Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer.

BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.

Nationwide Audit of Postoperative Mortality and Complications After Digestive Cancer Surgery: Will New Legal Thresholds be Sufficient?

BACKGROUND: French policymakers recently chose to regulate high-risk digestive cancer surgery (DCS). A minimum of five cases per year should be performed for each of the following types of curative cancer surgery: esophagus/esogastric junction (ECS), stomach (GCS), liver (LCS, metastasis included), pancreas (PCS), and rectum (RCS). This study aimed to evaluate the hypothetical beneficial effects of the new legal minimal volume thresholds on the rates of 90-day postoperative mortality (90POM) for each high-risk DCS. METHODS: This nationwide observational population-based cohort study used data extracted from the French National Health Insurance Database from 1 January 2015-31 December 2017. Mixed-effects logistic regression models were performed to estimate the independent effect of hospital volume. RESULTS: During the study period, 61,169 patients (57.1 % male, age 69.7 ±12.2 years) underwent high-risk DCS including ECS (n = 4060), GCS (n = 5572), PCS (n = 8598), LCS (n = 10,988), and RCS (n = 31,951), with 90POM of 6.6 %, 6.9 %, 6.0 %, 5.2 %, and 2.9 %, respectively. For hospitals fulfilling the new criteria, 90POM was lower after adjustment only for LCS (odds ratio [OR],15.2; 95 % confidence interval [CI], 9.5-23.2) vs OR, 7.6; 95 % CI, 5.2-11.0; p < 0.0001) and PCS (OR, 3.6; 95 % CI, 1.7-7.6 vs OR, 2.1; 95 % CI, 1.0-4.4; p<0.0001). With higher thresholds, all DCSs showed a lower adjusted risk of 90POM (e.g., OR, 0.38; 95 % CI, 0.28-0.51) for PCS of 40 or higher. CONCLUSION: Based on retrospective data, thresholds higher than those promulgated would better improve the safety of high-risk DCS. New policies aiming to further centralize high-risk DCS should be considered, associated with a clear clinical pathway of care for patients to improve accessibility to complex health care in France.

Effect of Adapted Physical Activity in Patients With Advanced Pancreatic Cancer: The APACaP GERCOR Randomized Trial.

BACKGROUND: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. PATIENTS AND METHODS: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. RESULTS: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were -0.98 (SD, 23.9; P=.39), -2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non-statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. CONCLUSIONS: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.

Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand-foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3-7.6) and 2.8 months (95% CI: 2.6-3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

BACKGROUND: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting. MATERIALS AND METHODS: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR). RESULTS: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007). CONCLUSION: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF. IMPLICATIONS FOR PRACTICE: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.

Implementation of a molecular tumor board at a regional level to improve access to targeted therapy.

BACKGROUND: With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. MATERIAL AND METHODS: Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. RESULTS: In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). CONCLUSIONS: In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

From early risk to 1-year mortality: a comprehensive assessment of postoperative venous thromboembolism in upper gastrointestinal cancer patients - a nationwide cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication following gastrointestinal cancer surgery, particularly early postoperatively. The incidence and risk factors of VTE within 1-year after esophageal (including esophago-gastric junction) (ECS) and gastric (GCS) cancer surgeries, and especially its impact on 1-year global mortality, are yet under-explored. METHODS: This nationwide observational population-based cohort study used data extracted from all patients undergoing ECS and GCS in France between 1 January 2015 and 31 December 2017. Multivariate logistic regression was used to identify risk factors for 90 postoperative days (POD) VTE (OR 95% CI). Cox proportional hazards models investigated the impact of 1-year postoperative VTE on 1-year global mortality [HR (95% CI)]. RESULTS: During the study period, 8005 patients underwent ECS ( N =3429) or GCS ( N =4576) (31.8% female; 66.7±12.1 years old). Majority ( N =4951) of patients had preoperative treatment (chemotherapy or radiochemotherapy). Ninety POD incidence of VTE were 4.7% (ECS=6.2%) (GCS=3.6%) (44.7% during first hospitalization, 19.0% needing readmission, and 36.3% ambulatory management). Main risk factors were three and two field esophagectomy [3.6 (2.20-5.83) and 2.2 (1.68-3.0)], obesity [1.9 (1.40-2.58)] and history of VTE [5.1 (2.72-9.45)]. Late-onset VTE rates (occurring between the 6th and 12th month) represented 1.80 and 1.46% of the overall ECS and GCS groups. Patients with VTE within 1-year had higher risks of 1-year global mortality: (2.04 1.52; 2.73) and 2.71 (2.09; 3.51), respectively. CONCLUSION: Our extensive analysis of a nationwide database highlights the significant risk of postoperative VTE after ECS and GCS, persisting within 90 POD and up to 1-year. Crucially, a higher risk of global mortality within 1-year for patients experiencing early or late VTE was found. These findings could advocate for further research into extended prophylactic regimens, particularly for those most at risk.

