Kaplan-Meier estimates of OS and PFS were presented stratified by treatment group and were compared using the log-rank test. For PFS, clinical progression (i.e., treatment discontinuation due to progression of disease) was also included as an event. Hazard ratio was estimated using the Cox proportional hazards model, including treatment group, with sex, smoking status, disease diagnosis and disease stage as covariates. Analyses of duration of OR and time to OR followed the same statistical approaches as for PFS and OS.

Most TEAEs were considered by the investigator as related to any study treatment (bevacizumab or chemotherapy) and were reported in a similar number of subjects with MB02 (264 [84.9%]) and with EU-bevacizumab (270 [87.1%]), observing a risk difference of <5% between treatment groups. Overall, 189 (30.4%) subjects had Grade 3 or 4 study drug-related TEAEs, with a similar distribution observed in each treatment group ( p=0.56). No differences were noted for IP-related TEAEs ( p=0.97). aAn adverse event was related if assessment of causality was possible, probable or very likely/certain The primary objective of the study was to investigate and compare the PK profiles of MB02‐SP, MB02‐DM, and US‐bevacizumab to establish bioequivalence between them. PK primary endpoints were area under the serum concentration–time curve from time zero to infinity (AUC0–∞) and maximum observed serum concentration ( C max). Results from secondary endpoints and sensitivity analyses reflected those of the primary analysis. Similar efficacy between MB02 and EU-bevacizumab was supported by the ad-hoc analyses of BORR at Week 18 based on IRC assessments in the ITT population (RR 0.926; 90% CI 0.818 to 1.049; RD −4.04%; 95% CI −11.86 to 3.78) (Table ​ (Table2 2). Eligible study population were male volunteers aged between 18 and 55years, weighted between 50 and 95kg with a body mass index (BMI) between 18.5 and 29.9kg/m 2 and any ethnic origin. Health status was evaluated through medical history, physical examination, 12‐lead electrocardiogram, vital sign measurement, and clinical laboratory evaluation (hematology, coagulation, urinalysis, and chemistry).

PK parameters that were not covered by the primary endpoints were assessed as secondary endpoints: time to maximum observed serum concentration, area under the serum concentration–time curve from time zero to the time of the last observable concentration (AUC[0– t]), total body clearance, apparent serum terminal elimination half‐life ( t 1/2), constant of the terminal phase; volume of distribution during the terminal phase after IV administration; and volume of distribution at steady‐state after IV administration. Secondary efficacy endpoints (PFS, OS, duration of OR and time to OR) and ad-hoc endpoints (BORR) were also comparable between treatment groups and were consistent with the observed results of the primary endpoint. In particular, BORR was assessed to confirm primary endpoint ORR results. BORR reduces potentially confounding factors of diverse cycles and delayed administration due to toxicity, and is commonly used in an oncological clinical setting. When comparing the analysis based on BORR up to Week 18 to that of primary ORR analysis, there was almost no difference, which is considered reassuring. The 90% CIs for the comparability ratios of the exposure parameters were within the prespecified acceptance range of 80.00%–125.00% for the comparison of the three products and are consistent with other bevacizumab biosimilar clinical trials. The present phase 1 clinical trial was designed to evaluate PK similarity among MB02‐SP, MB02‐DM, and US‐bevacizumab. To ensure the homogeneity of the population and to detect PK differences between groups healthy male subjects were selected, as in other biosimilar clinical trials. 11, 12, 13, 14 The use of healthy male volunteers avoids factors that can confound the interpretation of PK, safety result, and the influence of sex‐related factors upon bevacizumab clearance. Female PK data were obtained in STELLA phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02069704","term_id":"NCT02069704"}}NCT02069704). Descriptive statistics (sample size, mean, median, standard deviation, minimum, and maximum) were calculated for continuous variables. Frequency counts and percentages were tabulated for categorical variables.

Logistics->Logistics Execution->JIT Outbound->Environment->Inventory Management->Material Document->Change(MB02)The calibration standard and QC sample data indicated that the method performed satisfactorily for all reported runs. The primary efficacy endpoint was the objective response rate (ORR), defined as the rate of either CR or PR according to RECIST v1.1 at Week 18 as assessed by an IRC. Best objective response rate (BORR) was also assessed by the IRC, considering the best overall response (BOR) of either CR or PR achieved at any post-baseline time point up to, and including, Week 18. Any subjects who discontinue study treatment before Week 18 were classed as non-responders in the final analysis of the primary efficacy endpoint. SAP Program associated with transaction MB02For further details and documentation see program SAPMM07M