORM), although the overall results of the trial were negative, there was a trend for longer time to recurrence in the HCV-related cases.31

Following a proposal from the International Committee of Medical Journal Editors32, it is likely that individual patient data will become accessible to investigators unrelated to the original trial. Thus, as a condition of consideration for publication, it is proposed that authors will be required to include a description of the data-sharing plan in the submitted manuscript. Although the editors considered that “sharing data will increase confidence and trust in the conclusions drawn from clinical trials,”32(p468) our study shows how the benefits of access to completed trial data are not necessarily confined to reanalysis of the original hypothesis tested by the trial. Here, by a meta-analysis, we arrive at an answer to a question that was not considered when the trials were conceived and could not have been answered by any of the trials individually. It also illustrates the clinical benefit arising when enlightened pharmaceutical companies are prepared to share their data with an academic unit, even when the primary question does not relate to their products.

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The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma

The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma

1. R. Cabrera^*,
2. A. R. Limaye,
3. P. Horne,
4. R. Mills,
5. C. Soldevila-Pico,
6. V. Clark,
7. G. Morelli,
8. R. Firpi,
9. D. R. Nelson

Article first published online: 24 OCT 2012

DOI: 10.1111/apt.12098

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Summary
Background

Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.

Aim

To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.

Methods

We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time.

Results

Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: −0.1799–0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point.

Conclusion

Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

http://onlinelibrary.wiley.com/doi/10.1111/apt.12098/abstract

Combination of Tarceva, Nexavar fails to meet main goal of Phase III liver cancer study

July 23, 2012
Combination of Tarceva, Nexavar fails to meet main goal of Phase III liver cancer study
Last Updated:July 23, 2012 07:36

Bayer, Onyx Pharmaceuticals and Astellas announced Monday that a late-stage trial investigating the combination of Tarceva (erlotinib) and Nexavar (sorafenib) failed to meet the main goal of a late-stage trial in patients with unresectable hepatocellular carcinoma (HCC). "The data from SEARCH showed that the addition of Tarceva to Nexavar did not provide additional benefit to patients with unresectable HCC," remarked Dimitris Voliotis, vice president of global clinical development oncology at Bayer.

The SEARCH study randomised 720 patients with advanced liver cancer to receive treatment with Nexavar twice daily, either in combination with Tarceva once daily or placebo. Results demonstrated that the addition of Tarceva to Nexavar did not improve overall survival compared to Nexavar alone. The companies noted that data from the trial will be presented at a future medical meeting.

Nexavar, which is being jointly developed by Bayer and Onyx, is approved in the US and other countries for the treatment of patients with unresectable HCC and for the treatment of patients with advanced renal cell carcinoma. Tarceva is used to treat lung cancer and is co-marketed by Astellas and Roche's Genentech unit.

Analysts at Cheuvreux said the study results were a small negative for Bayer, but they left peak sales forecasts for Nexavar unchanged at 971 million euros ($1.2 billion) in 2019. Meanwhile, a spokesman for Roche noted while the company provided financial support as well as Tarceva for the trial, it did not have a development plan for the drug in liver cancer, either alone or as part of a combination.

Reference Articles

Bayer says Nexavar-Tarceva trial unsuccessful - (CNBC)

Bayer Says Phase III Tarceva-Nexavar Study Fails - (FinanzNachrichten)

Bayer Says Phase III Tarceva-Nexavar Study Fails - (NASDAQ)

Addition of Tarceva (erlotinib) to Nexavar (sorafenib) did not Provide Additional Benefit to Patients with Unresectable Liver Cancer Versus Nexavar alone in Phase 3 Trial - (PR Newswire) Source - http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=3BC42477F6134983B32824385309019C

Sorafenib beneficial in liver cancer regardless of etiology

By David Douglas

NEW YORK (Reuters Health) – Sorafenib improves survival and disease control consistently in patients with advanced hepatocellular carcinoma (HCC) of different etiologies, according to a new report.

