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Background Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with rare driver gene alteration combinations in most men, requiring large sample sizes for stratified evaluations. We therefore hypothesized that the number of driver genes or pathways would affect prognosis in patients initiating androgen receptor signalling inhibitors (ARSi, i.e abiraterone acetate or enzalutamide). Methods We performed a post hoc analysis of the circulating tumor DNA (ctDNA) mutational landscape in ARSi-treated men with mCRPC (n = 342), recruited in our prospective, non-interventional, cohort study (n = 142) and the prospective NCT02125357 trial (n = 200). The driver gene mutational burden was defined as the number of detectable hotspot, pathogenic and/or function-affecting perturbations in 39 overlapping genes, which in turn were associated with 13 pathways. Progression-free survival (PFS) estimates were inferred by Kaplan-Meier analysis and multivariable Cox regression models, including the following covariates: PSA and ctDNA levels, prior chemotherapy, prior ARSi exposure, and presence of visceral metastases. Results Driver gene perturbations were detectedin 192/342 (56.1%) evaluable patients at baseline, with 152/192 (79.2%) and 40/192 (20.8%) perturbed patients having 1-3 and ≥ 4 significant events, respectively. PFS decreased as the driver mutational burden increased (0, 1-3, ≥ 4 drivers, median PFS 12.5 vs 5.6 vs 2.7 months, p Conclusions We demonstrate for the first time that the elevated driver mutational burden or number of affected pathways is independently associated with poor prognosis in mCRPC patients starting ARSi. Legal entity responsible for the study CORE-ARV-CTC and ProBio Investigators. Funding The Belgian Foundation Against Cancer, Kom op tegen Kanker (the Flemish Cancer Society), Royal College of Surgeons/Cancer Research UK, The Erling-Persson Family Foundation, the Swedish Research Council, and the Swedish Cancer Foundation. Disclosure All authors have declared no conflicts of interest.

Background Salvage radiotherapy (SRT) is a potentially curative option for patients with rising PSA (biochemical recurrence) after radical prostatectomy. Recently, success rates of SRT were significantly improved through the use of concomitant anti-androgen (AAT) or androgen-deprivation (ADT) therapy. In RTOG 96-01, 2 years of bicalutamide 150 mg resulted in a 5% OS benefit at 12-years. In GETUG-AFU 16, 5-year progression-free survival was significantly improved when SRT was combined with 6 months of an LHRH agonist. Based on GETUG-AFU 16, most European urologists and (radiation) oncologists now combine SRT with at least 6 months of ADT. However, ADT comes with several serious side-effects, both physical (cardiovascular, metabolic, musculoskeletal) and psychological (sexual, emotional and cognitive). Considering RTOG 96-01, and in view of new AAT options, it appears worthwhile to look for alternatives. In that respect, apalutamide (ERLEADA®), a next-generation anti-androgen, is an interesting candidate. Trial design This is a phase II randomized, open-label study comparing SRT in combination with 6 months of LHRH (ant)agonist (arm A) versus 6 cycles of apalutamide 240 mg daily (each cycle is 28 +/- 2 days) (arm B) in hormone-naive patients with biochemical recurrence (PSA > 0.1 µg/L at least 8 weeks after radical prostatectomy). Patients with severe erectile dysfunction are excluded. All subjects will receive SRT as standard of care and will be randomly assigned in a 1:1 ratio to arm A or B. Primary objective is to compare sexual function, based on the EPIC-26 sexual domain score, at 9 months (i.e. 3 months after the end of hormonal treatment). Secondary endpoints include general quality of life (EPIC-26, EORTC QLQ C30 and PR25, FACT-P), acute as well as late toxicity (CTCAE version 5.0), and PSA (complete) response rates (i.e. decline from baseline in PSA level of 80% (90%) or greater). The trial was approved by the local ethics committee on April 2nd 2019 and started recruiting immediately thereafter. Clinical trial identification NCT03899077; 2018-004365-13. Legal entity responsible for the study GZA Hospitals. Funding Janssen. Disclosure All authors have declared no conflicts of interest.

