Long Terms Follow-Up of the Randomized MetaspHER Study Comparing Intravenous Versus Subcutaneous Trastuzumab in Patients' With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: The subcutaneous (H-SC) formulation of trastuzumab was demonstrated to be as effective and safe as intravenous (H-IV) and highly preferred by patients in early breast cancer. The present randomized MetaspHER trial (NCT01810393) has been the first study assessing patient's preference in metastatic setting and we report the final analysis with long term follow-up. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long terms response lasting more than 3 years were randomized to receive 3 cycles of 600 mg fixed-dose H-SC, followed by 3 cycles of standard H-IV, or the reverse sequence. The primary endpoint was overall preference for H-SC or H-IV at cycle 6 and was previously reported. Secondary endpoints included safety over 1 year of treatment and with 4 additional years follow up. Overall survival (OS) and progression free survival (PFS) were assessed in this final analysis. RESULTS: A total of 113 patients were randomized and treated and the median follow-up duration was 45.4 months (range: 0.8-48.8). After the cross over period all patients excepted 2 pursued the H-SC. During the 18 cycles overall treatment period, at least 1 adverse event (AE), 1 AE of grade ≥3, and 1 serious adverse events (SAE) were respectively reported among 104 patients (92.0%), 23 patients (20.4%), and 16 patients (14.2%), respectively. Also, 10 patients (8.9%) experienced at least 1 cardiac event, including 4 patients (3.5%) with ejection fraction decreased. Beyond cycle 18 no significant additional safety concern emerged. PFS and OS rates at months 42 were 74.8% (64.7%-82.4%) and 94.9% (88.2%-97.9%), respectively. No factor appeared related to the survival outcome excepted the complete response status at baseline. CONCLUSION: The safety was consistent with the known H-IV and H-SC profiles without any safety concern raised over a prolonged exposure to H-SC.

Unresectable hepatocellular carcinoma at dawn of immunotherapy era: real-world data from the French prospective CHIEF cohort.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma epidemiological data are limited in France. The Epidemio Liver Immunotherapy Tecentriq outcome research (ELITor) retrospective study, based on real-world data from the Carcinome HépatocellulaIrE en France (CHIEF) French cohort of hepatocellular carcinoma patients, aimed to get insight into the treatment patterns, the sociodemographic, clinical, biological, and etiological characteristics, and the quality of life of patients with unresectable hepatocellular carcinoma. METHODS AND RESULTS: Between 1 September 2019 and 4 December 2020, 367 patients from the CHIEF cohort received at least one locoregional (52.8%) chemoembolization or radioembolization or systemic treatment (88.3%) and were selected for ELITor. Most patients had a Barcelona Clinic Liver Cancer (BCLC) C (93.2%) hepatocellular carcinoma stage and were affected by cirrhosis (67.7%). Alcohol was confirmed as the main etiology both as a single etiology (29.1%) and in association with other risk factors (26.9%), mainly metabolic disorders (16.2%).Tyrosine-kinase inhibitors, mainly sorafenib, were the most administered systemic treatments in first line. Patients who received at least one combination of atezolizumab and bevacizumab during the study period ( N  = 53) had a better performance status and less portal hypertension frequency than the overall population and more hepatitis B virus infection and fewer metabolic disorders as single etiology. Overall, the global health score before treatment (62.3 ±â€…21.9) was in line with that of reference cancer patients and worsened in 51.9% of the cases after first-line palliative-intent treatment. CONCLUSION: This study provided real-life data on advanced hepatocellular carcinoma characteristics and treatment patterns and described the first patients to receive the atezolizumab-bevacizumab combination before it became the new standard of care for advanced hepatocellular carcinoma.

Innovative Approach for a Typology of Treatment Sequences in Early Stage HER2 Positive Breast Cancer Patients Treated With Trastuzumab in the French National Hospital Database.

Background: Our objective was to describe the hospital-based systemic treatment sequences in early stage HER2+ breast cancer patients treated with trastuzumab in France in 2016. Methods: This retrospective observational study was based on the national hospital discharge database (PMSI). Patients hospitalized for breast cancer in 2016 and administration of trastuzumab between 6 months prior and 1 year after surgery were included. The following treatments were identified: (1) trastuzumab ± chemotherapy; (2) chemotherapy alone; (3) q3w trastuzumab weekly chemotherapy. Hospital admissions for cardiac events before and after the surgery were investigated. An unsupervised machine learning technic called TAK (Time-sequence Analysis through K-clustering) was used to identify and visualize typical systemic treatment sequences. Results: Overall, 3531 patients were included: 2619 adjuvant cohort patients (74.2%) and 912 neoadjuvant cohort patients (25.8%). The mean age was 56.4 years (±12.3), 99.7% patients were female. Treatment initiation occurred within 6 weeks of the surgery in 58% and 92% of patients, and trastuzumab treatment lasted 12 months (±1 month) in 75% and 66% of patients in the adjuvant and neoadjuvant cohorts, respectively. Nevertheless, 12% and 22% of patients were treated with trastuzumab for <11 months in the adjuvant and neoadjuvant cohorts, respectively. There was not one standard sequence of treatments per cohort, but 4 and 3 typical treatment sequences in the adjuvant and the neoadjuvant cohorts, respectively, plus 2 treatment sequences with an early treatment withdrawal. The frequency of patients with ⩾1 hospital stay with a cardiac event was higher among patients with an early treatment withdrawal. Conclusions: The treatment sequences of most patients were in line with the recommendations in force. The machine learning approach provided a telling visual display of the results, thereby allowing healthcare professionals, health authorities, patients, and care givers to see the whole picture of the hospital-administered drug strategies.

