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Background Tilsotolimod, a synthetic toll-like receptor 9 (TLR9) agonist, modulates the tumor immune microenvironment and has antitumor activity as monotherapy in preclinical models. In the ILLUMINATE-204 phase I/II study of tilsotolimod in combination with ipilimumab in patients with refractory melanoma, increased antitumor immune activity was observed in injected and uninjected tumors at 24 hours following tilsotolimod treatment. The ILLUMINATE-101 phase Ib study explored the safety, efficacy, and immune effects of tilsotolimod monotherapy in multiple solid tumors. Methods Adults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8 mg to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced melanoma were enrolled into an expansion cohort at the 8-mg dose, the recommended phase II dose established for melanoma. Objectives included characterizing safety and efficacy, and immunological assessment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and 24 hours post treatment for immune analyses. Results As of May 6 2019, 54 patients have been enrolled, including 38 patients into the dose evaluation portion and 16 patients into the melanoma expansion cohort. No dose-limiting toxicities were observed. The most common treatment-related adverse events were fever, fatigue, and chills. Within 24 hours, fresh tumor biopsies showed increased gene expression for multiple immune checkpoint pathways, increased IFN gamma levels, activation of the type 1 IFN pathway, and upregulation of MHC class I and II, compared to pretreatment biopsies. Of 43 evaluable patients, 15 (35%) had a RECIST v1.1 disease assessment of stable disease (duration 1.2 to 11.1 months, 1 patient ongoing). Conclusions Tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type 1 IFN signaling. A phase II study of tilsotolimod in combination with nivolumab and ipilimumab has been initiated for the treatment of multiple solid tumors (ILLUMINATE-206; NCT03865082). Clinical trial identification NCT03052205. Editorial acknowledgement Ted Everson, Idera Pharmaceuticals, Inc. Legal entity responsible for the study Idera Pharmaceuticals, Inc. Funding Idera Pharmaceuticals, Inc. Disclosure H. Babiker: Advisory / Consultancy: Endocyte; Advisory / Consultancy: Celgene. V. Subbiah: Advisory / Consultancy: Idera Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Loxo Oncology. S. Rahimian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. C. Haymaker: Research grant / Funding (institution): Idera Pharmaceuticals. C. Bernatchez: Research grant / Funding (institution): Idera Pharmaceuticals. G. Bindra: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. I. Iverson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. S. Chunduru: Shareholder / Stockholder / Stock options, Full / Part-time employment: Idera Pharmaceuticals. A. Diab: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: Nektar Therapeutics; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Jounce Therapeutics; Honoraria (self): Novartis; Advisory / Consultancy: Idera. All other authors have declared no conflicts of interest.

Aim: Combined BRAF and MEK inhibition, compared with BRAF inhibitor alone, may delay the onset of resistance. Vemurafenib + cobimetinib (vem + cobi) was evaluated in patients naive to or previously treated with BRAF inhibitor (BRAFi) in a phase Ib trial: BRIM7 (NCT01271803). Modulation of signaling pathways and transcriptional profiles were assessed in tumor samples. Methods: Tumor tissues were collected at baseline, on-treatment at cycle 1 day 14 (C1D14), and at disease progression (PD). Modulation of cell-signaling pathways was assessed in tumor biopsy specimens by immunohistochemistry (IHC) or reverse-phase protein array (RPPA). Tumor transcriptional profiles were measured on a NanoString platform. Results: pERK levels were inhibited an average of 86 ± 14% with vem + cobi in paired biopsy specimens (n = 7) at C1D14 compared with baseline, which coincided with enhanced down-regulation of ERK transcriptional targets, compared with vem alone (n = 20). Cytoplasmic pERK was inhibited by 92 ± 3% in BRAFi-naive patients and by 95 ± 3% in patients with PR/CR responses. The inhibition of S6 ribosomal protein phosphorylation (pS6) showed significant differences based on treatment response and prior treatment status. By IHC, pS6 levels were clearly reduced in BRAFi-naive patients (82 ± 8%) compared with patients whose disease progressed with BRAFi treatment (31 ± 22%) and similarly in PR/CR patients (88 ± 11%) vs PD/SD patients (33 ± 19%). These observations were verified in independent samples by RPPA: levels of pS6 (S235/236 and S240/244) and a pS6 downstream effector, p4EBP1 (T37/46), were significantly inhibited in the same patients. At PD, tumor pERK, pS6, and Ki67 inhibition were attenuated to different degrees in each patient, whereas transcriptional programs largely reverted to baseline profiles. Conclusions: Vem + cobi treatment resulted in robust modulation of tumor cell signaling and transcriptional programs. In concordance with reports for single-agent BRAF or MEK inhibitor treatment, potent inhibition of pS6 was observed in BRAFi-naive patients and patients with PR/CR, which may contribute to the enhanced response to the vem + cobi combination. Disclosure: Y. Yan: Employee of Genentech, Inc.; G. McArthur: Consultant: Roche-Genentech, Novartis, GSK, BMS, Millenium, Amgen Research: Pfizer, Millenium, Novartis; T. Gajewski: Consultant: Bayer, B-I, Abbvie, Roche/Genentech, Jounce, Dendreon, Amgen Investigator: BMS, Merck, Roche/Genentech, Incyte, Ono; I. Puzanov: Consultant: Roche (honoraria) Investigator: Roche/Genentech (funds to university); O. Hamid: Research/advisory board/consultant/speaker: Genentech; R. Gonzalez: Research/consultant/honoraria: GSK, Roche/Genentech, BMS; Y. Wang: Employee: Genentech; S. Lu: Employee: Genentech; M. Wongchenko: Employee: Genentech; N.W. Choong: Employee: Roche/Genentech Stockholder: Roche; A. Ribas: Consultant: Amgen, GSK, Genentech, Merck Stockholder: Kite Pharma.