Background Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. Patients and methods Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). Results In phase I (n = 12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. Conclusion Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Background: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. Patients and methods: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) greater than or equal to 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m(2)/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m(2) dose schedule were eligible for a 200 mg/m(2) dose on the next cycle. Results: The primary endpoint was six-month progression- free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. Conclusions: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.

Summary Background CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer. Patients and methods Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks. Results Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%–25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade>3) were diarrhea, leuko-cytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. Thse toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents. Conclusion CPT-11 is an interesting moderately effective drug in pancreatic cancer.

Summary Background This phase II study with the topoisomerase I inhibitor topotecan was performed to determine its clinical activity and toxicity in patients with metastatic or locally unresectable colorectal cancer Patients and methods Topotecan 1.5 mg/m2 was administered intravenously by 30-minute infusion for 5 days. Fifty-nine patients entered the study, 2 were considered ineligible and 57 were evaluable for response and toxicity Results Partial response was obtained in 4 of 57 evaluable patients (7%). The median duration of the response was 11 months (range 9.3 to 12.2). This topotecan regimen was very well tolerated. A total of 290 courses were given, with a median of 4 courses per patient (range, 1 to 18). The major toxic effects were leuko- and neutropenia (91%), grade 3–4 in 48% and 79% of courses, respectively, but with only 2 infectious complications. Other side effects were grade 1 alopecia (77%) in 46%, nausea (35%), vomiting (10%), and maculo-papular rash (6%) Conclusions Topotecan administered as a daily-times-five regimen has only minor activity as a single-agent therapy in colorectal cancer

Background The pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 have demonstrated preclinical and clinical antitumor activity as single agents and in combination with other drugs. Here, we report interim results of BKM120 or BEZ235 + PTX in pts with advanced solid tumors. Methods In the first 2 arms of this 4-arm Phase Ib dose-escalation study, pts with metastatic or locally advanced solid tumors received once-daily oral BKM120 or BEZ235 + wkly IV PTX. Dose-escalation was guided by a Bayesian logistic regression model with overdose control. The primary objective was to determine the MTD of BKM120 or BEZ235 + PTX. Results 33 pts were treated with BKM120 (mg/d) + PTX (mg/m2) at 6 dosing levels: 40/70 (1 pt); 40/80 (5 pts); 60/80 (3 pts); 80/80 (4 pts); 100/80 (16 pts); and 120/80 (4 pts). DLTs were observed in 4 pts (1/16 at 100/80 and 3/4 at 120/80), including asthenia, hyperglycemia, and depression. The MTD of BKM120/PTX was declared as 100/80. Most common G3/4-suspected study treatment-related AEs (>5%) were neutropenia, hyperglycemia, and anemia. For the BEZ235 arm, 29 pts were treated with BEZ235 (mg/d) + PTX (mg/m2) at 4 dosing levels: 400/70 (2 pts); 400/80 (3 pts); 600/80 (4 pts); and 800/80 (20 pts). DLTs were observed in 4 pts (3/20 at 800/80 and 1/4 at 600/80), including GI events, peripheral neuropathy, and febrile neutropenia. The MTD of BEZ235/PTX was declared as 800/80. Most common G3/4-suspected study treatment-related AEs (>10%) were fatigue, diarrhea, and anemia. As of Feb 29, 29 pts were evaluable for response in each arm. In the BKM120/PTX arm, 1 CR (penile carcinoma [Ca]), 4 PRs (breast and ovarian Ca pts, each with multiple lines of prior therapy [12 and 3] and progression on prior PTX; cervical and vulvar Ca), and 11 SDs were observed. In the BEZ235/PTX arm, 1 PR (large-cell Ca of the lung, taxane-naive), and 9 SDs were observed. Conclusion BKM120 or BEZ235 + PTX were generally well tolerated and showed preliminary signs of efficacy. The MTDs of both BKM120/PTX and BEZ235/PTX were reached. For BKM120, the MTD in combination with PTX was the same as the single-agent MTD. Arms 3 and 4 will determine the MTD of BEZ235 or BKM120 + PTX and trastuzumab in pts with advanced HER2+ breast Ca. Disclosure M. Schuler: Martin Schuler is an advisor for Novartis, and receives research funding from Novartis. J. Machiels: Jean-Pascal Machiels is on an advisory board for Boehringer, and receives a research grant from Sanofi. D. Hess: Dagmar Hess owns N. Steeghs: Neeltje Steeghs receives research funding from Novartis. L. Paz-Ares: Luis Paz-Ares has been an advisor for Lilly, Bayer, Roche and Pfizer. He has also received honoraria from all of the above. R. von Moos: Roger von Moos is a participant of advisory boards for Amgen, Novartis, Roche, BMS, and MSD, and receives unrestricted research grants and speaker honoraria from Amgen and Roche. B. Rabault: Bertrand Rabault is a employee of Novartis Pharma AG and owns stock in novartis pharma. All other authors have declared no conflicts of interest.

