The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab–FOLFOX4 significantly improved ...progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study.
Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled.
A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months 95% confidence interval (CI) 9.3–11.4 months for arm 1 and 8.6 months (95% CI 7.5–9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67–0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3–27.7 months) for arm 1 and 19.7 months (95% CI 17.6–22.7 months) for arm 2; HR = 0.88; 95% CI 0.73–1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70–0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis.
In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab–FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab–FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.
Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and ...colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.
The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, ...and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo+FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes.
Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1:1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1:2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue) with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment.
Biomarker results were available from>80% (n=894) of patients. Analysis of the ME subset determined a VEGF-D level of 115pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME+MC populations found that the median OS in the ramucirumab+FOLFIRI arm compared with placebo+FOLFIRI showed an improvement of 2.4months in the high VEGF-D subgroup 13.9months (95% CI 12.5–15.6) versus 11.5months (95% CI 10.1–12.4), respectively, and a decrease of 0.5month in the low VEGF-D subgroup 12.6months (95% CI 10.7–14.0) versus 13.1months (95% CI 11.8–17.0), respectively. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers.
The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing.
NCT01183780.
Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of ...mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S.
Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments.
A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% 95% confidence interval (CI) 54–83 and 68% (95% CI 53–81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E.
No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted.
NCT01005199.
This double-blind, phase 3 study assessed the efficacy and safety of ganitumab plus gemcitabine as first-line treatment of metastatic pancreatic cancer. The study was stopped after a preplanned ...futility analysis indicated a positive outcome was unlikely at primary analysis. Ganitumab plus gemcitabine had manageable toxicity but did not improve OS versus gemcitabine alone in unselected patients.
This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer.
Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers.
Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months 95% confidence interval (CI), 6.3-8.2 in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494, and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77–1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3 were not associated with a treatment effect on OS or PFS by ganitumab.
Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer.
ClinicalTrials.gov NCT01231347.
Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) hazard ratio (HR)=0.84, 95% CI 0.73–0.98, ...P = 0.022. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.
Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum.
RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71–1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64–1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25–1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68–0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75–1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276).
In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant.
NCT01183780.
During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with ...the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research.
A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care.
The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP.
This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients.
•The burden of bureaucracy in clinical research is overwhelming investigators and clinical research teams.•This ESMO manuscript proposes a framework of principles to improve sponsoring and monitoring of clinical trials.•We expect this awareness call to streamline clinical research and to promote the welfare of patients.
The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage ...III colon cancer (CC). We report here the long-term survival results (S-AVANT).
Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab.
A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51–10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 95% confidence interval (CI) 1.07–1.55; P = 0.008 and 1.16 (95% CI 0.99–1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95–1.39; P = 0.147) and 1.1 (95% CI 0.93–1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III.
S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths.
NCT00112918.
•With a median follow-up of 6.73 years S-AVANT confirms the initial AVANT report, in patients with stage III Colon Cancer.•No benefit of bevacizumab addition to FOLFOX4 Cancer was observed in terms of Disease Free Survival.•In this exploratory analysis, bevacizumab addition to FOLFOX4 shows a negative statistically significant effect on OS.•This effect on OS was without increase in non-Colon Cancer related deaths.•Bevacizumab should not be used in adjuvant treatment of patients with curatively resected stage III Colon Cancer.
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a ...competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC.
This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate.
There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval CI: 0.81–1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm.
Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.
The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of ...advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers.
Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models.
The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS.
Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.
•RAINBOW trial showed a survival benefit for ramucirumab + paclitaxel in gastric cancer.•25 circulating biomarkers were assayed from plasma samples collected during the trial.•Some biomarkers showed changes during or after treatment.•Other biomarkers were associated with prognosis.•No biomarkers predictive of a ramucirumab benefit were identified.
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