Discussion
cancer, PD, tumour, non-visceral disease, TRAEs
CANCER, DISEASE, SKIN LESION, TUMOUR
In this study, addition of xentuzumab to everolimus and exemestane did not confer PFS benefit versus placebo in patients with HR-positive/HER2-negative metastatic breast cancer and non-visceral disease. There were no clear differences in safety profile between the treatment arms and no new safety signals were observed; overall rates of AEs, TRAEs and SAEs were similar across treatment groups.The IGF signalling pathway has long been recognised as a potential therapeutic target in many cancer types [While markers of target engagement were not assessed in this study, previous studies and preclinical data have shown that xentuzumab effectively inhibits IGF signalling, with reductions in IGF bioactivity following xentuzumab administration [Of note, median PFS in both arms of this trial was substantially longer than that observed in other recent trials undertaken in a similar setting, e.g. EMERALD (elacestrant versus endocrine monotherapy; median PFS 1.9–2.8 months) and VERONICA (venetoclax plus fulvestrant versus fulvestrant; median PFS 1.9–2.7 months) [This trial was unblinded and analysed early due to high rates of discordance between independent and investigator assessment of PFS. In both arms, median PFS was shorter when assessed by investigators rather than independently. In most cases, discordance was due to the investigator identifying PD when the independent reviewer did not. This is not unexpected in this patient population in which many patients had non-measurable disease. While independent reviewers were provided skin lesion photographs, biopsy reports from new lesions and supportive imaging if available, investigators may have been using additional parameters (e.g. specific tumour markers) to assess progression which were not considered for independent analysis. Similar observations were made in the BOLERO-2 trial (median PFS for everolimus/exemestane vs placebo/exemestane was 6.9 months vs 2.8 months [investigator assessment] and 10.6 vs 4.1 months [independent assessment]) [