Background: T-VEC is a herpes simplex virus-1 based oncolytic immunotherapy designed to selectively replicate in cancer cells and produce GM-CSF to initiate systemic antitumor immune responses. OPTiM, a phase 3 trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma, met its primary endpoint of higher durable response rate in favor of T-VEC. Objective response rate (ORR) was 26.4% vs 5.7%, with complete response (CR) 10.8% vs 0.7% in favor of T-VEC. Immune checkpoint blockade with ipi improves overall survival (OS) in advanced melanoma. Ipi has a 10-15% ORR with 1-2% CR by immune-related response criteria (irRC). A phase 1b/2 study was designed to evaluate safety and efficacy when T-VEC is added to ipi as a priming regimen (clinicaltrials.gov #NCT01740297). Phase 1b showed the combination was tolerable, and phase 2 opened in Aug 2013. Trial design: Phase 2 evaluates the efficacy and safety of T-VEC + ipi vs ipi alone in untreated, unresectable stage IIIB-IV melanoma. Approximately 140 patients will be randomized 1:1. The primary endpoint is OS. Secondary endpoints: safety, ORR, time to response, duration of response, progression-free survival, resection rate, 1- and 2-yr survival. Key eligibility criteria: unresectable stage IIIB-IV melanoma naive to systemic therapy (except adjuvant); ECOG performance status 0-1; measurable disease; ≥1 injectable cutaneous/ subcutaneous/ nodal tumor; no brain metastases; no symptomatic autoimmunity; no immunosuppression; no HIV/HBV/HCV; no antiherpetic therapy. T-VEC is injected into nonvisceral lesions up to 4 × 106 plaque forming units/mL (pfu/mL) on d1, wk 1; up to 4 × 108 pfu/mL d1, wk 4; then q2w. Ipi is dosed 3 mg/kg IV q3w × 4 starting wk 6 with the 3rd T-VEC dose. Treatment with T-VEC continues until all injectable tumors have disappeared, disease progression per irRC, or intolerance. Enrollment began in the USA and is expected to open in France/Germany by Dec 2014. Combining T-VEC and ipi represents a novel immunotherapeutic approach to promote the initiation of antitumor immunity and simultaneously enhance antitumor T-cell responses. Disclosure: F.A. Collichio: Dr. Collichio has served on an advisory board and received consultant fees from Amgen, Inc. She receives clinical trial research support from Amgen, Novartis, GlaxoSmithKline, Morphotec, and Bristol-Myers Squibb; M. Milhem: Dr. Milhem has participated on advisory boards for Genentech and Amgen, Inc.; R.H. Andtbacka: Dr. Andtbacka has participated in advisory boards for Amgen, Inc.; I. Puzanov: Dr. Puzanov has received honoraria for participation on advisory boards for Amgen, Inc. His institution receives research funding from Amgen, Inc.; Y. Saenger: Dr. Saenger has participated in advisory boards for Amgen, Inc.; J. Chesney: Dr. Chesney has served on an advisory board for Amgen, Inc. O. Hamid: Dr. Hamid has served as a consultant for Amgen, Inc. and has received clinical trials support from Amgen, Inc.; T. Logan: Dr. Logan's institution has received grant money, and writing assistance, medicines, equipment, or administrative support from Amgen, Inc.; J. Glaspy: Dr. Glaspy has served as a consultant to and received research support from Amgen, Inc.; C. Lebbe: Dr. Lebbe has participated in advisory boards for Roche, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Amgen, Inc.; J. Gansert: Dr. Gansert is a compensated employee and stockholder of Amgen, Inc.; A. Li: Ai Li is a compensated employee and stockholder of Amgen, Inc.; J. Chou: Dr. Chou is a compensated employee and stockholder of Amgen, Inc.; H. Kaufman: Dr. Kaufman has received honoraria from Amgen, Inc. for participation in advisory boards and has received research funding from Amgen, Inc. for conducting clinical trials. All other authors have declared no conflicts of interest.

Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, is active and tolerable in pts with advanced MEL (Topalian et al. NEJM 366:2443, 2012). We report long-term clinical activity, response duration off-therapy, tumor PD-1 ligand (PD-L1) expression associated with survival endpoints, and 3-yr overall survival (OS) for the MEL pts in this phase 1 trial. Methods: Previously treated pts with advanced MEL and no prior ipilimumab therapy received nivolumab 0.1, 0.3, 1, 3 or 10 mg/kg IV Q2W for ≤96 wks and were evaluated for OS and progression-free survival (PFS). Tumor cell surface expression of PD-L1 was retrospectively assessed in archival pretreatment specimens by a Dako immunohistochemistry assay, with PD-L1+ defined as ≥5% tumor cells expressing this marker. Results: From 2008–2012, 107 MEL pts initiated treatment with nivolumab: 25% had ≥3 prior therapies. One-, 2- and 3-yr OS rates were 63%, 48% and 41%, respectively. For the 33/107 (31%) pts with objective responses (OR; RECIST), median response duration was 22.9 months. Twenty-four OR pts stopped nivolumab for reasons other than disease progression; 11 (46%) maintained responses for ≥24 wks off drug (range: 24, 56+ wks). Four (4%) additional pts had unconventional “immune-related” responses; overall survival for these pts was 21.1, 28.6 + , 43.1+ and 48.0+ months as of September 2013. In a subset of 41/107 pts with available tumor samples, median OS for pts with PD-L1+ (n = 18) and PD-L1– (n = 23) tumors was not reached and 12.5 months, respectively; median PFS was 9.1 and 1.9 months, respectively. Safety has been previously reported (Topalian et al. J Clin Oncol 32:1020, 2014). Conclusions: In pts with advanced MEL, nivolumab demonstrated notable 2- and 3-yr OS rates, durable responses with several persisting following discontinuation of therapy, and an acceptable safety profile. Additional analyses will be presented on the correlation between key pt characteristics and response to nivolumab. Ongoing phase 3 trials are further evaluating nivolumab for MEL pts and will also explore the role of PD-L1 as a potential predictive biomarker for nivolumab activity. Disclosure: D.F. McDermott: Consultant advisor, BMS advisory board; Research Funding BMS; M. Sznol: Paid consultant and scientific advisory board-Bristol-Myers Squibb, Genentech/Roche, MedImunne, Amgen, Nektar, Symphogen, Merus, Amphivena, NeoStem, Anaeropharma, BeiGene, Kyowa-Kirin, Immune Design, Lion Biotechnologies, Seattle Genetics; R. Carvajal: Consultant- Aura Biosciences; S.L. Topalian: Consultant-BMS(uncompensated), Jounce Therapeutics (comp.), Sanofi (comp.); Stock options: Compugen, Amplimmune, NexImmune, Jounce Therapuetics; Research funding BMS; Other remuneration-BMS and Amplimmune Inc., patent royalties through Johns Hopkins Univ; M.B. Atkins: Consultant advisor, honoraria- BMS; J.D. Powderly: Employment-Biologics Human Application Lab; Consultant advisor-BMS, Genetech, Amplimmune, Merck; Honoraria-BMS; Research Funding-BMS, Genetech, Amplimmune, Merck, AstraZeneca; Other Rumuneration-BMS Speakers Bureau and Advisory Boards; W.H. Sharfman: Consultant advisor, honoraria-MerckM; D.C. Smith: Research funding-BMS; J.M. Taube: Consultant advisor, research funding-BMS; R.A. Anders: Research Funding BMS; C. Horak: BMS-employee, stock; G. Kollia: BMS-employee, stock; J.A. Sosman: Consultant advisor-BMS; Honoraria-Glaxo Smith Kline, Amgen; Research funding-BMS, Novartis, Glaxo Smith Kline; F.S. Hodi: Consultant advisor BMS-uncompensated. All other authors have declared no conflicts of interest.

