Summary Background Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. Findings Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6–12·0) for patients in the rilotumumab group and 9·4 months (5·3–13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7–10·2) in the rilotumumab group compared with 10·7 months (9·6–12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10–1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 ...

Background Many rectal cancer patients experience tumor downstaging and some are found to achieve a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT). Previous data suggest that there is an association between the time interval from nCRT completion to surgery and tumor response rates, including pCR. However, these studies have been primarily from single institutions with small sample sizes. The aim of this study was to examine the relationship between a longer interval after nCRT and pCR in a nationally representative cohort of rectal cancer patients. Study Design Clinical stage II–III rectal cancer patients undergoing nCRT with a documented surgical resection were selected from the 2006 – 2011 National Cancer Data Base. Multivariable logistic regression analysis was used to assess the association between nCRT-surgery interval time (<6 weeks, 6–8 weeks, >8 weeks) and the odds of pCR. The relationship between nCRT-surgery interval, surgical morbidity, and tumor downstaging was also examined. Results Overall, 17,255 patients met the inclusion criteria. A nCRT-surgery interval time >8 weeks was associated with higher odds of pCR (OR=1.12, 95%CI=1.01–1.25) and tumor downstaging (OR=1.11, 95%CI =1.02–1.25). The longer time delay was also associated with lower odds of 30-day readmission (OR=0.82, 95%CI: 0.70–0.92). Conclusions A nCRT-surgery interval time >8 weeks results in increased odds of pCR with no evidence of associated increased surgical complications compared to 6–8 weeks. This data supports the implementation of a lengthened interval after nCRT to optimize the chances of pCR and perhaps add to the possibility of ultimate organ preservation (non-operative management).

Introduction Nausea and vomiting are two of the most frequent and troubling side effects patients experience during chemotherapy, interfering with compliance with cancer therapies and quality of life. While newly available treatments have improved our ability to manage nausea and vomiting, anticipatory and delayed nausea and vomiting are still major problems for patients receiving chemotherapy. Many cancer patients consider delaying future chemotherapy cycles and some contemplate stopping chemotherapy altogether because of their fear of experiencing further nausea and vomiting. Areas Covered The purpose of this article is to provide an overview of the patho-psychophysiology of chemotherapy-induced nausea and vomiting, the recommended guidelines for treatment, current agents in late-stage clinical trials, and future research needs to address the continued challenges of treatment-related nausea and vomiting. Expert Opinion Despite advances in pharmaceutical and behavioral therapies, and the provision of standard clinical guidelines for effectively managing chemotherapy-induced nausea and vomiting (CINV), patients continue to experience CINV. Moreover, control of nausea, acute and delayed, and anticipatory nausea and vomiting (ANV) remains an important, unmet need among cancer patients. It is critical to focus attention on better understanding the mechanisms underlying nausea, anticipatory symptoms, and delayed symptoms.

SUMMARY Importance KRAS mutations are very common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy refractory pancreatic cancer. Objective SWOG S1115 was a randomized phase 2 study of selumetinib and MK-2206 versus modified FOLFOX in patients who failed gemcitabine-based therapy. Design, Setting, and Participants Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma who failed gemcitabine-based chemotherapy were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin 85 mg/m2 intravenous and 5-fluorouracil 2,400 mg/m2 intravenous infusion over 46–48 hours) on days 1 and 15 with each cycle being 28 days. Main Outcomes and Measures The primary endpoint of the study was overall survival. Secondary objectives included evaluating toxicities, objective tumor response and progression free survival (PFS). Results Median OS was shorter in the experimental arm (3.9 vs 6.7 months, HR=1.37, p=0.15). PFS was also inferior in the experimental arm (HR=1.61, p=0.02). One vs five patients had a partial response and 12 vs 14 patients had stable disease in the selumetinib plus MK-2206 arm versus (vs) mFOLFOX. Grade 3 or higher toxicities were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients on the experimental arm discontinued therapy due to adverse events, as well. Conclusions and Relevance Although, dual targeting of MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients who failed gemcitabine-based chemotherapy, this was the first randomized prospective evaluation of mFOLFOX in the U.S. population which showed comparable results to CONKO-003 and PANCREOX. Trial Registration ClinicalTrials.gov, number NCT01658943

Purpose This study was conducted in order to characterize the prevalence of falls and functional impairments (FIs) and their association with chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors. Methods We analyzed baseline assessments from a phase III RCT in cancer survivors with self-reported CIPN scores of ≥4 out of 10. Patients completed the EORTC QLQ-CIPN-20 for neuropathy and reported falls in the previous 3 months. FIs were defined using the Activities of Daily Living subsection of the Vulnerable Elder’s Scale. Associations of baseline characteristics and CIPN with falls and FIs were examined using logistic regression. Results Of 421 patients, 11.9 % experienced recent falls and 26.6 % reported FIs. Motor neuropathy was the only factor associated with falls (OR=1.127, p=0.01). Factors associated with FIs included non-white race (OR=0.335 white relative to non-white, 0.781, p=0.01) and greater motor neuropathy scores (OR=1.262, p<0.0001). Conclusion CIPN, primarily motor, is associated with falls and FIs. Future prospective research should investigate the ability of motor neuropathy severity to predict falls.