Panitumumab plus FOLFIRI demonstrated acceptable tolerability in this study, with a profile similar to that seen for this combination in the second-line setting
. The type and incidence of integument-related toxicities was consistent with that expected for an anti-EGFR antibody plus FOLFIRI and was similar to that observed with cetuximab when administered with irinotecan-based chemotherapy in this setting
. The median duration of integument-related toxicity and time taken for resolution of such toxicity was longer in the WT KRAS group, perhaps reflecting the higher mean cumulative panitumumab dose and number of panitumumab cycles delivered in this group compared with the MT group. Interestingly, the exposure-adjusted AE rates showed that integument-related toxicities (both overall and ≥ grade 3) were higher in the MT vs. the WT KRAS group. However, any apparent differences between KRAS groups should be interpreted within the context of the relatively small sample size included in this study.
Overall, patients with grade 2+ vs. grade 0/1 skin toxicity appeared more likely to respond to treatment, irrespective of tumour KRAS status, even though patients with MT KRAS tumours are not thought to benefit from panitumumab. However, as noted above, data from this study are potentially confounded by small patient numbers and differences in treatment exposure. For example, responding patients are likely to undergo a longer duration of treatment, which in turn is likely to lead to greater cumulative toxicity. Nonetheless, an association between severity of skin toxicity and improved outcome has previously been noted for both cetuximab
[23–25] and panitumumab
[26–29] in large phase III trials. The observation in the present study that patients with MT KRAS tumours also had better outcomes when they experienced grade 2+ vs. grade 0/1 skin toxicity, is in line with other reports suggesting that EGFR-related skin toxicity may be a prognostic rather than predictive marker of outcome during therapy
[25, 27]. For example, in an analysis of efficacy by skin toxicity grade from the PRIME study, significantly improved progression-free survival (PFS) and OS outcomes were observed in those experiencing higher grades of skin toxicity during panitumumab plus FOLFOX4 treatment, irrespective of tumour KRAS status
. Furthermore, in the recent German AIO CRC 0104 study, although overall, numeric differences in objective response rate, PFS and OS were observed between patients experiencing grade 2–3 vs. 0–1 skin toxicity during cetuximab plus chemotherapy treatment, these differences became statistically significant when the group of patients with tumours harbouring codon 12-mutated tumours were examined
. In subsequent multivariate analyses, male gender and younger age were significantly correlated with skin toxicity, but no correlation was found with molecular parameters including KRAS mutation, EGFR status (by fluorescence in situ hybridisation or immunohistochemistry) and EGFR intron-1 polymorphism status
. These data suggest that the reported association between EGFR inhibitor-related skin toxicity grade and outcome more likely relates to other factors in the patient impacting on prognosis than alterations in the EGFR pathway in the tumour, but further studies are required to more fully investigate the potential prognostic implications.
EGFR inhibitor-induced rash can have a negative impact on quality of life
 and proactive management is recommended
. A recent study demonstrated that pre-emptive treatment is well tolerated and that patients receiving such treatment during panitumumab therapy had fewer grade 2+ skin toxicities and less quality of life impairment than those assigned to reactive treatment after skin toxicity had developed
. Interestingly, not all studies have reported a negative impact of skin toxicity and/or anti-EGFR treatment on quality of life. In a study comparing panitumumab monotherapy plus best supportive care with best supportive care alone, more bothersome skin toxicity according to the modified dermatology life quality index (mDLQI) was associated with improved CRC symptoms and quality of life, and longer PFS and OS in panitumumab-treated patients
. Quality of life was also maintained or deteriorations lessened for cetuximab plus best supportive care vs. best supportive care alone in another study
. Further trials have shown either improvements or no deleterious impact on quality of life when cetuximab was given alongside irinotecan
 or FOLFIRI
vs. irinotecan/FOLFIRI alone. Results from the present study are generally in line with these observations; panitumumab plus FOLFIRI had minimal impact on quality of life as EQ-5D and QLQ-C30 scores remained stable throughout the study, despite the high incidence of integument-related toxicity. In line with this, in these present analyses, skin toxicity grade did not appear to significantly affect the overall change in quality of life during the study. To our knowledge, this is the first published report in which the impact of skin toxicity grade on quality or life (EQ-5D health state index and overall health rating scales) was directly assessed, and therefore adds to previous reports suggesting that EGFR-targeted mAb therapy in general or level of skin toxicity bother do not adversely impact on a patient's quality of life.
It appears that baseline EQ-5D scores may be prognostic of best tumour response in patients receiving panitumumab plus FOLFIRI. Overall, however, the PRO data showed a high degree of within-group variability due to the relatively small patient numbers in each subgroup and so any apparent differences should be interpreted with caution. Nonetheless, higher baseline quality of life has previously been associated with improved PFS and/or OS in patients with advanced gastrointestinal/colorectal tumours
[36, 37]. Although to our knowledge, this is the first report of improved quality of life specifically in patients responding to panitumumab plus FOLFIRI treatment, it is perhaps not unexpected as similar observations have been reported previously in patients with advanced gastrointestinal/colorectal tumours undergoing treatment with chemotherapy alone
[38, 39]. These observations are also in line with the well-documented association between baseline performance status and OS in colorectal cancer