Cetuximab Plus Carboplatin and Paclitaxel With or Without Bevacizumab Versus Carboplatin and Paclitaxel With or Without Bevacizumab in Advanced NSCLC (SWOG S0819): A Randomised, Phase 3 Study

Background EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. Methods We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Findings Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9–39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75–1·12; p=0·40; median 5·4 months [95% CI 4·5–5·7] vs 4·8 months [3·9–5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83–1·04; p=0·22; median 10·9 months [95% CI 9·5–12·0] vs 9·2 months [8·7–10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36–0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46–1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78–1·40; p=0·77; and 1·02, 0·77–1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68–1·14; p=0·34; and 0·99, 0·78–1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85–1·17; p=0·97; and 1·03, 0·88–1·20; p=0·69; respectively). The most common grade 3–4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [\u3c 1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Interpretation Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation

Molecular testing to optimize therapeutic decision making in advanced colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer death in the United States. In recent years, therapeutic advances have prolonged the survival of patients with advanced disease. Along with the addition of new treatments, an increasing body of literature explores the potential benefit of using molecular testing to define tumor, circulating, or host biomarkers of benefit to specific treatment strategies. At present, testing for specific mutations in exons 2, 3, and 4 of KRAS and NRAS has become accepted practice to select patients for treatment with epidermal growth factor receptor (EGFR)-targeted agents. Additionally, testing for the BRAF V600E mutation is used to refine decisions based on patient prognosis. The presence of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) *28 polymorphism is associated with toxicity from irinotecan, although it has not been universally applied. Nonetheless, molecular markers to predict response and toxicity of cytotoxic therapy are evolving. While the development of selection biomarkers for anti-angiogenic treatments has not proved fruitful to date, improved development strategies and novel targeted agents are anticipated to revolutionize the approach to treatment of advanced CRC in the near future. This review summarizes currently available data to select treatment strategies in patients with advanced CRC

Predictors of Neck Reoperation and Mortality After Initial Total Thyroidectomy for Differentiated Thyroid Cancer.

BackgroundIn an era of rising differentiated thyroid cancer incidence, the rate and impact of neck reoperation may inform the intensity of earlier interventions and surveillance. This study sought to define predictors of neck reoperation and to assess its impact on survival.MethodsUsing the California Cancer Registry linked to the California Office of Statewide Health Planning and Development records, a retrospective cohort study was performed of 24,230 patients with total or near-total thyroidectomy for papillary or follicular thyroid cancer between 1991 and 2008 and follow-up through 2013. The primary outcome was neck reoperation 91 days to 5 years after the initial thyroid surgery. Using logistic and Cox proportional hazards regression, the impact of sociodemographics, tumor staging, and hospital thyroid cancer surgery volume on neck reoperation and survival was determined.ResultsNeck reoperation was identified in 1231 (5.1%) patients in increasing odds from 1991 to 2008. In multivariable models, male sex, papillary thyroid cancer, and advancing tumor stage were associated with neck reoperation. Among men, neck reoperation was associated with Asian/Pacific Islander (odds ratio [OR] = 1.44 [confidence interval (CI) 1.07-1.94]) race/ethnicity. Among women, neck reoperation was associated with younger age (15-34 years; OR = 1.50 [CI 1.17-1.92] versus ≥55 years), and Asian/Pacific Islander (OR = 1.24 [CI 1.02-1.51]) or Hispanic (OR = 1.20 [CI 1.00-1.44]) race/ethnicity. After controlling for baseline characteristics, neck reoperation predicted worse thyroid cancer-specific survival (hazard ratio = 4.26 [CI 3.50-5.19]). The effect differed between men and women, and was most pronounced among women who received radioiodine in initial treatment (hazard ratio = 8.32 [CI 6.14-11.27]).ConclusionsNeck reoperation is becoming increasingly frequent and is strongly predictive of mortality. Advancing tumor stage, Asian/Pacific Islander race/ethnicity, male sex, as well as younger age and Hispanic ethnicity among women predict a higher risk for neck reoperation and subsequent mortality, reflecting a higher risk of persistent or more biologically aggressive disease

Predictors of Neck Reoperation and Mortality After Initial Total Thyroidectomy for Differentiated Thyroid Cancer

BackgroundIn an era of rising differentiated thyroid cancer incidence, the rate and impact of neck reoperation may inform the intensity of earlier interventions and surveillance. This study sought to define predictors of neck reoperation and to assess its impact on survival.MethodsUsing the California Cancer Registry linked to the California Office of Statewide Health Planning and Development records, a retrospective cohort study was performed of 24,230 patients with total or near-total thyroidectomy for papillary or follicular thyroid cancer between 1991 and 2008 and follow-up through 2013. The primary outcome was neck reoperation 91 days to 5 years after the initial thyroid surgery. Using logistic and Cox proportional hazards regression, the impact of sociodemographics, tumor staging, and hospital thyroid cancer surgery volume on neck reoperation and survival was determined.ResultsNeck reoperation was identified in 1231 (5.1%) patients in increasing odds from 1991 to 2008. In multivariable models, male sex, papillary thyroid cancer, and advancing tumor stage were associated with neck reoperation. Among men, neck reoperation was associated with Asian/Pacific Islander (odds ratio [OR] = 1.44 [confidence interval (CI) 1.07-1.94]) race/ethnicity. Among women, neck reoperation was associated with younger age (15-34 years; OR = 1.50 [CI 1.17-1.92] versus ≥55 years), and Asian/Pacific Islander (OR = 1.24 [CI 1.02-1.51]) or Hispanic (OR = 1.20 [CI 1.00-1.44]) race/ethnicity. After controlling for baseline characteristics, neck reoperation predicted worse thyroid cancer-specific survival (hazard ratio = 4.26 [CI 3.50-5.19]). The effect differed between men and women, and was most pronounced among women who received radioiodine in initial treatment (hazard ratio = 8.32 [CI 6.14-11.27]).ConclusionsNeck reoperation is becoming increasingly frequent and is strongly predictive of mortality. Advancing tumor stage, Asian/Pacific Islander race/ethnicity, male sex, as well as younger age and Hispanic ethnicity among women predict a higher risk for neck reoperation and subsequent mortality, reflecting a higher risk of persistent or more biologically aggressive disease

Phase II clinical trials on investigational drugs for the treatment of pancreatic cancers

IntroductionDespite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease.Areas coveredThis review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results.Expert opinionPromising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation

Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience

Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose–toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose–toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial