Targeted Radiation +/- Biologics News Briefing

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2 Targeted Radiation +/- Biologics News Briefing Wednesday, October 31, :00 a.m. 7:45 a.m. Catherine Park, MD Vice-chairman of the ASTRO Education Committee Eric Chang, MD ASTRO Annual Meeting Scientific Committee

3 Stereotactic body radiation therapy for T1N0M0 non-small cell lung cancer. First report for inoperable population of a phase II trial by Japan Clinical Oncology Group (JCOG-0403) Y. Nagata *, M. Hiraoka #, T. Shibata, H. Onishi, M. Kokubo, K. Karasawa, Y. Shioyama, R. Onimaru, E. Kunieda, S. Ishikura Radiation Therapy Study Group of Japan Clinical Oncology Group *Study Coordinator, # Primary Investigator ASTRO, Boston, Oct ,

4 Stereotactic body radiation therapy (SBRT) delivers very targeted beams of radiation to a small area over a few days SBRT is less invasive than surgery SBRT is considered to work against T1N0M0 lung cancers First report for operable population was presented in ASTRO This presentation is the first report for inoperable population.

5 First clinical trial to study SBRT for both inoperable & operable stage IA lung cancers From 2004 to 2008, 104 patients from 15 institutions with early-stage inoperable nonsmall cell lung cancer were studied Patients underwent 4 times daily radiotherapy over the course of four to eight days Each treatment is non-invasive and painless, much like receiving an X-ray

6 Patients followed for almost three years (37 months) after treatment Overall survival rate for patients three years after SBRT was 60 percent Patients reported only mild side effects from the treatment Patients with inoperable early lung cancer should consider this treatment

7 Conv RT vs. SBRT Author Number Age Stage Morita I Sibley I Krol I Dose (med) / Daily dose (64.7)/ 2Gy (64)/ Gy:QD Gy:BID 60-65/ 2.5-3Gy 3-y OS 5-y OS Year (2-y) This study (59-90) IA 48/12Gy 59.9* 40.8* * In all eligible patients (n=10

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9 Stereotactic Radiosurgery for Renal Cancer: Phase I Safety and Toxicity Rodney. J. Ellis 1,2,3, Ravi. B. Patel 1,2, Charles. Kunos 1,2, Yuxia. Zhang1, James. Brindle 1, Vijay. Kudithipudi 1,3, Deborah. A. Kaminsky 1, Lee. Ponsky 4,2 University Hospitals Seidman Cancer Center, Department of Radiation Oncology, Cleveland, OH 1, Case Western Reserve University Medical School, Cleveland, OH 2, Northeastern Ohio University College of Medicine, Rootstown, OH 3, University Hospitals Seidman Cancer Center, Department of Urology, Cleveland, OH 4

10 Example Cyberknife for Left Renal Mass

11 Phase I results summary 20 patients treated and followed for 2-41 months Dose escalation varied from 6 Gy x 4 to 12 Gy x 4 by 2 Gy increments in groups of 4-6 pts per cohort Acute toxicity limited to fatigue in 2 patients Late toxicity limited to increased chronic renal failure in 2 patients No GI or other significant Grade 3 toxicities

12 Phase I results summary Radiographic response rate 94% stable or decreased volumes Pathological biopsy incomplete response or failure rate 91% attributed to low total delivered dose in phase 1 Anticipate efficacy in expanded cohort at 16 Gy x 3 to 20 Gy x 3 for 12 additional patients Await limitations of normal tissues, especially bowel/gi

13 What s Next? We have not reached a dose limit by Toxicity Limits IRB approved for 12 additional patients going to a 3 Fraction Trial 16 Gy x 3 for four patients (3 patient have completed treatment at this level) 18 Gy x 3 for four patients 20 Gy x 3 for four patients Anticipate treating up to 9 additional patients if toxicity limits do not reach a stopping point in the trial.

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15 Phase I Study of Sorafenib and Stereotactic Body Radiotherapy (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 Cancer Centre, Toronto, ON, Canada

16 Hepatocellular Carcinoma (HCC) HCC occurs frequently in the setting of liver cirrhosis (hepatitis B/C virus, alcohol, metabolic) 3 rd leading cause of cancer death world wide (9 th in US, fastest increasing) Global 5 year survival < 10% Local therapy can be curative but co-morbidity and late diagnosis make treatment delivery challenging Sorafenib (targeted therapy, an oral inhibitor of tyrosine kinases VEGFR-2, PDGF-beta, Raf, c-kit) Sorafenib improves survival in patients with very advanced HCC ineligible for local therapies with good liver function (Child-Pugh Class A): Median overall survival 10.7 vs 7.9 months (Llovet NEJM 2008)

17 SBRT for Advanced HCC Stereotactic body radiotherapy (SBRT) to liver has shown promise in locally advanced, heavily pre-treated HCC pts Median OS 16.8 months post SBRT (Bujold et al, ASTRO 2011) Lab tumour models suggest combining sorafenib with radiation may improve tumour control This study evaluated concurrent sorafenib and SBRT (6 fractions in 2 weeks) in patients with advanced HCC Primary Objective: Determine maximum tolerated dose (MTD) and acute toxicity of sorafenib in combination with SBRT Trial Schema Strata I Small tumour(s) volume (<40% of liver) Strata II Large tumour(s) (40-60% of liver) Radiotherapy Sorafenib Wk 2 Wk 1 Wk 3 Wk 4 Wk 8

18 Combining SBRT and Sorafenib Patients had unresectable HCC, good performance status, good liver function (Child-Pugh Class A), >800 cc of non-tumor liver, and adequate hematologic, liver and kidney function, minimal extrahepatic disease 16 patients started therapy: strata I-small volume: II-large volume 4:12 Dose range strata I:II Gy/ 6 : Gy/ 6 3 patients completed study therapy as planned 1 patient died due to tumour rupture pre-rt 4 patients discontinued Sorafenib < 4 wks: tumor progression (2), toxicity (2) 3 Dose Limiting Toxicities (drug/radiation related) were observed within 12 weeks: (small bowel obstruction Gr 4, lower GI bleed Gr 3, upper GI bleed/tumour rupture Gr 5) in Strata 2 => sorafenib dose de-escalated Strata 1- small volume: MTD not reached (study closed early, 200 mg bid appeared tolerable) Strata 2- large volume: MTD 200 mg sorafenib daily, completed

19 Results Demographics Age (range) Child score 5 Hepatitis (B/C/EtOH) Tumor thrombus Extrahepatic disease Multiple lesions 61.5 (52-79) 62.5% 43/38/38% 62.5% 19% 62.5% Change in Liver function (Child Pugh Score/Class) and Grade 3 + Toxicity CP Class Decline Biochem/Liver Hematologic Other 36% 12.5% 25% 19% Response to Treatment Strata 1 (small volume), n=4 Strata 2 (large volume), n=11 CR 0 CR 0 PR 2 RR 50% RR PR 4 SD 2 36% SD 7 PD 0 PD 0

20 Conclusion Concurrent use of sorafenib and RT is challenging Reduced drug dose and irradiated volume are key factors in toxicity risk Despite advanced tumour burden and toxicity, response rates are impressive (40%) Concurrent sorafenib/ SBRT is not recommended for locally advanced HCC outside clinical trials Sequential SBRT followed by sorafenib will be tested in the RTOG 1112 phase III trial

21 Q & A

22 For additional questions or interviews, please contact the ASTRO Press Office or Michelle Kirkwood, Tami von Isakovics,