Abstract only
491
Background: Skin toxicity is a frequent adverse event of EGFR targeting agents. The role of cetuximab induced skin toxicity (Cet-ST), for the most acneiform skin rash, as a ...prognostic or a predictive factor of treatment efficacy is currently under discussion.
Methods: The prognostic and predictive value of Cet-ST in relation to treatment response and survival of patients of a randomized trial investigating CAPIRI plus cetuximab versus CAPOX plus cetuximab as first-line treatment of mCRC was analyzed. Cet-ST was grouped into clinically relevant (grade 2-3) and non relevant (grade 0-1) toxicity (NCI-CTCAE 3.0). KRAS mutations in codons 12 and 13, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism were evaluated in tumor specimens.
Results: A total of 149 patients got cetuximab until the first tumor assessment (6 weeks) and were used for this analysis. Overall response rate was higher in patients with grade 2-3 Cet-ST when compared to grade 0-1 (62.1% vs. 41.3%). Patients without Cet-ST (grade 0) had a short PFS (1.9 months) and OS (11.0 months). PFS (7.8 months vs. 5.2 months) and OS (30.3 months vs. 18.0 months) were longer in patients with Cet-ST grade 2-3 than in patients with grade 0-1 Cet-ST. Almost 90% of Cet-ST occurred during the first two cycles of treatment. When only KRAS codon-12 mutated tumors which are thought not to be sensitive to cetuximab were investigated, Kaplan-Meier differences in PFS and OS times between patients with grade 0-1 Cet-ST and grade 2-3 Cet-ST became statistically significant. In a multivariate analysis, male gender, age and EGFR intron-1 polymorphism were significantly correlated with Cet-ST.
Conclusions: Cetuximab related skin toxicity is a strong predictor of outcome. It is proposed that Cet-ST is rather a prognostic than a predictive factor since this effect is most evident in patients with KRAS codon-12 mutated tumors. EGFR intron-1 polymorphism appears to be a predictor of Cet-ST.
Abstract only
3519^
Background: We investigated the expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) as well as the amplification of the EGFR-gene in tumor specimens of mCRC ...patients (pts) treated first-line with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI. Expression levels were correlated with overall response rate (ORR), progression free survival (PFS) and overall survival (OS) to determine their relationship with effectiveness in this setting. Methods: A total of 185 mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by 250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine 800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of both agents for pts older than 65 years) or plus CAPOX (oxaliplatin 130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every three weeks). The primary study endpoint was ORR. KRAS mutational status did not correlate with treatment outcome. The cut-offs for EGFR-amplification using FISH, AREG and EREG levels determined by RT-qPCR were calculated using ROC analysis for ORR. Results: Within the subgroup of KRAS wildtype tumors, analysis of EREG- and AREG-expression was possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels correlated significantly with higher ORR (83% vs 46%, p=0.006, OR 0.31), longer PFS (9.6mo vs 4.9, p<0.001, HR 0.35) and longer OS (39.9mo vs 17.2mo, p<0.001, HR 0.36). Higher EREG levels showed a significant correlation with ORR (74% vs 47%, p=0.036, OR 0.54), longer PFS (7.9mo vs 4.9mo, p=0.026, HR 0.57) and OS (33.0mo vs 20.2mo, p=0.041, HR 0.57). EGFR-amplification correlated significantly with higher ORR (71% vs 33%, p=0.004, OR 0.49), longer PFS (8.4mo vs 4.6mo, p=0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p=0.001, HR 0.44). Conclusions: In the treatment setting of cetuximab combined with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors, EGFR-FISH and AREG expression have the strongest relationship with treatment efficacy.
