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Preview: Annals of Oncology - Advance Access

Annals of Oncology Advance Access

Published: Fri, 22 Sep 2017 00:00:00 GMT

Last Build Date: Fri, 22 Sep 2017 22:47:38 GMT


Overall survival analysis of EXAM, a phase 3 trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma


Primary analysis of the double-blind, phase 3 EXAM trial demonstrated significant improvement in progression-free survival (PFS) with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was performed after long-term follow-up.
Patients and Methods
EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.
Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 v 21.1 months), although the difference did not reach statistical significance (stratified hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.64 to 1.12; P = 0.24). In an exploratory assessment of OS, PFS, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo (HR, 0.60; 95% CI, 0.38 to 0.94; P = 0.03 [not adjusted for multiple subgroup analyses]), with correspoding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70–1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.
The secondary endpoint was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically non-significant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.
Trial Registration Number

Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer


BackgroundNRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown.Patients and MethodsHere we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.ResultsBoth tumours were found to be positive for NRG1 gene fusions. In patient 1 an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2 a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had previously been described. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.ConclusionThese observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.Clinical trial informationPersonalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621)

The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin lymphoma patients - the Polish Lymphoma Research Group (PLRG) Observational Study


Background: Interim PET after 2 ABVD cycles (iPET2) predicts treatment outcome in classical Hodgkin lymphoma (cHL). To test if an earlier assessment of chemosensitivity would improve the prediction accuracy, we launched a prospective, multicenter observational study aimed at assessing the predictive value (PV) of iPET after 1 ABVD (iPET1) and the kinetics of response assessed by sequential PET scanning.Patients and Methods: Consecutive patients with newly diagnosed cHL underwent interim PET scan after one ABVD course (iPET1). PETs were interpreted according to the Deauville score (DS) as negative (-) (DS 1-3) and positive (+) (DS 4,5). Patients with iPET1 DS 3-5 underwent iPET2.Results: 106 early (I-IIA) and 204 advanced (IIB-IV) patients were enrolled between 01/2008 and 10/2014. iPET1 was (-) in 87/106(82%) or (+) in 19/106(18%) of early, and (-) in 133/204(65%) or (+) in 71/204(35%) of advanced stage patients, respectively. Twenty-four patients were excluded from response analysis due to treatment escalation. After a median follow-up of 38.2 (3.2-90.2) months, 9/102-(9%) early and 43/184-(23%) advanced patients experienced a PFS event. At 36 months, negative and positive PV for iPET1 were 94% and 41% (early) and 84% and 43% (advanced), respectively. The kinetics of PET response was assessed in 198 patients with both iPETs. All 116 patients with iPET1(-) remained iPET2(-) (fast responders), 41/82 with IPET1(+) became iPET2(-) (slow responders), and the remaining 41 stayed iPET2(+) (non-responders); PFS at 36 months for fast, slow and non-responders was 0.88, 0.79 and 0.34, respectively.Conclusion: The optimal tool to predict ABVD outcome in HL remains iPET2 since it distinguishes responders, whatever their time to response, from non-responders. However, iPET1 identified fast-responders with the best outcome and might guide early treatment de-escalation both in early and advanced-stage HL.

Adjuvant Chemotherapy in Patients with Stage I Endometrioid or Clear Cell Ovarian Cancer in the Platinum Era: A Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013