“The data from the study demonstrate the safety of sorafenib for all types of patients with liver cancer,” lead author Dr. Jordi Bruix, of the University of Barcelona in Spain, told Reuters Health by email.

The study, published online June 19 in the Journal of Hepatology, was funded by Onyx Pharmaceuticals and Bayer Healthcare, which markets sorafenib.

Dr. Bruix and colleagues note that the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial showed that in patients with well-preserved liver function and advanced disease, the drug improves overall survival and is safe. An Asia-Pacific trial confirmed those findings.

However, the researchers note, “Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment.”
To determine if this might be the case in the SHARP trial, the researchers examined data on the 602 participants, who had been randomized to sorafenib or placebo. The hazard ratio for improved median overall survival was 0.69 with sorafenib.

When analyzed according to disease etiology, tumor burden, performance status, tumor stage, and prior therapy, the overall survival findings were similar to those in the complete cohort.
The hazard ratio ranged from 0.50 in patients positive for anti-hepatitis C virus antibody to 0.85 in those with extrahepatic spread. Eight out of 15 comparisons achieved statistical significance.
Sorafenib also consistently improved median time to progression (HR, 0.40 to 0.64), except in patients positive for hepatitis B virus (HBV) (HR, 1.03). The disease control rate was consistently improved as well.

The most common grade 3 and 4 adverse events included diarrhea and fatigue and did not differ appreciably among subgroups
The researchers note that the results are limited by small patient numbers in some subgroups. For example, there were only 60 HBV-positive patients.

Nevertheless, they conclude that “the efficacy and safety of sorafenib, relative to placebo, in patients with advanced HCC and well-preserved liver function do not appear to be affected by baseline health status, disease etiology, tumor burden, tumor stage, or prior therapy.”
“All together,” added Dr. Bruix, “the information provided by the SHARP trial and the Asian-Pacific trial with sorafenib has represented a major breakthrough for patients diagnosed with this disease.”

SOURCE: http://bit.ly/NohkoJ

J Hepatol 2012

http://www.thedoctorschannel.com/view/sorafenib-beneficial-in-liver-cancer-regardless-of-etiology/

Positive Clinical Data of JX-594 in Combination W-Sorafenib in Advanced Liver Cancer

Jennerex and Green Cross Announce Publication of Positive Clinical Data of JX-594 in Combination With Sorafenib in Advanced Liver Cancer

SAN FRANCISCO and SEOUL, South Korea, April 20, 2011 /PRNewswire/ -- Jennerex, Inc., a private clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class targeted oncolytic products for cancer, and Green Cross Corporation, a leading company in the development, manufacturing, and commercialization of viral vaccines and other biological products, today reported positive clinical data from a Phase 2 trial evaluating JX-594 for liver cancer which was conducted in South Korea.  The data were reported in the journal Molecular Therapy.

Patients enrolled in a Phase 2 clinical trial for hepatocellular carcinoma (HCC) received three intratumoral administrations of JX-594.  A subset of three patients subsequently received sorafenib, the current standard of care for HCC and the only approved systemic therapy for this indication to date.  All three of these patients exhibited rapid and marked tumor necrosis as quantitated by serial dynamic MRI imaging; all patients had both Choi (necrotic) and modified Response Evaluation Criteria in Solid Tumor (mRECIST) type responses.  The responses were rapid—as early as 2.5 weeks after sorafenib initiation—and occurred in both JX-594-injected and non-injected tumors.  Notably, similar responses were not seen in HCC patients treated with sorafenib alone at the same institutions (zero of 15 patients). The treatment regimen was well tolerated in each of the patients, and sorafenib toxicities were consistent with the documented historical profile. The JX-594-sorafenib combination regimen is currently being further investigated in another Phase 2 trial.

"Given the strength of the clinical and preclinical data we have observed from our JX-594 trials in liver cancer, we are planning further clinical trials of JX-594 as a single agent and in combination with VEGFR inhibitors.  TRAVERSE, our planned randomized Phase 2b clinical trial of JX-594 used as a single agent, will evaluate survival in advanced HCC patients who have progressed after treatment with sorafenib," stated David H. Kirn, M.D., president and chief executive officer of Jennerex.