Summary Tropisetron is a 5-HT3 receptor antagonist which suppresses nausea and vomiting induced by cancer chemotherapeutic agents. In this study, tropisetron was evaluated on a compassionate-need basis in 545 cancer patients who had either proved refractory to antiemetic treatment during previous chemotherapy or who were at high risk of emesis as a result of current therapy. Tropisetron (5 mg or 10 mg) was administered as a 15-minute infusion prior to chemotherapy, with the further possibility of an additional dose, either orally or parenterally, on one or more subsequent days. In some patients the drug was administered orally on the day before treatment. On Day 1 of Course 1, 64.7% of patients had a complete response to tropisetron, i.e. no nausea or vomiting, and 26.9% of patients had a partial response. More than 80% of patients with a complete response in Course 1 had a complete response in Course 2 and of the partial responders in Course 1, 37% achieved a complete response in Course 2. Of the 7.6% failures in Course 1, a further 26% achieved a complete response in Course 2. Tropisetron was well tolerated, with adverse effects recorded in only 45 (8%) patients.

Aim: Aberrant hedgehog (Hh) signaling has been observed in tumors with dysregulated PI3K signaling. Sonidegib (LDE225; smoothened inhibitor that blocks Hh activity) and buparlisib (BKM120; pan class I PI3K inhibitor) show antitumor activity in ph I studies and combined, enhanced activity in xenograft models. In this ph Ib study (NCT01576666), the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetic (PK) interaction, and preliminary antitumor activity of LDE225 + BKM120 were assessed in pts with metastatic breast cancer (mBC), pancreatic adenocarcinoma (PANC), metastatic colorectal cancer (mCRC), or recurrent glioblastoma (GBM). Methods: Adult pts received different daily doses (followed by Bayesian logistic regression model) of LDE225 and BKM120, starting at 400 and 60 mg, respectively. Safety, tolerability, PK, antitumor activity, and biomarkers (PIK3CA/PTEN) were assessed. Safety and PK are reported. Results: Pts (N = 46; 7 mBC, 9 PANC, 19 mCRC, 11 GBM) were enrolled into 5 cohorts (Table). As of Dec 12, 2013, 44 pts (95.7%) discontinued, primarily due to disease progression (n = 29) and adverse events (AEs; n = 7). G 3/4 AEs (> 5%) regardless of study drug included increased alanine and aspartate aminotransferase (21.7% each), increased blood creatine phosphokinase (17.4%), hyperglycemia (8.7%), and increased blood alkaline phosphatase, aphasia, nausea, fatigue (6.5% each). See Table for dose-limiting toxicities (DLTs); MTD was not reached. At the RDE (LDE225 400 mg/BKM120 80 mg), no drug-drug interaction was observed, the interindividual variability of LDE225 and BKM120 PK (cycle 1 D 1) was ≈ 67% and ≈ 30%, respectively, and trough levels over time aligned with single-agent exposure. Summary of Dose-Limiting Toxicities