News Release. Embargoed until 1:45 p.m. ET, Sunday, October 28, 2012

Transcription

1 News Release Embargoed until 1:45 p.m. ET, Sunday, October 28, 2012 Contact: Michelle Kirkwood Concurrent use of sorafenib and stereotactic body radiotherapy for advanced liver cancer patients is not recommended outside of clinical trials Sequential treatment of SBRT and sorafenib may offer a safer option, though further research is needed Boston, October 28, 2012 Concurrent use of sorafenib and stereotactic body radiotherapy (SBRT) for advanced liver cancer patients resulted in high toxicity and is not recommended outside of clinical trials, according to research presented today at the American Society for Radiation Tami von Isakovics tami@ellipsespr.com Press Room in Boston October or Oncology s (ASTRO s) 54 th Annual Meeting. This is the first prospective study of SBRT combined with sorafenib for hepatocellular carcinoma (HCC) patients, and initial outcomes indicate that further testing is needed for more effective treatment options and/or more effective sequencing of therapies. This phase I trial was designed to test the safety of the combination of SBRT and sorafenib in HCC patients. Sorafenib is a targeted therapy that reduces cancer cell proliferation and cancer blood vessel formation; it is the standard of care for patients with locally advanced HCC. In this study, SBRT was delivered after 1 week of sorafenib, and sorafenib was continued during and after SBRT in 16 patients. Four patients in the study had a low burden of HCC, requiring less than 30 percent of their liver to be irradiated (low effective liver volume irradiated, Veff), and 12 had a larger burden of HCC, requiring 30 to 60 percent of their liver to be irradiated (high Veff). Twelve patients were classified as stage C on the Barcelona Clinic Liver Cancer (BCLC) rating system and exhibited symptomatic tumors, vascular invasion or extrahepatic spread. Ten of sixteen patients in the study Page 1 of 5

2 exhibited tumor invasion involving major vessels. The study found that the toxicity of sorafenib, even at lower than standard doses and sometimes before SBRT was started, was higher than expected. The study authors recommend sequential SBRT followed by sorafenib for future studies, rather than a concurrent approach. For the low liver Veff group, 400 mg of sorafenib daily (half of standard dose) was the maximum tolerated dose without toxicity, although one patient was taken off therapy due to very low platelets (grade 3 thrombocytopenia). Due to the toxicity levels reported at the 400 mg dose, patients in this group were not advanced to the next higher dose of sorafenib. For the high Veff group, 200 mg of sorafenib daily was the maximum dose tolerable; 400 mg of sorafenib daily resulted in luminal gastrointestinal (GI) toxicity in two patients approximately three months after SBRT treatment. Two patients were removed from the study prior to SBRT due to liver enzyme increase and tumor rupture after seven and three days of sorafenib, respectively. One of six patients in the high Veff group, who was treated with 200 mg of sorafenib daily, developed tumor rupture five weeks after SRBT. There was one death reported after eight weeks of treatment. Another patient developed grade 3 liver enzymes after seven days of sorafenib and was removed from the study. Despite these toxicities, the median survival of the 12 patients who received any SBRT, including those with dose-limiting toxicity, was 8.4 months. Patients who participated in the study had locally advanced HCC not suitable for standard local or regional therapies. They had intact liver function and were classified as having Child-Pugh score A. The Child-Pugh scoring assesses the severity of liver disease and a patient s estimated survival rate based on the liver function, according to the degree of ascites (fluid build-up in the abdomen), the plasma concentrations of bilirubin and albumin, the prothrombin time and the degree of encephalopathy (confusion). The dose escalation plan for sorafenib began with 400 mg (200 mg by mouth twice daily) and was planned to be increased in 200 mg increments to reach a maximum dosage of 800 mg (400 mg by mouth twice daily, standard dose). Patients received study dose sorafenib one week prior to, during and four weeks post SBRT with continuation of standard dose sorafenib where possible. Dose-limiting toxicity was defined as grade 4 or 5 related toxicity occurring within 3 months following SBRT. SBRT doses ranged from 39 to 54 Gy in six fractions over two weeks Page 2 of 5

3 and the maximum permitted dose to hollow GI organs (e.g. stomach, large or small bowel) was 31 to 34 Gy. Evaluable patients had to receive at least three weeks of the study dose of sorafenib and SBRT, and be followed for at least three months without progressive liver cancer. Patients with advanced hepatocellular carcinoma are most often not suitable for potentially curable treatments such as surgery, liver transplant or radiofrequency ablation. Some of these patients are candidates for treatment with sorafenib, the present standard of care, which delays progression modestly but does not cure, said Laura A. Dawson, MD, lead author of the study and a radiation oncologist at Princess Margaret Hospital in Toronto. SBRT is a promising therapy for patients with locally advanced liver cancer, and our prior studies demonstrated that the majority of patients treated had control of their irradiated tumor at one year following treatment. Our present study investigated the combination of SBRT and sorafenib in patients with advanced liver cancer. We found that even though low levels of sorafenib combined with SBRT were tolerated by patients requiring a low volume of normal liver to be irradiated, serious toxicity was seen more commonly than expected with the combination. In order to minimize toxicity levels, we believe additional research is needed and, off-study, sequential treatment with SBRT and sorafenib is preferred to concurrent use of these therapies. The abstract, Phase I Study of Sorafenib and SBRT for Advanced Hepatocellular Carcinoma, will be presented in detail during a scientific session at ASTRO s 54 th Annual Meeting at 1:45 p.m. Eastern time, on October 28, To speak with Anthony Brade, MD, co-author and presenting author of the study in Boston, call Michelle Kirkwood on October 28 31, 2012, in the ASTRO Press Office at the Boston Convention and Exhibition Center at or , or michellek@astro.org. ASTRO s 54 th Annual Meeting, held in Boston, October 28 31, 2012, is the premier scientific meeting in radiation oncology and brings together more than 11,000 attendees including oncologists from all disciplines, medical physicists, dosimetrists, radiation therapists, radiation oncology nurses and nurse practitioners, biologists, physician assistants, practice administrators, industry representatives and other health care professionals from around the world. The theme of the 2012 Annual Meeting is Advancing Patient Care through Innovation and examines how innovation in Page 3 of 5

