Cetuximab and Irinotecan With or Without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial.

BACKGROUND: Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. PATIENTS AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). CONCLUSION: In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted.Clinical Trial Registration: NCT02292758.

Behavioral and health outcomes from the NRG Oncology/NSABP B-36 trial comparing two different adjuvant therapy regimens for early-stage node-negative breast cancer.

BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.

Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial.

IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256.

DeImplementing Ineffective and Low-Value Clinical Practices: Research and Practice Opportunities in Community Oncology Settings.

Patients, practitioners, and policy makers are increasingly concerned about the delivery of ineffective or low-value clinical practices in cancer care settings. Research is needed on how to effectively deimplement these types of practices from cancer care. In this commentary, we spotlight the National Cancer Institute Community Oncology Research Program (NCORP), a national network of community oncology practices, and elaborate on how it is an ideal infrastructure for conducting rigorous, real-world research on deimplementation. We describe key multilevel issues that affect deimplementation and also serve as a guidepost for developing strategies to drive deimplementation. We describe optimal study designs for testing deimplementation strategies and elaborate on how and why the NCORP network is uniquely positioned to conduct rigorous and impactful deimplementation trials. The number and diversity of affiliated community oncology care sites, coupled with the overall objective of improving cancer care delivery, make the NCORP an opportune infrastructure for advancing deimplementation research while simultaneously improving the care of millions of cancer patients nationwide.

Impact of Diabetes and Insulin Use on Prognosis in Patients With Resected Pancreatic Cancer: An Ancillary Analysis of NRG Oncology RTOG 9704.

PURPOSE: Diabetes mellitus (DM) has been proposed to be tumorigenic; however, prior studies of the association between DM and survival are conflicting. The goal of this ancillary analysis of RTOG 9704, a randomized controlled trial of adjuvant chemotherapy in pancreatic cancer, was to determine the prognostic effects of DM and insulin use on survival. METHODS AND MATERIALS: Eligible patients from RTOG 9704 with available data on DM and insulin use were included. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and variable levels were compared using log-rank test. Cox proportional hazards models were created to assess the associations among DM, insulin use, and body mass index phenotypes on outcomes. RESULTS: Of 538 patients enrolled from 1998 to 2002, 238 patients were eligible with analyzable DM and insulin use data. Overall 34% of patients had DM and 66% did not. Of patients with DM, 64% had insulin-dependent DM, and 36% had non-insulin-dependent DM. On univariable analysis, neither DM nor insulin dependence were associated with OS or DFS (P > .05 for all). On multivariable analysis, neither DM, insulin use, nor body mass index were independently associated with OS or DFS. Nonwhite race (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.35-3.50; P = .0014), nodal involvement (HR, 1.74; 95% CI, 1.24-2.45; P = .0015), and carbohydrate antigen 19-9 (CA19-9) ≥90 U/mL (HR, 3.61; 95% CI, 2.32-5.63; P < .001) were associated with decreased OS. Nonwhite race (HR, 1.67; 95% CI, 1.05-2.63; P = .029) and CA19-9 ≥90 U/mL (HR, 2.86; 95% CI, 1.85-4.40; P < .001) were associated with decreased DFS. CONCLUSIONS: DM and insulin use were not associated with OS or DFS in patients with pancreatic cancer in this study. Race, nodal involvement, and increased CA19-9 were significant predictors of outcomes. These data might apply to the more modern use of neoadjuvant therapies for potentially resectable pancreatic cancer.

Neratinib-Plus-Cetuximab in Quadruple-WT (KRAS, NRAS, BRAF, PIK3CA) Metastatic Colorectal Cancer Resistant to Cetuximab or Panitumumab: NSABP FC-7, A Phase Ib Study.

PURPOSE: In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment. PATIENTS AND METHODS: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies. RESULTS: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples. CONCLUSIONS: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

SWOG S1400A (NCT02154490): A Phase II Study of Durvalumab for Patients With Previously Treated Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-study).