Observed in the Dose-Escalation Phase Cohort Dose Level (once daily) DLTs Occurring Within 6 Weeks of First Dose (n = 1 for each) No. of Pts Enrolled No. of Pts With DLTsa/ No. of Evaluable Ptsb 1 LDE225 400 mg + BKM120 60 mg None 6 0/4 2 LDE225 800 mg + BKM120 60 mg - Grade 3 aspartate aminotransferase elevation - Grade 3 anorexia - Grade 3 creatine phosphokinase elevation - Grade 4 creatine phosphokinase elevation 7 2/5 3 LDE225 400 mg + BKM120 80 mg Grade 3 creatine phosphokinase elevation 15 1/7 4 LDE225 400 mg + BKM120 100 mg - Grade 2 photosensitivity - Grade 3 rash - Grade 3 alanine aminotransferase elevation - Grade 3 aspartate aminotransferase elevation 9 3/9 5 LDE225 200 mg + BKM120 100 mg Grade 3 alanine aminotransferase elevation 9 1/4 a Pts w/multiple occurrences of a DLT at 1 dose level were each counted once. b Pts who met the minimum exposure criteria to be included in the dose-determining set. Conclusions: LDE225 + BKM120 is tolerable, with expected DLTs, consistent with ph I studies. PKs of each agent in combination appear similar to PKs observed in single-agent studies. Based on these data, further study of the combination is warranted. Disclosure: M. Schuler: participated in advisory boards (compensated) for AstraZeneca, Boehringer Ingelheim (BI), Novartis (NVS), Pfizer; received research funding from BI, NVS; received honoraria for CME lectures from Alexion, BI, Celgene, GSK, Lilly, NVS, Pfizer; A. Rampersad: is employed by Novartis Pharmaceuticals Corporation; J. Zhou: is employed by Novartis Pharmaceuticals Corporation; Y. Wu: is employed by Novartis Pharmaceuticals Corporation and owns stock; S. Kalambakas: is employed by Novartis Pharmaceuticals Corporation and owns stock; P.Y. Wen: participated in an advisory board for Novartis and received research funding from Novartis.All other authors have declared no conflicts of interest.

Aim: The BOLT phase 2 study, comparing 2 doses of sonidegib, a hedgehog pathway inhibitor (HhPI), in pts with advanced BCC (aBCC; NCT01327053), met its primary endpoint of objective response rate ≥30% in both arms in analyses of data collected up to 6 mo after randomization of the last pt (June 28, 2013, cutoff; median follow-up [f/u], 13.9 mo; Migden, ASCO 2014). Associations of GLI1 (marker of Hh pathway activation) with clinical outcome (as of June 28, 2013) and updated 12-mo efficacy and safety data (Dec 31, 2013, cutoff; median f/u, 20.0 mo) are presented. Methods: Pts with locally advanced BCC (LaBCC; n = 194) not amenable to curative surgery or radiation or metastatic BCC (mBCC; n = 36) were randomized 1:2 to receive sonidegib 200 or 800 mg daily. Clinical response was assessed by central review using modified RECIST (LaBCC) or RECIST 1.1 (mBCC). Exploratory analyses in a subset of pts (LaBCC, n = 137; mBCC, n = 13) assessed GLI1 levels by qRT-PCR in tumor tissue collected at baseline (BL), wk 9, and wk 17. Results: GLI1 levels decreased from