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Objectives Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. Materials and methods Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. Results Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naive. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. Conclusions Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

Background SORCE is a randomised, double-blind trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) at intermediate or high risk of recurrence (Leibovich classification). Methods We recruited patients from 147 sites in the UK, Australia, France, Belgium, Denmark, The Netherlands and Spain and randomised them (2:3:3) between three years of placebo (A), one year of sorafenib followed by two years of placebo (B) and three years of sorafenib (C). The initial sorafenib dose was 400mg twice per day orally, amended during trial recruitment to a reduced starting dose of 400mg daily. The primary outcome is investigator-reported disease-free survival (DFS). Given the results of the ASSURE and S-TRAC trials, and blinded to SORCE outcomes, we revised the primary analysis to compare three years of sorafenib (arm C) vs placebo (arm A) to focus on the question of longer exposure to sorafenib. Results Between July 2007 and April 2013, we randomised 1711 patients; 430, 642, and 639 to arms A, B, and C respectively. Median age was 58 years; 71% male, 84% clear cell histology, 53% at intermediate risk of recurrence and 47% at high risk of recurrence. We observed no differences in DFS or OS in any of our pre-planned and pre-powered analyses: all randomised patients, high-risk patients only, and patients with clear cell RCC only. Median DFS was not reached for three years sorafenib or for placebo (HR 1.01, 95% CI 0.83 -1.23, p=0.95). We observed non-proportional hazards: restricted mean survival time (RMST) was 6.81 years for three years of sorafenib and 6.82 years for placebo, RMST difference 0.01, 95% CI -0.49 – 0.48, p=0.99. Despite offering treatment adaptations, over half of patients stopped treatment early. Grade 3 hand-foot syndrome was reported in 24% of patients on sorafenib. Conclusions Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence following nephrectomy; it is the appropriate control of our current international adjuvant RCC trial, RAMPART. Clinical trial identification ISRCTN38934710; EudraCT: 2006-006079-19; NCT00492258. Legal entity responsible for the study University College London (UCL). Funding Cancer Research UK, UK Medical Research Council, Educational Grants and Drug Supply from Bayer, Cancer Australia Support for Cancer Clinical Trials Program and University College London. Disclosure T.Q.G. Eisen: Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (self): Pfizer; Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): GSK; Honoraria (self): AVEO; Honoraria (self): Astellas; Honoraria (self): Boehringer Ingelheim. I.D. Davis: Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche / Genentech; Research grant / Funding (institution): MSD Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bristol-Myers Squibb. M.R. Stockler: Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Binomics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Tilray. J.M.G. Larkin: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Achilles Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Covance; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Aveo; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Eisai; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: GSK; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Imugene; Advisory / Consultancy: Incyte; Advisory / Consultancy: iOnctura. A. Bex: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy, Non-remunerated activity/ies: BMS; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eusa; Non-remunerated activity/ies: Roche. S. Joniau: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas ; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ferring; Speaker Bureau / Expert testimony: GSK; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): MDX Health; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony: Sanofi. J. Bellmunt: Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre-Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Takeda; Shareholder / Stockholder / Stock options: Biocline. All other authors have declared no conflicts of interest.