INTRODUCTION: The objective of the Lung-MAP sub-study S1400A was to evaluate the response rate to durvalumab, an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with squamous non-small-cell lung cancer (SqNSCLC). PATIENTS AND METHODS: Patients who progressed on at least 1 prior platinum-based chemotherapy were eligible. The study was designed as a phase II/III trial comparing durvalumab with docetaxel but was modified to a single-arm, phase II trial with the primary endpoint of objective response when immunotherapy became an approved treatment. RESULTS: A total of 116 patients were registered to this sub-study; 78 to durvalumab and 38 to docetaxel. Of the 78 patients, 9 were ineligible, and 1 was not evaluable for endpoints. Responses were achieved in 11 patients among the 68 eligible and evaluable patients on durvalumab (overall response rate, 16%; 95% confidence interval [CI], 7%-25%). The disease control rate was 54% (95% CI, 43%-66%), the median overall survival was 11.6 months (95% CI, 10.2-14.3 months), and the median progression-free survival was 2.9 months (95% CI, 2.0-4.0 months). PD-L1 data was available for 43 patients on durvalumab, with 14 (33%) patients who were PD-L1-positive (≥ 25%) and 2 responses (overall response rate, 14%; 95% CI, 0%-33%), the disease control rate was 57% (95% CI, 31%-83%), the median overall survival and progression-free survival were 10.7 months (95% CI, 9.2-14.3 months) and 2.3 months (95% CI, 1.4-4.2 months), respectively. Grade ≥ 3 treatment-related adverse events occurred in 22 (32%) patients on durvalumab, with 6 discontinuing owing to drug-related adverse events (9%; 95% CI, 2%-16%). CONCLUSIONS: Durvalumab shows single-agent activity and toxicities in this sub-group of patients that is comparable with other anti-programmed cell death protein 1/PD-L1 antibodies.

Dual VEGF inhibition with sorafenib and bevacizumab as salvage therapy in metastatic colorectal cancer: results of the phase II North Central Cancer Treatment Group study N054C (Alliance).

BACKGROUND: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. METHODS: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1-5 and 8-12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. RESULTS: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progression-free at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). CONCLUSIONS: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity. CLINICALTRIALSGOV IDENTIFIER: NCT00826540, URL:http://clinicaltrials.gov/ct2/show/NCT00826540.

SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).

BACKGROUND: S1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC). METHODS: Eligible patients had tumoral phosphatidylinositol-4,5-biphosphate 3 kinase catalytic subunit alpha (PIK3CA) alterations by next-generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4-mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival and duration of response. RESULTS: Twenty-six patients treated with taselisib comprised the full evaluable population (FEP); 21 patients comprised the PAP. Median age for patients in the FEP was 68 years (range: 53-83 years), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% response rate, 95% confidence interval [CI]: 0%-24%). Two possibly treatment-related deaths (one respiratory failure, one cardiac arrest) were observed; one patient had grades 4 and 11 had grade 3 adverse events. Median progression-free survival and overall survival in the PAP group were 2.9 months (95% CI: 1.8-4.0 mo) and 5.9 months (95% CI: 4.2-7.8 mo), respectively. These numbers were nearly the same in the FEP. CONCLUSIONS: Study S1400B evaluating taselisib in PIK3CA-altered sqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in sqNSCLC.

Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The TAPUR Study, a phase II, prospective, non-randomized, multi-basket, pragmatic clinical trial aims to identify signals of drug activity when Food and Drug Administration (FDA) approved drugs are matched to pre-specified genomic targets in patients with advanced cancer, outside of approved indications. METHODS: Patients eligible to participate in TAPUR are ages 12 years and older, with advanced, measurable or evaluable solid tumors, multiple myeloma or B cell non-Hodgkin lymphoma. Eligible participants are matched to any of the sixteen FDA approved study drugs based on protocol specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments certified, College of American Pathologists accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies, or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration and drug. The primary study endpoint within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary endpoints include safety, progression-free survival and overall survival. RESULTS: More than 1000 participants have thus far been registered and more than 800 treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment due to lack of anti-tumor activity and 12 have expanded to the second stage of enrollment due to promising preliminary activity. CONCLUSION: The TAPUR Study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant.

A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913.

Background: This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma. Methods: Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities. Results: A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors. Conclusion: Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

BACKGROUND: The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). PATIENTS AND METHODS: Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. RESULTS: A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. CONCLUSION: The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.

Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial.

BACKGROUND: Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. METHODS: This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954. FINDINGS: Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination. INTERPRETATION: Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population. FUNDING: ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.

Toxicity-Related Factors Associated With Use of Services Among Community Oncology Patients.

PURPOSE: Community oncology practices frequently manage chemotherapy-associated toxicities, which may disrupt treatment, impair quality of life, and induce unplanned service use. We sought to understand the patterns and correlates of unplanned health care service use among patients receiving first-cycle chemotherapy at five community-based ambulatory oncology practices. PATIENTS AND METHODS: A survey study examined the dichotomous outcome of unplanned service use, defined as oncologist visits, emergency department visits, and hospitalizations, resulting from toxicity-related factors. Newly diagnosed patients with breast, lung, head and neck, or colorectal cancer or non-Hodgkin lymphoma were recruited during the first chemotherapy cycle. Before beginning the second cycle of chemotherapy, patients completed a questionnaire that measured unplanned service use and overall distress, plus severity of nausea, vomiting, diarrhea, constipation, mouth sores, intravenous catheter problems, pain, fever and chills, extremity edema, and dyspnea on a 5-point scale (1, did not experience; 5, disabling). Medical record reviews captured chemotherapy doses, comorbid conditions, and supportive care interventions. Mixed-effects logistic regression was used to identify factors associated with unplanned service use, with random effects specified for each clinic. RESULTS: Among 106 patients (white, 98%; female, 74.5%; mean age ± standard deviation, 60 ± 11 years), frequently reported toxicities were pain, nausea, diarrhea, and constipation. Thirty-six patients (34%) reported unplanned service use: 29% reported oncologist visits, 14% reported emergency department visits, and 8% reported hospitalizations. Factors significantly associated with unplanned service use were high patient-reported distress and receipt of colony-stimulating factor. CONCLUSION: Service use resulting from toxicity-related factors occurs frequently in community oncology settings. Monitoring toxicity patterns and outcomes can inform proactive symptom management approaches to reduce toxicity burden between scheduled visits.

"Enjoy glass of wine before eating:" a randomized trial to test the orexigenic effects of this advice in advanced cancer patients.

BACKGROUND: Because the extant literature suggests wine increases appetite, this study sought to determine whether this effect could be observed in advanced cancer patients with appetite loss. METHODS: Advanced cancer patients with self-reported loss of appetite were randomly assigned to white wine with ≤15 % alcohol content twice a day for 3-4 weeks versus a nutritional supplement, such as Boost® or Ensure®. Patients assigned to wine were encouraged to also take a nutritional supplement, whereas patients assigned to the nutritional supplement arm were told to abstain completely from alcohol. Patient-reported outcomes were captured with a validated questionnaire to assess the primary endpoint of appetite improvement. RESULTS: A total of 141 patients (118 evaluable) were enrolled. Twenty-eight patients (48 %) in the wine arm reported an improvement in appetite at some point during the treatment period, whereas 22 patients (37 %) assigned to the nutritional supplement arm also reported improvement (p = 0.35). Other appetite-related questions and questionnaire items showed no statistically significant differences between treatment arms. In both arms, approximately 9 % of patients achieved weight stability (p = 0.98); median survival was not statistically different. Both interventions were well tolerated. CONCLUSION: As prescribed in this trial, wine does not improve appetite or weight in advanced cancer patients.

Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed.

PURPOSE: Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. PATIENTS AND METHODS: In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. RESULTS: In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). CONCLUSION: Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621.

INTRODUCTION: To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). METHODS: Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. RESULTS: All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48-82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1-34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10-48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5-5.1) and median OS was 11.2 months (95% CI: 9.9-13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). CONCLUSIONS: Saracatinib at a dose of 175 mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment.

Doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy: a phase III, randomized, double-blind trial (NCCTG-N09C6 [Alliance]).

PURPOSE: Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. PATIENTS AND METHODS: In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. RESULTS: Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. CONCLUSION: A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.

A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG-0720, NCT00792701).

BACKGROUND: This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm. METHODS: At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival. RESULTS: Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected. CONCLUSIONS: Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development.