Global trends in oncology research: A mixed-methods study of publications and clinical trials from 2010 to 2019.

PURPOSE: To evaluate the cancer research effort of some major countries over two 5-year periods (2010-2014 and 2015-2019) on the basis of scientific publications and interventional clinical trial metrics and to analyze the relationship between research effort and cancer burden (incidence and mortality). MATERIALS AND METHODS: Clinical trials were extracted from ClinicalTrials.gov using a specific query. Publications were identified in Web of Science (WoS) using a query based on keywords and were then analyzed using InCites, a bibliometric tool. Bibliometric indicators were computed per country and per period. RESULTS: During 2010-2019, 1 120 821 cancer-related publications were identified in WoS, with 447 900 and 672 921 (+50%) articles respectively published in 2010-2014 and 2015-2019. Meanwhile, 38% and 7% of the articles were published in oncology and cell biology journals, respectively. Exactly 30% of the published articles were contributed by the USA. In the study period, China strongly increased its production and overspecialization. Apart from China, which had a low normalized citation impact (NCI), almost all countries increased their NCIs; in particular, France's NCI increased from 1.69 to 2.44. As for clinical trials, over 36 856 were opened worldwide during that period. Over 17 000 (46.5%) opened in the USA, which remained the leader during the study period. China ranked second worldwide in terms of the number of open trials in 2015-2019. Results revealed that the 17 cancer localizations versus cancer burden and research effort showed no evident relationship. CONCLUSION: The results may provide a scientific basis for decision making for continued research. Based on bibliometric data, this type of study will aid public health policymaking and lead to a more transparent public fund allocation.

Radiomics Approaches for the Prediction of Pathological Complete Response after Neoadjuvant Treatment in Locally Advanced Rectal Cancer: Ready for Prime Time?

In recent years, neoadjuvant therapy of locally advanced rectal cancer has seen tremendous modifications. Adding neoadjuvant chemotherapy before or after chemoradiotherapy significantly increases loco-regional disease-free survival, negative surgical margin rates, and complete response rates. The higher complete rate is particularly clinically meaningful given the possibility of organ preservation in this specific sub-population, without compromising overall survival. However, all locally advanced rectal cancer most likely does not benefit from total neoadjuvant therapy (TNT), but experiences higher toxicity rates. Diagnosis of complete response after neoadjuvant therapy is a real challenge, with a risk of false negatives and possible under-treatment. These new therapeutic approaches thus raise the need for better selection tools, enabling a personalized therapeutic approach for each patient. These tools mostly focus on the prediction of the pathological complete response given the clinical impact. In this article, we review the place of different biomarkers (clinical, biological, genomics, transcriptomics, proteomics, and radiomics) as well as their clinical implementation and discuss the most recent trends for future steps in prediction modeling in patients with locally advanced rectal cancer.

Prognostic value of pre-therapeutic FDG-PET radiomic analysis in gastro-esophageal junction cancer.

The main aim of this study was to evaluate the prognostic value of radiomic approach in pre-therapeutic 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET/CT) in a large cohort of patients with gastro-esophageal junction cancer (GEJC). This was a retrospective monocenter study including 97 consecutive patients with GEJC who underwent a pre-therapeutic FDG-PET and were followed up for 3 years. Standard first-order radiomic PET indices including SUVmax, SUVmean, SUVpeak, MTV and TLG and 32 textural features (TFs) were calculated using LIFEx software on PET imaging. Prognostic significance of these parameters was assessed in univariate and multivariate analysis. Relapse-free survival (RFS) and overall survival (OS) were respectively chosen as primary and secondary endpoints. An internal validation cohort was used by randomly drawing one-third of included patients. The main characteristics of this cohort were: median age of 65 years [41-88], sex ratio H/F = 83/14, 81.5% of patients with a histopathology of adenocarcinoma and 43.3% with a stage IV disease. The median follow-up was 28.5 months [4.2-108.5]. Seventy-seven (79.4%) patients had locoregional or distant progression or recurrence and 71 (73.2%) died. In univariate analysis, SUVmean, Histogram-Entropy and 2 TFs (GLCM-Homogeneity and GLCM-Energy) were significantly correlated with RFS and OS, as well as 2 others TFs (GLRLM-LRE and GLRLM-GLNU) with OS only. In multivariate analysis, Histogram-Entropy remained an independent prognostic factor of both RFS and OS whereas SUVmean was an independent prognostic factor of OS only. These results were partially confirmed in our internal validation cohort of 33 patients. Our results suggest that radiomic approach reveals independent prognostic factors for survival in patients with GEJC.

Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first-line platinum-based chemotherapy: Phase 2 study results.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB-290) is a small molecule inhibitor of PARP1 and PARP2. METHODS: The PARALLEL-303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. The primary endpoint of this double-blind, randomized, global phase 2 study was progression-free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. RESULTS: In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. CONCLUSIONS: Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

Occupational Exposures and Esophageal Cancer: Prog Study.

Esophageal cancer is the sixth most common cause of cancer death worldwide. In France, Brittany is one of the regions most seriously affected. This increased incidence is usually linked to high rates of alcohol overconsumption and smoking, established risk factors for esophageal cancer, but the region has special occupational exposures. We aim to describe the occupational exposures of patients with esophageal cancer. Between June and October 2020, we conducted a monocentric descriptive study in a French Teaching Hospital and identified 37 eligible patients. We gathered data through a systematic individual interview for each participant and by an analysis of their medical file. We were able to include 36 patients; most were men (n = 27, 75.0%) and smokers (n = 25, 69.4%), 21 (58.3%) presented an adenocarcinoma esophageal cancer, 13 (36.1%) a squamous cell cancer, and 2 other types. On occupational exposure, patients declared respectively high exposure by manipulating asbestos materials for 11 (30.6%) patients, regularly in contact with benzene by handling fuel in 7 cases (19.4%), chlorinated solvents in 4 cases (11.1%), pesticides in 4 cases, and ionizing radiation exposure in 3 patients (8.3%). Our findings support the creation of a large-scale study to explore the impact of occupational exposures, particularly exposure to asbestos and hydrocarbons.

Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181.

PURPOSE: In the phase III KEYNOTE-181 study (NCT02564263) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations. PATIENTS AND METHODS: HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales. RESULTS: The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, -1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups. CONCLUSION: In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.

Regorafenib-avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial.

BACKGROUND: Regorafenib has shown substantial clinical activity in patients with advanced biliary tract cancers (BTCs). Preclinical data suggested that this drug modulates antitumour immunity and is synergistic with immune checkpoint inhibition. PATIENTS AND METHODS: This is a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks/4, 160 mg quaque die (once a day) (QD); avelumab 10 mg/kg IV was given every two weeks, beginning at C1D15 until progression or unacceptable toxicity. The primary end-point was the confirmed objective response rate under treatment, as per Response Evaluation Criteria in Solid Tumours 1.1. The secondary end-points included the following: 1-year non-progression rate; progression-free survival (PFS) and overall survival; safety and biomarkers studies performed on sequential tumour samples obtained at baseline and at cycle 2 day 1. RESULTS: Thirty-four patients were enrolled in four centres. Twenty-nine patients were assessable for efficacy after central radiological review. The best response was partial response for four patients (13.8%), stable disease for 11 patients (37.9%) and progressive disease for 14 patients (48.3%). The median PFS and overall survival were 2.5 months (95% confidence interval [CI] [1.9-5.5]) and 11.9 months (95%CI [6.2-NA]) respectively. The most common grade 3 or 4 clinical adverse events related to treatment were hypertension (17.6%), fatigue (14.7%) and maculopapular rash (11.8%). High baseline levels of programmed cell death ligand 1 and of indoleamine 2, 3-dioxygénase expression were associated with improved outcomes. CONCLUSIONS: Regorafenib combined with avelumab has antitumour activity in a subset of heavily pretreated biliary tract cancer population. Further investigations are needed in patients selected based on tumour microenvironment features. CLINICAL TRIAL REGISTRATION: NCT03475953.

[HER2 and gastric cancer. Recommendations for clinical practice in 2011]. / HER2 et cancer gastrique. Recommandations pour la pratique clinique en 2011.

Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin has been approved by the European Medicines Agency (EMEA) for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]-positive or IHC 2+/ silver in situ hybridization [SISH]-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal (GE) junction. HER2 testing in gastric cancer (GC) differs from testing in breast cancer (BC) due to major differences in the tumor biology; as the disease is progressing rapidely, we recommend to test every GC at diagnosis and to offer a rapid testing (less than five days) in the metastatic setting. IHC should be the initial testing methodology and FISH or SISH should be used to retest IHC 2+ samples. As GC more frequently shows incomplete membrane staining and focal staining for HER2, HER2 testing guidelines have been adapted from BC protocols. The scoring system is slightly different in respect to the characteristics of GC. For in situ hybridization, SISH should be used in order to identify heterogeneous staining with a higher accuracy than FISH. Enrollment in training and quality assurance programs is highly recommended. In case of negativity on biopsy, it is recommended to retest for HER2, when possible, on surgical specimens and/or metastasis. This will ensure accurate and consistent HER2 testing results, which will allow the appropriate selection of patients eligible for treatment with trastuzumab.

Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial.

PURPOSE: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models. PATIENTS AND METHODS: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. RESULTS: Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8-5.4] and 10.8 months (95% CI, 5.9-NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome. CONCLUSIONS: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.

Prospective study of dynamic whole-body 68Ga-DOTATOC-PET/CT acquisition in patients with well-differentiated neuroendocrine tumors.

To present the feasibility of a dynamic whole-body (DWB) 68Ga-DOTATOC-PET/CT acquisition in patients with well-differentiated neuroendocrine tumors (WD-NETs). Sixty-one patients who underwent a DWB 68Ga-DOTATOC-PET/CT for a histologically proven/highly suspected WD-NET were prospectively included. The acquisition consisted in single-bed dynamic acquisition centered on the heart, followed by the DWB and static acquisitions. For liver, spleen and tumor (1-5/patient), Ki values (in ml/min/100 ml) were calculated according to Patlak's analysis and tumor-to-liver (TLR-Ki) and tumor-to-spleen ratios (TSR-Ki) were recorded. Ki-based parameters were compared to static parameters (SUVmax/SUVmean, TLR/TSRmean, according to liver/spleen SUVmean), in the whole-cohort and according to the PET system (analog/digital). A correlation analysis between SUVmean/Ki was performed using linear and non-linear regressions. Ki-liver was not influenced by the PET system used, unlike SUVmax/SUVmean. The regression analysis showed a non-linear relation between Ki/SUVmean (R2 = 0.55,0.68 and 0.71 for liver, spleen and tumor uptake, respectively) and a linear relation between TLRmean/TLR-Ki (R2 = 0.75). These results were not affected by the PET system, on the contrary of the relation between TSRmean/TSR-Ki (R2 = 0.94 and 0.73 using linear and non-linear regressions in digital and analog systems, respectively). Our study is the first showing the feasibility of a DWB 68Ga-DOTATOC-PET/CT acquisition in WD-NETs.

Clinical Assessment of 177Lu-DOTATATE Quantification by Comparison of SUV-Based Parameters Measured on Both Post-PRRT SPECT/CT and 68Ga-DOTATOC PET/CT in Patients With Neuroendocrine Tumors: A Feasibility Study.

PATIENTS AND METHODS: Patients with WD-GEP-NET who benefited from a pretherapeutic 68Ga-DOTATOC PET/CT and a 177Lu-DOTATATE SPECT/CT after the cycle 1 of peptide receptor radionuclide therapy were prospectively included. SPECT/CT acquisitions were performed on a system calibrated with a conversion factor of 9.48 counts/MBq per second and were reconstructed with an iterative algorithm allowing quantification using the SPECTRA Quant software (MIM Software, Cleveland, OH). For each patient, different SUV parameters were recorded on both PET/CT (Ga parameters) and SPECT/CT (Lu parameters) for comparison: physiological uptakes (liver/spleen), tumor uptake (1-10/patient; SUVmax, SUVmean, SUVpeak, MTV), tumor-to-liver and tumor-to-spleen ratios according to liver/spleen SUVmax and SUVmean (TLRmax, TLRmean, TSRmax, and TSRmean, respectively). RESULTS: Ten patients (8 female; 2 male) aged from 50 to 83 years presenting with a metastatic progressive WD-GEP-NET (7 small intestine, 2 pancreas, 1 rectum) were included. Median values of lesional Lu-SUV were significantly lower than the corresponding Ga-SUV (P < 0.001), whereas median values of lesional Lu-MTV, Lu-TLR, and Lu-TSR were significantly higher than the corresponding Ga-MTV, Ga-TLR, and Ga-TSR (P < 0.02). Pearson correlation coefficients were strong for both SUV and MTV parameters (0.779-0.845), weak for TLR parameters (0.365-0.394), and moderate-to-strong for TSR parameters (0.676-0.750). CONCLUSIONS: Our results suggest the feasibility of 177Lu-DOTATATE SPECT/CT quantification in clinical practice and show a strong correlation of several SUV-based parameters with the corresponding in 68Ga-DOTATOC PET/CT.