Quality of life during first-line FOLFOX4±panitumumab in RAS wild-type metastatic colorectal carcinoma : results from a randomised controlled trial

Metastatic colorectal cancer is rarely curable. Improving quality of life is therefore a key treatment goal. We report quality of life for patients with RAS wild-type metastatic colorectal cancer in the PRIME study. A randomised phase 3 open-label study of first-line panitumumab+FOLFOX4 vs FOLFOX4 enrolled adults with untreated metastatic colorectal cancer and an Eastern Cooperative Oncology Group performance status of 0-2. This analysis includes patients with wild-type RAS tumours (n=505). Quality of life (prespecified end point) was assessed using the EuroQoL 5-domain health state index and overall health rating in all patients and by early tumour shrinkage status (≥30% reduction in size by week 8; exploratory end point). Differences in quality of life were assessed using analysis of covariance and a mixed-effect piecewise linear model, and were also analysed by skin toxicity severity. There were no statistically significant differences between treatment arms from baseline to progression or to discontinuation. Grade 3+ skin toxicity was reported by 38% of patients receiving panitumumab+FOLFOX4 and 2% receiving FOLFOX4 alone. There were no significant differences in quality of life between patients with grade 0-2 skin toxicity and those with grade 3+ skin toxicity. More patients receiving panitumumab+FOLFOX4 vs FOLFOX4 had early tumour shrinkage (p<.001). In patients with tumour symptoms at baseline, there were statistically significant improvements in quality of life in those with early tumour shrinkage versus those without early tumour shrinkage. Addition of panitumumab to FOLFOX4 in first-line therapy for metastatic colorectal cancer prolongs survival and has no negative effect on overall quality of life compared with FOLFOX4 alone. Specific quality of life assessments for skin toxicity should be included in study designs to better define the direct effect of these adverse events. NCT00364013

A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer

AbstractBackgroundHead-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC).MethodsA PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point.ResultsThree trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68–0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/‘other’ RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab.ConclusionsThis meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited

Author Correction: Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials.

The authors would like to include the following changes in the published article

Impact of primary tumour location on outcomes in patients with metastatic colorectal cancer undergoing first-line panitumumab + FOLFIRI treatment

Background: Prognosis in pts with mCRC is affected by PTL; PTL may also affect the activity of the epidermal growth factor receptor inhibitor Pmab (+ FOLFIRI). Methods: In this phase II, single-arm study (NCT00508404), pts received first-line Pmab+FOLFIRI Q2W until disease progression (PD); primary endpoint: objective response rate (ORR). Analyses included pts with RAS wild-type (WT) mCRC (no mutations in KRAS/NRAS exons 2, 3 and 4). Baseline demographics/disease characteristics were summarised by PTL and the effect of PTL on outcome was analysed. Early tumour shrinkage (ETS) was defined as a ≥30% reduction in the sum of the longest diameters of measurable target lesions at week 8. Depth of response (DpR) was the maximum % change from baseline to nadir in pts with shrinkage, or the change at PD in pts with no shrinkage. DpR was positive for shrinkage, negative for growth and zero for no change. Progression-free survival (PFS) was analysed by PTL and ETS status. There was no long-term follow-up of overall survival in this study. Results: PTL could be determined in 52/69 (75%) RAS WT pts; 45/52 (87%) had left (L)-sided disease. Pts with L- vs right (R)-sided disease were more likely to have BRAF WT mCRC (91% vs 71%), an ECOG performance status of 0 (56% vs 43%) and liver+other metastases (53% vs 29%). Pts with L- vs R-sided disease had longer median (95% CI) PFS (11.2 [7.6,17.0] vs 7.2 [1.1,19.1] months) and were more likely to experience ETS ≥30% (53% vs 29%). ORR (60% vs 57%), median (95% CI) duration of response (DoR; 13.2 [9.3,47.7] vs 14.3 [3.5,17.3] months), median DpR (61% vs 60%), and resection rates (any: 13% vs 14%; R0: 7% vs 14%) were similar for L- and R-sided pts. ETS ≥30% was associated with improved PFS irrespective of PTL (HR [95% CI] vs ETS < 30%: 0.53 [0.22,1.29] on L; 0.35 [0.03,3.54] on R). Conclusions: These post-hoc data are in line with larger previous studies suggesting improved ETS/PFS with Pmab treatment in RAS WT left-sided mCRC; ORR, DoR and DpR were similar regardless of PTL. No formal conclusions can be drawn regarding the activity of Pmab+FOLFIRI in right-sided mCRC due to the small pt numbers, but ETS may also predict PFS benefit in right-sided diseas