C. E. Lyons1, R. Jin4, A. D. Smith1, H. Zhu4, C. L. Slingluff2 1University Of Virginia, School Of Medicine, Charlottesville, VA, USA 2University Of Virginia, Department Of Surgery, Division Of Surgical Oncology, Charlottesville, VA, USA 4University Of Virginia, School Of Medicine, Department Of Public Health Sciences, Division Of Biostatistics, Charlottesville, VA, USA
Introduction:
We have observed differences in treatment benefit as a function of patient's biological sex in long-term clinical outcomes of a melanoma peptide vaccine trial (Mel44, NCT00118274), suggesting an impact of sex on immune therapy outcomes. With checkpoint blockade immunotherapy (CBI), some studies have shown increases in some treatment-related adverse events (TRAEs) in biological females compared to biological males as well as higher rates of clinical response in males. We hypothesized that females experienced higher rates and grades of TRAEs in this trial of cancer vaccines.
Methods:
Mel44 was a multicenter clinical trial randomizing patients to 2 different vaccine regimens (Arms A+B, C+D) and randomizing to pretreatment with Cyclophosphamide (CY) (with CY: Arms B+D, without CY: Arms A+C). TRAE data compiled from patient diaries using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 were extracted, and 46 unique TRAEs occurring at least 8 times in the study (in at least 4.8% of the study population) were evaluated for incidence as a function of sex and vaccine arm. The mean of the maximum grades of these toxicities were also compared as a function of sex. Comparative analyses utilized Fisher’s exact and chi-square test for incidence. A linear mixed effect model was used to compare the means of the maximum grades. Multiple comparisons were addressed using the Benjamini-Hochberg procedure. Confidence intervals (95%CI) were calculated with the Clopper-Pearson exact test.
Results:
There were differences (unadjusted p<0.05) in the incidence of 7 TRAEs (15%) among the sexes, with 5 (71%) occurring more often in females. With correction for multiple comparisons, the incidence of 1 TRAE (nausea) was higher (adjusted p<0.05) in females. For 2 TRAEs (nausea, hair loss), the lower bound of the 95%CI for female incidence exceeded the upper bound of that incidence for males. The mean TRAE grade was higher for females in 28 TRAEs (61%) and higher in males in 18 (39%) in the overall study population. However, when pulling all TRAEs together, an exploratory analysis using a linear mixed effect model did not reveal a significant difference in TRAE grade between biological sexes. There was a significant difference in the grade of TRAEs by study arm, with higher grades in Arm B.
Conclusions:
These data indicate that females had higher rates of nausea, even with correction for multiple comparisons. The data also suggest that there might be sex-related differences in some other TRAEs. Future work will include assessment of differences in adverse events between males and females across a range of treatments. Further, if biological females are experiencing higher rates and grades of treatment-related AEs, they might be removed from treatment early, which warrants further investigation.