Background Preclinical models show that combined inhibition of BRAF and MEK can delay the acquisition of resistance compared to BRAF inhibitor monotherapy. BRIM7 evaluated safety/tolerability of combined BRAF + MEK inhibition with vemurafenib (vem) + GDC-0973. Methods Eligible pts had BRAFV600-mutated unresectable or metastatic melanoma, and ECOG PS 0–1. Pts were either naive to vem or had disease progression on vem. The study consisted of dose-escalation and expansion stages. Pts received vem 720 mg or 960 mg BID continuously. GDC-0973 was used at doses of 60 mg, 80 mg or 100 mg QD 14 days (d) on/14 d off (14/14); 21 d on/7 d off (21/7); or continuously. Primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and PK. Results Of the 44 pts treated as of 17 April 2012, 72.7% are male, the median age is 55 y (range: 27–74), 77.3% are M1c and 68.2% had prior systemic therapy. The median no. of cycles to date is 3. One DLT (Grade 3 QT prolongation related to vem, leading to discontinuation of vem) was observed in the vem 960 mg BID + GDC-0973 60 mg QD 21/7 cohort (n = 6). Most common adverse events (AEs) for all pts regardless of attribution were diarrhoea (54.5%), rash (50.0%), nausea (38.6%), fatigue/asthenia (34.1%), liver function abnormality (25.0%) and photosensitivity/sunburn (25.0%). Most frequent treatment-related Grade ≥3 AEs were diarrhoea (6.8%), rash (6.8%), increased creatine phosphokinase (6.8%) and liver function abnormality (4.5%). Only 1 pt developed cutaneous squamous cell carcinoma. Dose reduction was required for vem in 1 pt, GDC-0973 in 2 pts and both drugs in 1 pt. Two dose levels: vem (720 mg & 960 mg BID) + GDC-0973 60 mg QD 21/7 were selected for expansion. Preliminary efficacy data in 8 evaluable vemurafenib-naive pts showed that all 8 pts had tumour reduction. Updated efficacy/safety will be reported. Conclusions GDC-0973 in combination with vem was tolerable and AEs were manageable. The combination can be delivered safely at the respective single-agent MTDs of vem (960 mg BID) and GDC-0973 (60 mg 21/7). Plans are underway for phase 3 testing of vem + GDC-0973. Disclosure R. Gonzalez: Roche/Genentech consulting, advisory boards and also corporate sponsored research for Roche/Genentech A. Ribas: A compensated consultant for Roche-Genentech. A. Daud: I have research funding from Roche and Genentech. No honoraria or advisory boards in the last year. A. Pavlick: I have participated in Genentech advisory boards and been part of the speakers bureau for Genentech. T.F. Gajewski: I participated in a Roche advisory board last year. I. Puzanov: Advisory board, speaker at the Zelboraf World Wide launch conference. M.S.L. Teng: I am a full time employee of Genentech. I. Chan: I am a full time employee of Genentech. N.W. Choong: I am a full time employee of Genentech. G. McArthur: Research support Pfizer, Novartis & Millennium

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

Introduction Dabrafenib (D) combined with trametinib (T) shows enhanced activity in BRAF V600-mutated cancer cell lines and xenograft models compared with either drug alone. Preclinically, D + T delays resistance and prevents BRAFi-induced proliferative skin lesions. Safety and efficacy of D + T, were evaluated in a four-part Phase 1–2 study. Safety and efficacy from Part C, the randomised study of D + T vs D are presented. Methods BRAFV600E/K mutation-positive, MM, BRAFi and MEKi treatment-naive pts (≥ 18 yrs; ECOG PS Results Pt (n = 162) baseline characteristics were balanced across the three arms. Investigator assessed median PFS for 150/2 was 9.4 mo v 5.8 for D mono (HR 0.39, 95% CI 0.25–0.62; p Conclusions D + T provided a statistically significant and clinically meaningful improvement in PFS, RR and DoR compared to D mono in pts with BRAF V600 mutation-positive MM. The data is consistent to Part B reported with D + T. Increased incidence and severity of pyrexia and lower incidence of hyperproliferative skin lesions are observed with D + T compared to D mono. Phase 3 studies are ongoing. Disclosure G.V. Long: Has participated in advisory boards for GlaxoSmithKline, Bristol Myers Squibb and Roche. Has received research funding and honoraria from Roche. J.A. Sosman: Has received research funding from GlaxoSmithKline. J.S. Weber: Has participated in