BL with both doses at wk 9 and 17 (median % changes [200 mg], -91.07 and -93.75; P Conclusions: Reduced GLI1 levels vs BL were seen in pts with disease control. With longer f/u, sonidegib continued to demonstrate clinically meaningful tumor shrinkage, sustained responses, and prolonged progression-free survival in pts with aBCC. The 200-mg dose had a better benefit-risk profile. Clinical Responsea with Sonidegib in Pts with Advanced BCC in the Full Analysis Setb by Central Review Parameter LaBCC mBCC Sonidegib 200 mg n = 66 Sonidegib 800 mg n = 128 Sonidegib 200 mg n = 13 Sonidegib 800 mg n = 23 ORR (CR + PR; 95% CI), % CR, % PR, % Disease control (CR + PR + SD), % 57.6 (44.8-69.7) 4.5 53.0 90.9 43.8 (35.0-52.8) 1.6 42.2 81.3 7.7 (0.2-36.0) 0 7.7 92.3 17.4 (5.0-38.8) 0 17.4 91.3 TTR, median (95% CI), mo 4.0 (3.8-5.6) 3.8 (3.7-5.5) 1.8 (NE) 1.0 (1.0-2.1) DOR Events (PD or death)/responders, n Median (95% CI), mo 12-mo event-free probability (95% CI), % 7/38 NE 62.3 (33.0 -81.7 ) 11/56 15.7 (NE) 71.5 (49.7-85.1) 0/1 NE 100 (NE) 1/4 NE NE PFS PFS events, n Median (95% CI), mo 12-mo event-free probability (95% CI), % 11 22.1 (NE) 82.1 (66.9-90.8) 22 21.5 (NE) 80.4 (67.4-88.6) 6 13.1 (5.6-16.9) 58.9 (23.4-82.5) 11 11.1 (NE) 42.0 (17.6-64.9) CR, complete response; DOR, duration of response, NE, not estimable; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to tumor response. a Data cutoff: December 31, 2013. b Intent-to-treat population. Disclosure: R. Dummer: has served an advisory role, received honoraria, and research funding from Astra Zeneca, Novartis, Cephalon, MSD, BMS, GSK, Roche, Amgen, and Bayer; A. Guminski: has served an advisory role for Novartis; R. Gutzmer: has served an advisory role for Roche, MSD, BMS, Novartis, GSK; received honoraria from Roche, BMS, MSD, Janssen, Amgen, GSK, Almirall, Novartis, MerckSerono, Pfizer; and has received research funding from Roche, Novartis, Pfizer; R. Herd: has received research funding from Novartis; M. Kaatz: declares research funding from:BMBF, Bristol-Myers-Squibb, Roche Pharma AG, GlaxoSmithKline GmbH, MSD SharpD A. Stratigos: discloses consultancy for Novartis and Roche Genentech; research funding from Pfizer; and honoraria from Leo Pharma and Bristol Myers Squib; R. Plummer: discloses research funding from Novartis; T. Yi: is employed by Novartis and owns stock; A.L.S. Chang: discloses research funding from Novartis, Genentech, and Lilly; R. Kudchadkar: has served an advisory role and received honoraria from Genentech and BMS; U. Trefzer: has served an advisory role and received honoraria from Roche; J. Lear: has received honoraria from Novartis; D. Sellami: is employed by Novartis and owns stock; M.R. Migden: has received honoraria from Genentech, Novartis, Lilly; has received institutional research funding from Genentech; and has provided expert testimony on behalf of Novartis. All other authors have declared no conflicts of interest.