4 technology and patient care delivery can lead to improved patient outcomes. The four-day scientific meeting includes six plenary papers and 410 oral presentations in 63 oral scientific sessions, and 1,724 posters and 130 digital posters in 18 tracks/topic areas. ABOUT ASTRO ASTRO is the largest radiation oncology society in the world, with more than 10,000 members who specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, biology and physics, the Society is dedicated to improving patient care through education, clinical practice, advancement of science and advocacy. For more information on radiation therapy, visit To learn more about ASTRO, visit ### Page 4 of 5

5 Embargoed until October 28, 2012, 1:45 p.m. ET 2012 (ASTRO) 54 th Annual Meeting News Briefing, Wednesday, October 31, 2012, 7:00 a.m. Eastern time Scientific Session: Sunday, October 28, 2012, 1:45 3:15 p.m. Eastern time, Boston Convention & Exhibition Center 24 Phase I Study of Sorafenib and SBRT for Advanced Hepatocellular Carcinoma L. A. Dawson, A. Brade, C. Cho, J. Kim, J. Brierley, R. Dinniwell, R. Wong, J. Ringash, B. Cummings, J. Knox, Princess Margaret Hospital, Toronto, ON, Canada Purpose: To determine the maximally tolerated dose of sorafenib, a tyrosine kinase inhibitor with anti-angiogenic properties, delivered pre, during and post SBRT in hepatocellular carcinoma (HCC). Methods: Eligible patients had advanced HCC not suitable for standard local or regional therapies, with Child Pugh A liver function. SBRT was delivered in 2 strata: 1) Low effective liver volume irradiated (Veff) (< 30%, dose range: 39-54Gy in 6 fractions (fr) over 2 weeks) and 2) High Veff (30-60%, dose range Gy in 6 fr). Maximal permitted dose to luminal GI tissue was Gy. Study sorafenib was delivered one week prior to, during and 4 weeks post SBRT, at which point escalation to full dose sorafenib was permitted. The study sorafenib dose was planned to be escalated in each strata from 400 mg (200 mg po bid) to 600 mg (400 mg po q am and 200 mg po q pm) to 800 mg (400 mg po bid) in a phase I trial design. Dose-limiting toxicity was defined as grade 4 or 5 related toxicity. Evaluable patients had to receive at least 3 weeks of study dose sorafenib and SBRT and be followed for at least 3 months (mo) without liver PD. Results: 24 patients consented to this study. 8 were screened ineligible, leaving 16 eligible HCC patients who initiated study therapy (4 Low Veff, median dose 51Gy; 12 High Veff, median dose 33Gy). 75% of patients were BCLC stage C. The majority had main branch portal vein tumor thrombosis. In the low Veff strata, none of 3 evaluable pts treated with SBRT combined with sorafenib 400 mg developed DLT. A fourth patient was not evaluable due to discontinuation of sorafenib after 11 days due to gr 3 thrombocytopenia. The sorafenib dose level was not escalated in this strata due to poor accrual. In the high Veff strata, 2 of 3 evaluable patients treated with sorafenib 400 mg po daily developed DLT (1 gr 3 large bowel bleed 3.5 mo post SBRT and 1 gr 3 bowel obstruction 3 mo post SBRT). Two other patients were taken off study prior to SBRT due to liver enzyme increase and tumor rupture after 7 and 3 days of sorafenib respectively. Thus, sorafenib was de-escalated to 200 mg po daily. 1 of 6 evaluable pts at this dose level developed DLT (tumor rupture, after 5 weeks of sorafenib and SBRT, with death at 8 weeks). Another pt developed grade 3 liver enzymes after 7 days of sorafenib, and was taken off study. Median survival of the 12 evaluable patients in both strata, including those with DLT, was 8.4 mo (range mo). Follow-up is ongoing. Conclusions: Low liver Veff (<30%) HCC SBRT delivered concurrently with sorafenib 400 mg po daily appears tolerable. However, in high liver Veff (30-60%) HCC SBRT, 400 mg was not tolerable due to luminal GI toxicity, and sorafenib 200 mg po daily was the maximally tolerated dose. Strategies to reduce toxicity from SBRT and sorafenib are needed. Sequential SBRT followed by sorafenib, rather than a concurrent approach, is recommended. Author Disclosure Block: L.A. Dawson: E. Research Grant; Bayer. O. Patent/License Fee/Copyright; Raysearch. A. Brade: E. Research Grant; Bayer. C. Cho: None. J. Kim: None. J. Brierley: None. R. Dinniwell: None. R. Wong: None. J. Ringash: None. B. Cummings: None. J. Knox: None. Page 1 of 5