Long-term outcomes in patients with PET-predicted poor-responsive HER2-positive breast cancer treated with neoadjuvant bevacizumab added to trastuzumab and docetaxel: 5-year follow-up of the randomised Avataxher study.

BACKGROUND: The open-label, randomised Phase 2 AVATAXHER study (NCT01142778) demonstrated that early PET assessment identified HER2-positive breast cancer patients who responded poorly to neoadjuvant docetaxel plus trastuzumab. Adding neoadjuvant bevacizumab for PET-predicted poor-responders improved pathological complete response (pCR) rates (43.8% vs 24.0%). We investigated long-term study outcomes. METHODS: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹8F]-FDG PET conducted before each cycle. Those with ≥70% change in the maximum standardised uptake value (∆SUVmax) received four further cycles of standard neoadjuvant therapy (PET responders). PET-predicted poor-responders (∆SUVmax <70%) were randomised (2:1) to neoadjuvant therapy with (Group A) or without (Group B) bevacizumab for cycles 3-6. All patients received one further cycle of trastuzumab before surgery plus adjuvant trastuzumab (11 cycles). FINDINGS: 142 patients were randomized and treated (PET responders, n = 69; Group A, n = 48; Group B, n = 25). 5-year disease-free survival rates were 90.5% (95% CI: 80.0-95.6%) in PET responders, 90.2% (95% CI: 75.9-96.2%) in Group A, and 76.0% (95% CI: 54.2-88.4%) in Group B. However, no difference was observed between randomised arms in a sensitivity analysis. During adjuvant therapy, the incidence of Grade ≥3 (Group A: 25.6%; Group B 12.5%) and serious adverse events (Group A: 18.6%; Group B 12.5%) was higher in Group A vs Group B, but with no apparent effect on cardiac events. INTERPRETATION: In patients with HER2-positive breast cancer, an intervention based on early PET assessment and improvement of pCR does not modify disease-free survival. FUNDING: Roche France.

A multidisciplinary approach to oncology trials: Study conduct of the ANTHALYA trial.

Clinical trials that combine medical therapy and surgical treatment pose a number of challenges. The ANTHALYA trial investigated the efficacy and safety of adding bevacizumab to neoadjuvant carboplatin-paclitaxel chemotherapy prior to interval debulking surgery (IDS) in patients with ovarian cancer. The success of the trial depended on the efficacy and the safety of the combination and on the surgical effort. Furthermore, at the time of study design, neoadjuvant bevacizumab had not been investigated in ovarian cancer patients and it was unknown if neoadjuvant angiogenic therapy would be well tolerated or would negatively impact the success of IDS. Therefore, safety in the ANTHALYA trial was paramount. To overcome these challenges we conducted the trial in collaboration with French oncologists and surgeons who were experts in the multidisciplinary treatment of ovarian cancer. Toxicity was monitored during the neoadjuvant and IDS periods using a Bayesian approach which provided flexibility in the decision-making process regarding the continuation or rapid discontinuation of the trial in response to a safety signal. We implemented a stopping rule for safety based on a number of pre-defined bevacizumab-related complications of special interest. We also developed an electronic case report form, which greatly facilitated the collection and dissemination of safety information and other trial data. Here we describe how we used these tools to ensure the successful conduct of ANTHALYA and report how it is possible to mix a Bayesian approach for monitoring toxicity and a frequentist approach for evaluating efficacy within the same trial.

Efficacy and safety of bevacizumab-containing neoadjuvant therapy followed by interval debulking surgery in advanced ovarian cancer: Results from the ANTHALYA trial.

AIM: To investigate whether adding bevacizumab to neoadjuvant carboplatin-paclitaxel (CP) helps achieve optimal debulking, measured by complete resection rate (CRR) at interval debulking surgery (IDS), in patients with initially unresectable International Federation of Gynecology and Obstetrics stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma. METHODS: Multicentre, open-label, non-comparative phase II study. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP ±3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS. Primary objective is to evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab-related adverse events (AEs) of special interest was implemented. RESULTS: In the BCP group (N = 58), IDS was performed in 40 (69%) patients, of whom 85% had a complete resection. The CRR of this group was therefore 58.6% (34 patients), statistically over pre-defined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS (85% had a complete resection). Grade ≥3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached. CONCLUSION: The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab's role in this setting should be further investigated.