Aim: Advanced BCC can cause considerable morbidity and severe disfigurement, leading to emotional and psychological distress and reduced QOL. The hedgehog (Hh) pathway is aberrantly activated in ≥ 95% of BCCs. Sonidegib blocks the Hh pathway by selective inhibition of smoothened. In a phase 2 study (BOLT; NCT01327053), patients (pts) with advanced BCC achieved meaningful disease control with sonidegib. The impact on pt-reported QOL is presented here. Methods: Pts with locally advanced BCC (LaBCC) not amenable to curative surgery or radiotherapy (n = 194) or metastatic BCC (mBCC; n = 36) were randomized to receive sonidegib 200 or 800 mg (1:2) once daily. QOL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the associated Head and Neck cancer module (HN and 11.1, 11.3, 5.6, and 16.5 months for physical functioning, social functioning, fatigue, and weight loss, respectively, and NE for other scales with 800 mg. Conclusions: Overall, pts treated with sonidegib in the BOLT trial maintained or improved their functioning and QOL, supporting the treatment effect observed in pts with advanced BCC and the favorable tolerability of sonidegib. Table. Pt-Reported QOL in Pts With Advanced BCC Treated With Sonidegib. Pts Na n (%)b Sonidegib 200 mg once daily Sonidegib 800 mg once daily LaBCC mBCC LaBCC MBCC EORTC QLQ-C30 Physical functioning N = 61 N = 13 N = 110 N = 20 Improvement from BL 22 (36.1) 9 (69.2) 35 (31.8) 8 (40.0) No change from BL 29 (47.5) 3 (23.1) 38 (34.5) 10 (50.0) Social functioning N = 61 N = 13 N = 109 N = 20 Improvement from BL 16 (26.2) 5 (38.5) 22 (20.2) 7 (35.0) No change from BL 40 (65.6) 6 (46.2) 75 (68.8) 12 (60.0) Pain N = 61 N = 13 N = 110 N = 20 Improvement from BL 19 (31.1) 6 (46.2) 36 (32.7) 11 (55.0) No change from BL 36 (59.0) 7 (53.8) 52 (47.3) 7 (35.0) Fatigue N = 61 N = 13 N = 109 N = 20 Improvement from BL 23 (37.7) 6 (46.2) 21 (19.3) 8 (40.0) No change from BL 26 (42.6) 6 (46.2) 55 (50.5) 8 (40.0) EORTC HN R. Gutzmer: has served an advisory role for Roche, MSD, BMS, Novartis (NVS), GSK; received honoraria from Roche, BMS, MSD, Janssen, Amgen, GSK, Almirall, NVS, MerckSerono, Pfizer; and received research funding from Roche, NVS, Pfizer; M.R. Migden: has served an advisory role and received honoraria from Genentech, Novartis, Lilly; received institutional research funding from Genentech; provided expert testimony on behalf of Novartis; K. Higuchi: Keiko Higuchi is employed by Novartis; S. Gogov: is employed by Novartis and owns stock; T. Yi: Dr. Tingting Yi is employed by Novartis and owns stock; R. Herd: has received research funding from Novartis; R. Kudchadkar: has served an advisory role and received honoraria from Genentech and BMS; U. Trefzer: has served an advisory role and received honoraria from Roche; J. Lear: has received honoraria from Novartis; D. Sellami: is employed by Novartis and owns stock; A. Guminski: has served an advisory role for Novartis. All other authors have declared no conflicts of interest.

Thymidine incorporation studies performed in animal tumour models, revealed major differences in endothelial cell proliferation when tumour tissue was compared with normal tissue. The fraction of proliferating endothelial cells is reported to be increased by a factor of 30 to 40 in tumour tissue.To make it possible to analyze the endothelial cell proliferation in human tumours, an immunohistochemical double staining technique comprising CD31, an endothelial cell marker, and Ki-67, a proliferation marker, was developed. Endothelial cell proliferation was analysed in 21 primary human colorectal adenocarcinomas and in the adjacent mucosa.Proliferating endothelial cells were found throughout the entire carcinoma. The mean overall endothelial cell labeling index (ECLI) was 9.9% (range, 5.4-18.0), and the labeling index of endothelial cells in areas of intense neovascularisation was even higher. Mean ECLI in the vascular hot spots was 21.0% (range, 6.8-35.0), and the mean tumour cell labeling index (TCLI) in the maximally Ki-67 immunostained areas was 78.3% (range 47.0-89.7). In 14 of 21 carcinomas, these areas were predominantly found at the luminal margin of the tumour, as were the vascular hot spots. A significant positive correlation was found between tumour vascularity, measured in the vascular hot spots, and tumour cell proliferation, measured in the maximally Ki-67 immunostained areas (p0.05). To analyse this relation in more detail, microvessel density (MVD), TCLI and ECLI were determined per x400 microscopic field by scanning in sequence from the luminal tumour margin to the invasive tumour base. In all tumours, the pattern of the MVD per x400 field, from the luminal margin to the tumour base, was similar to that of the TCLI and ECLI.These findings confirm that the fraction of cycling endothelial cells is higher in human colorectal carcinoma than in the adjacent mucosa which suggests that endothelial cells are proliferating in most of the individual capillaries in tumour tissue. Regional differences in MVD correlate with differences in tumour cell proliferation in these tumours.