"While the subset of patients in this trial is small, the data are quite compelling.  In prior studies we have demonstrated JX-594's ability to induce necrotic responses as a single agent. This is the first publication showing that JX-594 may sensitize tumors to subsequent treatment with VEGFR inhibitors, such as sorafenib," stated BG Rhee, Ph.D., president, Green Cross Corporation.

The publication also highlighted a case report of a complete and durable response in a patient with metastatic renal cell carcinoma (RCC) who received JX-594 in a Phase 1 intratumoral dose-escalation trial.  The patient, who had a baseline life expectancy of less than six months, had locally bulky and widely metastatic RCC.  The patient received four intratumoral injections of JX-594 and subsequently received standard therapy with sunitinib, an approved drug for RCC of the same class as sorafenib.  CT and PET scanning showed a whole-body complete response, and the patient remains alive and disease-free over four years after treatment initiation.

About JX-594
JX-594 is a proprietary, engineered oncolytic virus that is designed to selectively target and destroy cancer cells. JX-594 is designed to attack cancer through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the reduction of the blood supply to tumors through vascular targeting and destruction, and the stimulation of the body's immune response against cancer cells, i.e., active immunotherapy. Phase 1 and Phase 2 clinical trials in multiple cancer types to date have shown that JX-594, delivered either directly into tumors or systemically, induces tumor shrinkage and/or necrosis and is well-tolerated by patients. Objective tumor response has been demonstrated in a variety of cancers including liver, colon, kidney, lung and melanoma.

Transgene (NYSE Euronext Paris: FR0005175080), a bio-pharmaceutical company specialized in the development of immunotherapeutic products, holds an exclusive license to develop and commercialize JX-594 in Europe and neighboring countries. Green Cross Corporation holds an exclusive license to develop and commercialize JX-594 in South Korea, and Lee's Pharmaceutical Ltd. holds an exclusive license to develop and commercialize JX-594 in China.

About Liver Cancer and Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related deaths world-wide with about 660,000 patients dying from the disease annually. Most HCC cases develop on the background of chronic liver cirrhosis; in regions with the highest incidence of HCC, East Asian and African countries, the majority of cases are related to hepatitis B; in developed Western countries and Japan the disease is commonly related to hepatitis C, heavy alcohol consumption and non-alcoholic fatty liver due to metabolic syndromes such as diabetes and obesity. There is accumulating evidence that the incidence of HCC is increasing in Western countries. Despite recent advances, the treatment of advanced HCC remains a significant unmet medical need with a median expected survival under current therapies of less than one year.

About Jennerex
Jennerex, Inc. is a clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer. The Company's lead product JX-594 is currently in two Phase 2 clinical trials in patients with primary liver cancer—an international, randomized, Phase 2 clinical trial, and a Phase 2 study of JX-594 in combination with sorafenib. Published studies designed to establish optimal dose levels and the safety profile of JX-594 have shown its ability to selectively target and cause destruction of a variety of common cancer types. JX-594 and other product candidates under development are designed to attack cancer tumors through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction and the stimulation of the body's immune response against the cancer. Jennerex is headquartered in San Francisco and has related research and development operations in Ottawa, Canada and Pusan, South Korea. For more information about Jennerex, please visit http://www.jennerex.com/.

About Green Cross Corp.
Green Cross Corp. is a publicly traded and leading Korean biopharmaceutical company specialized in development and commercialization of vaccines, plasma-derivatives, recombinant proteins and therapeutic antibodies in oncology and infectious diseases. Green Cross Corp. has been collaborating with Jennerex in Korea since 2006 to jointly conduct the Phase 1 and 2 clinical trials in patients with liver cancer. Additional information about Green Cross Corp. is available on the internet at www.greencross.com.
SOURCE Jennerex, Inc.

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