Purpose: To assess the role of pathologic complete response (pCR) after neoadjuvant therapy as surrogate end point of disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, we performed a trial-based meta-regression of randomized studies comparing different neoadjuvant systemic treatments. Methods: The systematic literature search included electronic databases and proceedings of oncologic meetings. Endocrine therapy trials were excluded. Treatment effects on DFS and OS were expressed as hazard ratios (HRs), and treatment effects on pCR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome. Results: Twenty-nine trials, 59 arms, and 30 comparisons, for a total of 14,641 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for DFS or the log(HR) for OS on the log(OR) for pCR demonstrated only weak associations (R² = 0.08; 95% CI, 0 to 0.47; and R² = 0.09; 95% CI, 0.01 to 0.41, respectively). Better associations were found in an exploratory analysis assessing a subset of trials comparing intensified/dose-dense chemotherapy versus standard-dose regimens (DFS: R² = 0.79; 95% CI, 0.26 to 0.95; P = .003; and OS: R² = 0.57; 95% CI, 0.19 to 0.93; P = .03). Conclusion: This meta-regression analysis of 29 heterogeneous neoadjuvant trials does not support the use of pCR as a surrogate end point for DFS and OS in patients with breast cancer. However, pCR may potentially meet the criteria of surrogacy with specific systemic therapies.

Context: In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14mg/liter or greater and metabolite formation. Objective: The study was performed to confirm the correlation of the currently used mitotane (o,p′DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p′-dichlorodiphenyl) acetic acid (o,p′DDA) and o,p′DDE (1,1-(o,p′-dichlorodiphenyl)-2,2 dichloroethene) levels for predicting tumor response. Subjects/Methods: Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively. O,p′DDD and metabolites were assessed and related to tumor response and survival. Receiver operating characteristic curves were used. Sensitivity and specificity were calculated for different cutoff levels of o,p′DDD and metabolites. Results: Objective tumor response was observed in 19% of patients. Median o,p′DDD level was higher in responders (P = 0.03). More responders were found among patients achieving o,p′DDD levels 14 mg/liter or greater (P = 0.02). Univariate and multivariate analysis showed significantly longer survival for patients with o,p′DDD levels 14 mg/liter or greater (hazard ratio 0.52, P = 0.04, hazard ratio 0.46, P = 0.03). An o,p′DDD cutoff value of 14 mg/liter was associated with a sensitivity of 65% and specificity 69%. An o,p′DDD level 20 mg/liter or greater or 14 mg/liter or greater combined with o,p′DDA level 92 mg/liter or greater was associated with a specificity of 90 and 92%, respectively. Conclusions: Our data confirm the value of o,p′DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level in the therapeutic management of ACC patients. Furthermore, our results suggest additional benefit of higher levels of o,p′DDD and combined measurement of o,p′DDD and o,p′DDA.

Background: There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells.Objective: We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro.Design: Multicenter, prospective phase II trial.Setting: Referral centers for ACC.Methods: Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m² every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity.Results: Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose–response and time–response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel.Conclusions: Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.

PURPOSE: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs.PATIENTS AND METHODS: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780 ) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety.RESULTS: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions.CONCLUSION: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.