advisory boards for, and has received honoraria from, GlaxoSmithKline. K.T. Flaherty: Has acted as a data safety monitoring board member and consultant (compensated) for, and has received research funding from GlaxoSmithKline. J.R. Infante: Has participated in an advisory board for GlaxoSmithKline. O. Hamid: Has acted as a consultant (uncompensated) for GlaxoSmithKline. Has received research funding from Bristol Myers Squibb. L. Schuchter: Has participated in advisory boards for Merck and has received research funding from GlaxoSmithKline, Merck and Genentech. J.S. Cebon: Has participated in GlaxoSmithKline advisory boards, and has received research funding and honoraria from GlaxoSmithKline. I. Puzanov: Has acted as a paid consultant to GlaxoSmithKline. A.P. Algazi: Has received research funding from GlaxoSmithKline. K. Lewis: Has received research funding from GlaxoSmithKline. W. Hwu: Has acted as a compensated consultant for Merck. Has received research funding from Bristol Myers Squibb. R.F. Kefford: Has participated in an advisory board for GlaxoSmithKline. P. Sun: Is a GlaxoSmithKline employee (Statistician) and owns GlaxoSmithKline stocks and shares. S.M. Little: Is a GlaxoSmithKline employee (Clinical Development Manager) and owns GlaxoSmithKline stocks and shares. R. Gonzalez: Has acted as a consultant to, and has received research funding from, GlaxoSmithKline. K. Patel: Is a GlaxoSmithKline employee (Director, Oncology Clinical Development) and owns GlaxoSmithKline stocks and shares. K.B. Kim: Has received research funding from GlaxoSmithKline. All other authors have declared no conflicts of interest.

Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Rationale Gem + taxane combinations have shown activity in some advanced cancers. Cbz (a novel taxane) + prednisone (P) improved overall survival vs mitoxantrone + P in pts with metastatic castration-resistant prostate cancer previously treated with docetaxel (de Bono 2010). Methods A Phase I study (NCT01001221) was conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + Gem (parts 1a and 1b) and to evaluate antitumour activity at the MTD (part 2). Pts with histologically or cytologically confirmed metastatic or unresectable solid tumours without existing standard treatment were eligible. Cohorts of 3–6 pts were treated with Cbz (15–20 mg/m2 1-h infusion) followed by Gem (700–1000 mg/m2) on d1 and Gem alone on d8 (part 1a). The administration sequence on d1 was then reversed (part 1b), based on preliminary PK data. Results Of the 12 pts in part 1a, 5 pts were treated at Cbz 20 mg/m2 + Gem 1000 mg/m2 dose level (DL 20/1000), 5 pts at DL 15/900 and 2 pts at DL 15/700. In part 1b, all 6 pts were treated at the lowest DL (700/15) allowed. At all DLs, ≥ 2 pts experienced a DLT, regardless of administration sequence. DLTs were febrile neutropenia (FN) (4 pts), Grade (Gr) 4 neutropenia (2 pts), Gr 4 thrombocytopenia (2 pts) and Gr 3 AST increase (1 pt). No MTD was established and part 2 was not performed. All pts experienced at least 1 treatment-emergent AE (TEAE); the most frequent all grade non-haematological TEAEs were fatigue 66.7%, decreased appetite 50.0%, diarrhoea 44.4%, nausea 38.9% and weight decrease 33.3%. Gr 3–4 haematological toxicities included neutropenia 66.7%, thrombocytopenia 33.3% and FN 22.2%. Nine pts continued study treatment and received 6–22 cycles; 3 pts had a partial response (melanoma, prostate small cell and appendiceal tumours), while 8 pts experienced stable disease. PK analysis did not reveal a drug–drug interaction between Cbz and Gem. Conclusion The MTD of Cbz + Gem could not be established due to DLTs. Antitumour activity was observed and drug administration sequence did not affect the toxicity profile. Further investigation of alternative dosing regimens is warranted in an effort to establish a tolerable combination. Disclosure P.M. LoRusso: Has received research funding from Sanofi. J. Yin: Is a Sanofi employee and owns Sanofi stocks and shares. S. Doroumian: Is a Sanofi employee (pharmacokineticist) and owns Sanofi stocks and shares. X. Zhi: Is a Sanofi employee (statistician) and owns Sanofi stocks and shares. A.J. Olszanski: Research funding - Sanofi supplies support for the conduct of the study. All other authors have declared no conflicts of interest.