E4599 demonstrated an overall survival advantage in patients receiving PCB.8
In an unplanned, exploratory subset analysis, females did not appear to have a survival benefit that males did with PCB, although females on both arms survived longer than males. In fact, the 13.1 month median survival of females in the PC arm was longer than in any previously reported ECOG trial using a chemotherapy doublet in the first line treatment setting for NSCLC. Although retrospective analyses are limited and should be viewed with caution, causes for the improved survival of females on the control arm remain unclear. Presumably, differences in eligibility criteria do not account for this difference, given that the 8.7 month median survival for males treated with PC on this study is similar to the 8.3 month median survival observed on E1594. Unmeasured differences in second line therapy may be responsible and may have the most effect on overall survival. However the proportion of males and females on both the control and experimental arms receiving second line therapy were roughly the same, although incomplete data collection limits this analysis. It is possible that the surprisingly good survival for females on the PC arm is due to chance alone or other unmeasured prognostic factors such as epidermal growth factor mutations, smoking status, or co-morbidities, limiting our ability to detect an improvement with the addition of bevacizumab.
The poor prognostic characteristics of the males in the PC arm and the females in the PCB arm do not fully explain the differences in survival. Unfortunately, we do not have epidermal growth factor mutation information on the subjects in this study. Epidermal growth factor mutations are known to be more common in neversmokers and are associated with improved prognosis with any treatment. 15
Females on PCB may have been less likely to receive chemotherapy in the second-line setting. However, complete data is not available on second-line therapy prescribed. Females on PCB also experienced more toxicity and had more liver involvement compared to females treated with PC alone. Adjusting for other factors, the difference in the treatment effect between males and females slightly narrowed, but remained substantial.
To our knowledge this is the first detailed report of a sex difference in outcomes from bevacizumab. Reck and colleagues reported subset differences via forest plots of hazard ratios on the AVAiL data (The phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first line therapy for nonsquamous NSCLC). In both the 7.5 and 15 mg/kg bevacizumab dose groups, the overall survival was not statistically improved for males or females. Though for both groups the overall survival was greater than 13 months. Specific data on sex differences and overall survival was not published. Interestingly, for PFS, females had a statistically improved PFS at 15 mg/kg of bevacizumab where males did not and vice versa at the 7.5 mg/kg bevacizumab dose. Data reported provided only minimal details regarding these differences. Unfortunately, due to this lack of information, the AVAiL trial does not substantiate the findings of the ECOG 4599 sex differences data. 16, 17
Other trials of bevacizumab in advanced colon cancer demonstrated a benefit in both males and females.18
One possible reason for the differences observed in this study may be related to sex hormones. Wakelee and colleagues examined ECOG 4599 and found an age-sex interaction in that females younger than 60 years of age had an improved survival when treated with PCB but females older than 60 did not.19
Thus, menopausal status may play a role in these differences as it has with paclitaxel poliglumex.20
Other factors that may cause differences in toxicity and potentially a lack of benefit may include factors that affect clearance of bevacizumab. Lu and colleagues described sex differences in the clearance (CL) and central compartment volume of distribution (Vic).21
Clearance was 26% faster in males than in females. Slower clearance in females could account for the increased toxicity in females on the PCB arm. The postulated reason why clearance is faster in males may be related to greater muscle mass in males compared to females. In our study, no measurements were available other than BMI to allow the examination of differences in muscle mass between females on the two arms. The previous study found an association between low serum albumin concentration (≤ 29 g/L) and a 20% increase in clearance compared to an average patient treated.21
Low serum albumin is a marker of poor nutrition and poor liver function which could be caused by liver involvement with disease. However, liver involvement with metastasis is probably not important for bevacizumab since bevacizumab complexes are cleared by the Fc receptor within the endothelial system and not the hepatocyte or biliary system.22
Thus, an increased proportion of females with liver involvement on the PCB arm would not explain higher toxicity rates. Also in our study, the number of subjects with low albumin levels was similar between the sexes. However, the lower proportion of females with liver metastases in the PC arm may have contributed to why that group did better than expected.
While, both progression free survival and response rate were improved with the addition of bevacizumab in both males and females, our data provides preliminary information that bevacizumab may have different effects on overall survival in males and females with NSCLC. The reasons for this remain unclear and need to be further studied prospectively in future trials with this antibody. Bevacizumab is an active drug in women in NSCLC, where the addition of bevacizumab did result in significant improvements in RR and PFS. The survival in the control group of females treated with PC was unexpectedly high, suggesting that the lack of a difference in survival may be also in part by related to characteristics of this group or due to unknown differences in second-line therapy given in each group. Because of these potential sex differences in treatment benefits and a better overall survival in female patients with advanced NSCLC, sex is an important stratification factor to include in all randomized trials of advanced disease.