Frank Hermann

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial

BACKGROUND For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting. PATIENTS AND METHODS OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis. RESULTS In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively). CONCLUSIONS Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI. CLINICALTRIALSGOV NCT00778102.

Self-Reported Compliance with Capecitabine: Findings from a Prospective Cohort Analysis

Objectives: While oral anticancer treatment has increased the convenience for patients with no risk of venous access complications compared to intravenous drug administration, a high level of compliance cannot always be assumed. The aim of the present report was to evaluate real-life drug adherence in a prospective cohort analysis of patients with gastrointestinal or breast cancer treated with capecitabine-based chemotherapy. Methods: Twenty-nine Swiss oncologists recruited patients receiving capecitabine, either as monotherapy or in combination with other chemotherapeutic agents, in a prospective fashion. Patients recorded both their capecitabine intake and any adverse effects each day in patient diaries. Results: A total of 177 patients were included, 143 (81%) with gastrointestinal tumours and 34 (19%) with breast cancer. Overall, 161 patients (91%) were considered as fully compliant, while 16 patients (9%) reported some kind of compliance error. Reasons for non-compliance included forgetting to take treatment (n = 9), side effects (n = 4) and misunderstanding instructions (n = 3). Self-reported compliance was not influenced by age or Eastern Cooperative Oncology Group performance status, but there was a trend towards better compliance with capecitabine therapy if fewer adverse effects occurred (p = 0.07, simple logistic regression). Conclusions: Self-reported compliance with capecitabine-based therapy in clinical practice is high and seems to be adversely affected by side effects.

Pre-existing antihypertensive treatment predicts early increase in blood pressure during bevacizumab therapy: the prospective AVALUE cohort study.

Background: Antiangiogenic therapy is routinely used in a variety of cancer entities. Hypertension is the most common side effect of all currently available antiangiogenic treatments. Patients and Methods: In this prospective observational clinical trial, we investigated risk factors for blood pressure elevation in patients exposed to an antiangiogenic agent and explored the correlation between hypertension and the duration of antiangiogenic treatment. Results: In 169 patients, pre-existing antihypertensive medication was the most prominent risk factor associated with increased blood pressure during therapy. Between visits 1 and 3, the median systolic blood pressure increased by 10.85 mmHg in patients with pre-existing hypertension receiving antihypertensive medication while it increased by only 2.69 mmHg in patients without hypertension. The median increase in diastolic pressure was 7.28 versus 0.11 mmHg in patients with versus without pre-existing hypertension. Increases in blood pressure occurred early (within 6 weeks of starting therapy). In spite of this significant increase in the blood pressure, no major bleeding events or other related complications were observed during antiangiogenic therapy. Conclusions: Pre-existing hypertension and treatment with antihypertensive medication correlated with a more pronounced increase in blood pressure. Thus, intensified antihypertensive therapy might be warranted early during bevacizumab therapy in patients already receiving antihypertensive treatment.

A Review of Clinical Studies and Practical Guide for the Administration of Triplet Chemotherapy Regimens with Bevacizumab in First-line Metastatic Colorectal Cancer

Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen.

Clinical development of 4SC-202, a combined epigenetic inhibitor of HDAC class I and LSD1, to overcome anti-PD-1 refractoriness and increase efficacy of checkpoint inhibition.

e14096Background: Checkpoint inhibitor (CI) like anti-PD(L)-1 antibodies are a breakthrough innovation, but a high unmet medical need remains for a large proportion of patients not responding. Low ...

520POVERALL SURVIVAL ACCORDING TO PATIENT SUBGROUPS: RESULTS FROM A POOLED ANALYSIS OF 5 OBSERVATIONAL OR PHASE IV STUDIES OF BEVACIZUMAB IN METASTATIC COLORECTAL CANCER

ABSTRACT Aim: Randomized controlled trials (RCTs) have demonstrated benefits in overall survival (OS) for patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab (BV) in the first-line setting. While RCTs have demonstrated clinical efficacy in a wide range of pts, there is a need to examine outcomes in daily clinical practice. Herein we describe results of a pooled analysis of OS according to pt subgroups from 5 observational or phase IV studies of BV in mCRC. Methods: Pt-level data were pooled from the BRiTE (USA), ARIES (USA), BEAT (ex-USA), CONCERT (France), and AWB (Germany) studies. The majority of the studies enrolled pts with previously untreated mCRC who received BV in combination with chemotherapy and prospectively collected data on survival and safety. Using descriptive methodology, OS in the pooled dataset was evaluated in first-line pts grouped according to age ( Results: The dataset included 7688 pts; OS was evaluable in 7631 patients. Median age was 62.9 y (range, 18–101); 58% of pts were male; 49% had ECOG PS 0. Median OS according to age is shown in the table. Median OS was 26.9 mo for pts with ECOG PS of 0 and 18.7 mo for pts with ECOG PS of ≥1. Median OS for males and females was 22.7 mo and 22.3 mo, respectively. OS results observed in the pooled population were generally consistent with those in each study. Conclusions: In this large, pooled population from 5 observational or phase IV studies of BV in mCRC, median OS was generally consistent with what has been shown with BV in RCTs. Consistency among subgroup OS results was observed across individual studies, despite regional differences in care likely received by patients. Additional subgroup analyses are ongoing; the dataset may be expanded to include other observational studies. Median OS according to age subgroup Pooled population n = 7631 BRiTE n = 1912 ARIES n = 1550 BEAT n = 1916 CONCERT n = 476 AWB n = 1777 Median OS, mo (95% CI) 23.7 (22.9–24.5) 21.1 (19.7–22.1) 25.1 (23.0–26.9) 23.3 (22.1–24.6) 27.5 (22.7–34.3) 25.7 (24.0–27.4) ≥70 y 19.8 (18.8–20.8) 16.3 (14.8–18.0) 19.6 (17.9–21.0) 19.8 (17.5–22.0) 24.6 (19.9–32.6) 23.0 (21.2–24.9) All patients 22.5 (22.1–23.0) 19.5 (18.3–20.5) 23.2 (21.2–24.8) 22.7 (21.6–23.7) 26.1 (22.7–30.7) 24.8 (23.7–26.1) Disclosure: A. Grothey: Corporate-sponsored research: Genentech, Eisai, Bayer, Eli-Lilly BBI; D. Arnold: Advisory board: Roche, compensated; E. Van Cutsem: Advisory board: Roche Corporate-sponsored research: Roche, paid to university;T. Bekaii-Saab: Other substantive relationship: Consultant to Genentech;M. Kozloff: Advisory board: Roche, Genentech Other substantive relationships: Roche, Genentech; J. Bennouna: Advisory board: Roche, Boehringer Ingelheim, Novartis, Celgene;C. Revil: Stock ownership: I bought shares from Roche from 2005 until 2012 Other substantive relationships: Roche employee, Stamford consultants AG, Dornach, Switzerland; M. Donica: Other substantive relationships: Roche; N. Sommer: Stock ownership: Roche Other substantive relationships: Genentech employee; B. Leutgeb: Other substantive relationships: Roche employee;M. Ekstrand-Olsen: Other substantive relationships: Roche employee; F. Hermann: Stock ownership: Non-voting share of Roche; H. Hurwitz: Corporate-sponsored research and compensated consultant: Genentech, Inc., F. Hoffmann-La Roche, Ltd., Pfizer, Sanofi, Regeneron, Bristol-Meyers Squibb, Eli Lilly, Merck KGA, Novartis, Incite, and Threshold Compensated consultant: GSK.