Data Cut-off Point Research Articles

Abstract P5-21-22: Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer

Abstract Palbociclib, a first-in-class CDK 4/6 inhibitor, in combination with letrozole or fulvestrant is now licensed for the first or second line treatment of postmenopausal women with hormone-sensitive HER-2 negative metastatic breast cancer (MBC), but its activity in later lines is unknown. In Belgium, a compassionate Use Program (CUP) was temporarily established to provide palbociclib after at least 4 lines of systemic treatment for MBC. The UZ Leuven Multidisciplinary Breast Center included 82 patients in this CUP from September 28th 2015 to March 14th 2017. This analysis describes retrospectively collected efficacy (Revised RECIST guideline, version 1.1) and safety data from 68 patients with at least 6 months follow-up at the data cut-off point. The primary endpoint was clinical benefit, defined as being on treatment for at least 6 months (CR + PR + SD). Most of the patients (89.7%) used palbociclib in combination with letrozole. Other combinations are with tamoxifen (2.9%), fulvestrant (2.9%), exemestane (1.5%), anastrazole (1.5%) and megestrol (1.5%). At the data cut-off point, 18 patients are still on-treatment with palbociclib. The average duration of treatment is 5.7 months [range 2m- 17m]. The mean age of the patients was 66.3 years [range 34.8y – 85.9y] at the time of inclusion. Patients had had an average of 5.7 lines of systemic therapy [range 4 – 11 lines] before starting palbociclib, which was in 61.8% at least one line of chemotherapy. In this highly pretreated setting, 29 patients experienced stable disease lasting ≥ 6 months, resulting in an overall clinical benefit rate of 42.6%. 19.1% (13/68) showed stable disease for ≥ 9 months and 8% for ≥ 12 months. The subjective tolerance of the combination treatment was good, with 38% (26/68) of the patients discontinuing or delaying treatment following adverse events which were in the vast majority hematologic but asymptomatic. No factors predicting clinical benefit could be identified: use of chemotherapy before starting Palbociclib (p = 0.4644), age (p = 0.7029), time between primary breast cancer diagnosis and starting palbociclib (p = 0.1919) or time between first metastasis and starting palbociclib (p = 0.1108) and bone-only disease (p = 1,0000) were not significantly associated with clinical benefit at 6 months. These data not only support the findings of the PALOMA studies, but also show unexpectedly high clinical benefit and safety of palbociclib in heavily pretreated endocrine-resistant hormone receptor positive HER-2 negative advanced breast cancer. An update of these data will be presented. Citation Format: Hoste G, Punie K, Wildiers H, Neven P, Berteloot P, Van Nieuwenhuysen E, Han S, Concin N, Salihi R, Lefever I, Vergote I. Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-22.

Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations

BackgroundThe North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events.Patients and methodsProgression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80).ResultsAt the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report.ConclusionsThis updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice.Trial registration numberUMIN C000002789, Post-results.

Evaluating the Efficacy, Safety, and Dose Dependent Activities of Entospletinib in Patients with Chronic Lymphocytic Leukemia

Evaluating the Efficacy, Safety, and Dose Dependent Activities of Entospletinib in Patients with Chronic Lymphocytic Leukemia

Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.

Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.

Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of pertuzumab (Roche) to submit evidence for the clinical and cost effectiveness of pertuzumab+trastuzumab+docetaxel for the treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic or locally recurrent unresectable breast cancer in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee's (AC) initial decision. At the time of writing, final guidance had not been published by NICE. The clinical evidence was mainly derived from an ongoing phase III randomised double-blind placebo-controlled international multicentre clinical trial (CLEOPATRA), designed to evaluate efficacy and safety in 808 patients, which compared pertuzumab+trastuzumab+docetaxel (pertuzumab arm) with placebo+trastuzumab+docetaxel (control arm). Both progression-free survival (PFS) and overall survival (OS) were analysed at two data cut-off points-May 2011 (median follow-up of 18months) and May 2012 (median follow-up of 30months). At both time points, PFS was significantly longer in the pertuzumab arm (18.5months compared with 12.4months in the control arm at the first data cut-off point and 18.7 versus 12.4months at the second data cut-off point). Assessment of OS benefit suggested an improvement for patients in the pertuzumab arm with a strong trend towards an OS benefit at the second data cut-off point; however, due to the immaturity of the OS data, the magnitude of the OS benefit was uncertain. Importantly, cardiotoxicity was not increased in patients treated with a combination of pertuzumab+trastuzumab+docetaxel. The ERG's main concern with the clinical effectiveness data was the lack of mature OS data. An additional concern of the AC was that the majority of patients in the randomised controlled trial were trastuzumab naïve, which does not reflect current clinical practice. The incremental cost-effectiveness ratios (ICERs) generated by the manufacturer's model are considered to be commercial in confidence data and therefore cannot be published. Nevertheless, the results of the manufacturer's probabilistic sensitivity analyses suggest that pertuzumab+trastuzumab+docetaxel has a 0% probability of being cost effective at a willingness-to-pay of £30,000 per quality-adjusted life-year gained when compared with trastuzumab+docetaxel. The ERG believes that more realistic estimates of the ICERs are considerably higher, almost double those presented by the manufacturer. This is because the ERG believes that due to the manner in which the economic model is constructed, the additional survival benefit following disease progression that is generated for patients treated with pemetrexed+trastuzumab+docetaxel is unrealistic. At the time of writing, NICE had not made a final decision regarding this technology but had instead referred the issue of the assessment of technologies that are not effective at a zero price to their Decision Support Unit for advice.

Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

Eating habits and psychopathology: translation, adaptation, reliability of the Nutrition Behavior Inventory to Portuguese and relation to psychopathology

Objective: The Nutrition-Behavior Inventory (NBI) is a self-administered instrument that allows eating habits to be correlated with psychopathological symptoms. The objective was to translate and adapt the NBI to Portuguese, and test the Portuguese NBI’s reliability. The second aim was to verify its sensitivity for identification of risk factors in terms of behavior/eating habits in children and adolescents. Methods: The NBI was translated, adapted, and back-translated. The Portuguese version of the NBI was then applied (N = 96; 9-12 years). In order to verify the internal consistency, Cronbach’s alpha was used. The psychopathological indicators of the participants were accessed using the Child Behavior Checklist (CBCL). The mean CBCL scores were analyzed in relation to the NBI data (cutoff point: ≥ 30 with indicators, and &lt; 30 without). Results: Internal consistency was high (Cronbach’s alpha = 0.89) for the NBI. The CBCL scores correlated significantly with NBI (&gt; 30) on the following: anxiety and depression (p = 0.041), social difficulties (p = 0.028), attention problems (p = 0.001), aggressive behavior (p = 0.015); ADHD (p &lt; 0.001), and conduct problems (p = 0.032). Conclusion: The present results indicate that the NBI is a reliable instrument. The NBI can be useful for evaluating psychopathological symptoms related to the eating habits and behaviors of children and adolescents.

Tamoxifen and anastrozole as a sequencing strategy in postmenopausal women with hormone-responsive early breast cancer: updated data from the Austrian breast and colorectal cancer study group trial 8.

Abstract Abstract #14 Background: Historically, standard endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer (EBC) was 5 years' tamoxifen. However, the inclusion of an aromatase inhibitor (AI) is now considered standard practice. There is increasing evidence that whether as initial adjuvant treatment or as a switch treatment following 2-3 years of tamoxifen therapy, Ais improve patients' outcomes compared with 5 years' tamoxifen monotherapy.&amp;#x2028; To date, there is limited evidence comparing a prospective sequencing strategy of 2 years of tamoxifen followed by 3 years of an AI compared with 5 years' tamoxifen. Previously presented data from ABCSG Trial 8 (SABCS 2005), at a median follow-up of 55 months, revealed a 24% reduction in the risk of recurrence in favor of a sequencing strategy compared with 5 years' tamoxifen (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.56-1.02), although the difference was not statistically significant (p=0.07). Here we present updated data from ABCSG Trial 8.&amp;#x2028; Methods: Postmenopausal women with histologically verified G1 or G2, locally radically treated invasive or minimally invasive hormone receptor-positive breast cancer were eligible for inclusion. Newly diagnosed patients were randomized to receive 5 years' tamoxifen therapy or 2 years' tamoxifen followed by anastrozole for 3 years. The primary endpoint was event-free survival, including locoregional and distant metastatic recurrences and new contralateral breast cancers.&amp;#x2028; Results: This final analysis will report the data cut-off point, the number of eligible patients, and the median follow-up period of the trial, which will exceed 5 years. The incidence of first events, local recurrences, distant metastases, and contralateral breast cancers for the two treatment arms of the study will be presented. The effect of treatment on the trial endpoint will be analyzed using a Cox proportional hazards model and data will be presented as estimated HRs with two-sided 95% CIs and p-values.&amp;#x2028; Conclusions: The updated analyses of ABCSG Trial 8 will provide evidence regarding 2 years' treatment with tamoxifen followed by 3 years' anastrozole in comparison to 5 years' tamoxifen for postmenopausal women with newly diagnosed hormone-sensitive EBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 14.

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer

ZD9331 is a novel antifolate inhibitor of thymidylate synthase (TS). This multicentre, randomised, phase II/III study compared the efficacy and safety of ZD9331 with gemcitabine in 55 patients with chemonaı̈ve, locally advanced or metastatic pancreatic cancer. Patients received intravenous (i.v.) ZD9331 (n=30), on days 1 and 8 of a 3-week cycle or i.v. gemcitabine (n=25), once a week for 7 weeks followed by a 1-week rest, then on days 1, 8 and 15 of a 4-week cycle. Objective tumour response and clinical benefit response (CBR) were similar for both groups. More ZD9331 patients were alive at the data cut-off point compared with gemcitabine patients (13 and 8%, respectively). Median survival (152 versus 109 days, respectively) and time to progression (70 versus 58 days, respectively) were longer in the ZD9331 group. Nausea and vomiting (grade 1/2) were the most common toxicities in both groups. These results suggest that, in pancreatic cancer, ZD9331 is equivalent to gemcitabine and may offer a promising alternative to current therapies.