Background Vismodegib (Erivedge™, GDC-0449) is a first-in-class small-molecule inhibitor of the Hedgehog signaling pathway, which is implicated in the pathogenesis of BCC. ERIVANCE BCC is the pivotal trial of vismodegib for treatment of locally advanced (laBCC) and metastatic BCC (mBCC) patients (pts) for whom there are no other effective therapies. The study met its primary endpoint of overall response rate by independent review (Dirix, ESMO 2011 LBA#1). On behalf of the ERIVANCE BCC investigators, we present the previously unreported updated investigator-assessed (I-A) efficacy and safety endpoints as of Nov 28, 2011 (additional 12 months of follow-up). Methods In this multicenter, nonrandomized 2-cohort study, pts with histologically confirmed laBCC (deemed inoperable or for whom surgery would be significantly disfiguring) or mBCC with RECIST-measurable disease, received 150 mg oral vismodegib daily. Results 104 pts (71 laBCC/33 mBCC) enrolled at 31 global sites. I-A efficacy endpoints were: Nov 26, 2010 Data Cut Nov 28, 2011 Data Cut Parameter mBCC (n = 33) laBCC (n = 63) mBCC (n = 33) laBCC (n = 63) Overall Response Rate (ORR), n (%) [95% CI] 15 (45.5) [28.1–62.2] 38 (60.3) [47.2–71.7] 16 (48.5) [30.8–66.2] 38 (60.3) [47.2–71.7] Median Duration of Response (DOR), months [95% CI] (n = 15) 12.9 [5.6–12.9] (n = 38) 7.6 [7.4–NE] (n = 16) 14.7 [5.6–NE] (n = 38) NE [9.0–NE] Median Progression-free Survival (PFS), months [95% CI] 9.2 [7.4–NE] 11.3 [9.5–16.8] 9.3 [7.4–16.6] 12.9 [10.2–NE] Median Overall Survival (OS), months [95% CI] NA NA 24.1 [14.3–NE] NE [NE–NE] With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78% (95% CI 63.6–92.4%) and 60% (95% CI 42.6–78.1%), for mBCC and 93.1% (95% CI 86.6–99.6%) and 85% (95% CI 75.6–94.7%), for laBCC. Adverse events (AEs) in >30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea (in 2/6 female nonmenopausal pts). Serious AEs were reported in 33 pts (32%), compared with 26 (25%) in Nov 2010. Conclusions This 12-month update of I-A efficacy and safety data from the ERIVANCE BCC study confirms the significant clinical benefit of vismodegib in laBCC and mBCC reported at primary analysis. Median DOR and PFS increased numerically with further follow-up. The AE profile was consistent with the prior data cut. Following approval of vismodegib by the FDA, these data further support vismodegib as an effective treatment option for pts with advanced BCC. Disclosure A. Sekulic: Speaker bureau: Genentech/Roche. M.R. Migden: Advisory board: Genentech. A. Oro: Grant: Genentech, Novartis, Infinity. K. Lewis: Grant: Genentech Consulting fee/honoria: Genentech. J. Hou: Employee: Genentech Shareholder: Genentech. H. Yue: Employee: Genentech Shareholder: Genentech. A. Hauschild: Consult/honoraria:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI Reviews:Roche Spker bureau:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI. All other authors have declared no conflicts of interest.