Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial.

BACKGROUND: Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy-naïve chemotherapy-refractory advanced colorectal cancer. PATIENTS AND METHODS: This single-center, single-arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy-naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4-week cycle. The primary endpoint was progression-free survival (PFS) rate at week 8. RESULTS: Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1-64.3); median PFS was 3.5 months (95% CI, 1.8-3.6). Median OS was 7.4 months (95% CI, 5.3-8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib-related grade ≥3 adverse events were hypertension (36%), hand-foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib-related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0-1 (5.4 months). CONCLUSION: These findings support the antitumor activity of regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory mCRC. IMPLICATIONS FOR PRACTICE: The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment-refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single-center, single-arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic-naïve patients with chemotherapy-refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand-foot skin reaction.

Antitumor effect of everolimus in a patient with type 3 gastric neuroendocrine tumor.

BACKGROUND: Gastric neuroendocrine tumors (NET) are rare and are classified into 3 types: type 1 and 2 (characterized by hypergastrinemia), and type 3 (characterized by normal gastrin). Surgery is the standard procedure, and systemic treatment is reserved for unresectable disease. Currently, targeted therapies are being evaluated in NET. The activity of everolimus, an mTOR inhibitor, has been shown in pancreatic NET but not reported in type 3 gastric carcinoid tumors. CASE REPORT: Here we report a case of a patient who, after multiple lines of systemic therapy, had a prolonged disease control of nearly 1 year, significant clinical benefit, and minor tumor shrinkage with oral everolimus 10 mg continuously. CONCLUSION: There is no effective treatment for type 3 gastric carcinoid tumors. The frequency of mTOR expression in these tumors is not known, but the case reported here suggests that inhibition of this pathway may play an important role.

Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair-deficient advanced solid tumours: Results from the KEYNOTE-158 study.

BACKGROUND: In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K). PATIENTS AND METHODS: Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score. RESULTS: At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]). CONCLUSIONS: Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

Evaluation of 18F-FDG PET-CT as a prognostic marker in advanced biliary tract cancer.

BACKGROUND: Advanced biliary tract cancers have a dismal prognosis. Treatment with gemcitabine plus cisplatin has resulted in a significant improvement in survival; however, early assessment of outcomes poses a challenge. OBJECTIVE: We carried out a prospective study to evaluate the prognostic role of fluorine-18 fluorodeoxyglucose (F-FDG) PET-CT scans in patients with advanced biliary tract cancer. PATIENTS AND METHODS: Patients with advanced unresectable or metastatic biliary tract cancer starting first-line chemotherapy with gemcitabine plus cisplatin underwent F-FDG PET-CT studies at baseline and after two cycles of therapy. The total lesion glycolysis (TLG) measured at baseline as well as the variation in TLG between the two studies were analyzed as prognostic indicators of overall survival. The survival analyses were carried out using Kaplan-Meier curves and the comparison of survival curves was performed using the Breslow test. RESULTS: Of the 42 patients included, 37 had the first F-FDG PET-CT and 27 had the second F-FDG PET-CT. Patients with lower TLG values at baseline or after two cycles of therapy presented a higher median survival than patients with higher baseline TLG values. Patients with a higher decrease in the TLG values between the two studies also had a higher median survival time. However, these results only trended for statistical significance (P values ranging between 0.05 and 0.16). CONCLUSION: Lower baseline TLG measured by F-FDG PET-CT as well as a decrease in metabolic uptake after chemotherapy were associated with a trend toward longer median survival among patients with advanced biliary cancers.

Sample Size Calculation in Oncology Trials: Quality of Reporting and Implications for Clinical Cancer Research.

OBJECTIVES: Sample size calculation (SSC) is a pivotal step in clinical trial conception and design. Herein, we describe the frequency with which oncology phase III trials report the parameters required for SSC. MATERIALS AND METHODS: We systematically searched for phase III trials published in 6 leading journals, which were accompanied by editorials from January 2008 to October 2011. Two blinded investigators extracted required and optional parameters for SSC according to the primary endpoint. RESULTS: We retrieved 140 eligible phase III trials. The median target sample size was 596 subjects (50 to 40,000); in 66.4% of cases, the number of enrolled subjects was at least 90% of the target. The primary endpoint was a continuous variable in 5.7%, categorical in 30.0%, and a time-to-event variable in 64.3% of phase III trials. Although nearly 80% reported a target sample size, only 27.9% of the trials provided all the required parameters for proper SSC. The most commonly reported parameters for sample size computation were α (93.6%) and ß (90.7%) errors. The parameters least reported were the expected outcomes in the control or experimental groups, each provided in only 57.9% of trials. CONCLUSIONS: The quality of SSC reporting in phase III cancer trials is poor. Such incomplete reporting may compromise future study designs, pooling of data, and interpretation of results. Lack of transparency in SSC reporting may also have ethical implications.

Self-reported conflicts of interest of authors, trial sponsorship, and the interpretation of editorials and related phase III trials in oncology.

PURPOSE: Growing participation by industry in cancer research has resulted in increased reporting of conflicts of interest (COI). We aimed to test any association between authors' conclusions and self-reported COI or trial sponsorship in cancer studies. METHODS: Editorials and related phase III trials published in six clinical oncology journals in the last 3.5 years were analyzed independently by two investigators who classified study conclusions according to authors' endorsement of the experimental therapy. Logistic regression multivariable models were used to assess predictors of favorable conclusions of editorialists and of phase III authors. RESULTS: From January 2008 to October 2011, 1,485 articles were retrieved: 150 phase III trials and 150 editorials were eligible. Among the phase III trials, 82 (54.7%) had positive results, and 78 (52.0%) were entirely or partially funded by industry. Any COI were disclosed in 103 phase III trials (68.7%) and in 71 editorials (47.3%). Multivariable analysis showed that phase III trial results were the only significant predictor for a positive conclusion by trial authors (odds ratio [OR], 92.2; 95% CI, 19.7 to 431.6; P < .001). Sponsorship did not predict for positive conclusion by phase III authors (OR, 0.86; 95% CI, 0.3 to 2.5; P = .788). The only factor associated with positive conclusions by editorial authors was a positive conclusion by phase III trial authors (OR, 36.3; 95% CI, 6.8 to 194.2; P < .001). CONCLUSION: The interpretation of recently published phase III cancer trials by their authors or by editorialists was not influenced by financial relationships or industry sponsorship. Increased awareness of COI policies may have led to more integrity in cancer research reporting.