Background: We sought to evaluate the impact of adjuvant chemotherapy on overall survival (OS) in patients with stage I endometrioid epithelial ovarian cancer (EEOC) or ovarian clear cell cancer (OCCC) using a national database.Patients and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I EEOC or OCCC from 2000-2013. We sought to identify predictors of chemotherapy use and to assess the impact of chemotherapy on OS in these patients. OS was compared using the log-rank test and Cox proportional hazards model.Results: 3,552 patients with FIGO stage I EEOC and 1,995 patients with stage I OCCC were identified. Of the 1,600 patients (45%) with EEOC who underwent adjuvant chemotherapy, the 5-year OS rate was 90%, compared with 89% for those who did not undergo adjuvant chemotherapy (P=0.807). Of the 1,374 (69%) patients with OCCC who underwent adjuvant chemotherapy, the 5-year OS rate was 85%, compared with 83% (P=0.439) for those who did not undergo adjuvant chemotherapy. Chemotherapy use was associated with younger age, higher substage, and more recent year of diagnosis for both the EEOC and OCCC groups. Only in the subgroup of patients with FIGO substage IC, grade 3 EEOC (n=282) was chemotherapy associated with an improved 5-year OS—81% compared with 62% (P=0.003) in untreated patients (HR: 0.583; 95%CI: 0.359-0.949; P=0.030). In patients with OCCC, there was no significant effect of adjuvant chemotherapy on OS in any substage.Conclusions: Adjuvant chemotherapy was associated with improved OS only in patients with substage IC, grade 3 EEOC. In stage I OCCC, adjuvant chemotherapy was not associated with improved OS.

Activity and safety of crizotinib in patients with advanced clear cell sarcoma with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 “CREATE”


Background: Clear cell sarcoma (CCSA) is an orphan malignancy, characterised by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor (TKI) crizotinib in patients with advanced or metastatic CCSA.Patients and methods: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary endpoint was objective response rate (ORR), secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), overall survival rate (OSR) and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization (FISH).Results: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and evaluable. 26/28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval:0.1-19.6). Further efficacy endpoints in MET+ CCSA were DCR:69.2% (48.2-85.7%), median PFS:131 days (49-235), median OS:277 days (232-442). The 3, 6, 12 and 24 month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two evaluable MET- patients, one had SD and one had progression. The most common treatment-related adverse events were nausea (18/34[52.9%]), fatigue (17/34[50.0%]), vomiting (12/34[35.3%]), diarrhea (11/34[32.4%]), constipation (9/34[26.5%] and blurred vision (7/34[20.6%]).Conclusions: The PFR with crizotinib in MET+ CCSA is similar to results achieved first-line in metastatic soft tissue sarcomas with single-agent doxorubicin. In further lines, the PFS is similar to pazopanib in previously treated sarcoma patients.Clinical trial number: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926

Risks and benefits from CDK inhibitors for advanced HR+ Her 2- breast cancer.


AbemaciclibRibociclibPalbociclibhormonal therapybreast cancermeta-analysis

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3508)


Background: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor (IGF-IR) that can potentially reverse resistance and enhance the efficacy of chemotherapy.Methods: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small cell lung cancer (NSCLC) and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of 6 cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg IV weekly (arm B).Results: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI, 5.4-7.1) in arm A vs. 7 months (95% CI, 5.7-7.6) in arm B (p = 0.33); hazard ratio 0.92 (95% CI, 0.65-1.31). Objective response was 46.2% vs. 58.7% in arm A vs. arm B (p = 0.15). The median overall survival was 16.2 months in arm A vs. 16.1 months in arm B (p = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab.Conclusions: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in NSCLC. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II Identifier: NCT00955305

A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study


Background Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.Material and methods We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2,982 incident breast cancer cases matched to 2,982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q-values) was computed to control for multiple comparisons. Subgroup analyses were performed by estrogen receptor (ER) and progesterone receptor (PR) expression in the tumours.Results A high level of palmitoleic acid (odds ratio, OR for the highest quartile compared with the lowest OR[Q4-Q1]=1.37; 95%CI=1.14-1.64; p for trend=0.0001, q-value=0.004) as well as a high desaturation index (DI16) (16:1n-7/16:0) (OR[Q4-Q1]=1.28; 95%CI=1.07-1.54; p for trend=0.002, q-value=0.037), as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumors (OR for the highest tertile compared with the lowest [T3-T1]=2.01; 95% CI = 1.03-3.90; p for trend=0.047), while no association was found for ER-positive tumors (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.Conclusion These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumorigenesis. Dietary trans fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.