Cetuximab Skin Toxicity Has Predictive and Prognostic Correlation With OS in mCRC

The addition of cetuximab to irinotecan, fluorouracil, and folinic acid leucovorin demonstrated superior overall survival compared with the addition of bevacizumab in patients with metastatic colorectal cancer who developed skin toxicity from cetuximab exposure, according to results from the phase II FIRE-3 trial, published in the Annals of Oncology.

Julian Walter Holch, MD

The addition of cetuximab (Erbitux) to irinotecan, fluorouracil (5-FU), and folinic acid leucovorin (FOLFIRI) demonstrated superior overall survival (OS) compared with the combination of bevacizumab (Avastin) and FOLFIRI in patients with metastatic colorectal cancer (mCRC) who developed skin toxicity from cetuximab exposure, according to results from the phase II FIRE-3 trial (NCT00433927), published in theAnnals of Oncology.

A total of 400 patients withRASwild-type (WT) tumors were included in the study and randomized to either the cetuximab-plus-FOLFIRI arm (n = 199), or the bevacizumab-plus-FOLFIRI-arm (n = 201). Proportionally, 85% of patients in the cetuximab group had cetuximab-induced skin toxicity (Cet-ST), which was evaluated using the National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI-CTCAE) version 3 and was based on the degree of skin toxicity during cycle 1 through 3 of treatment.

The predictive relevance of Cet-ST in patients with mCRC was assessed by comparing the treatment effects of cetuximab plus FOLFIRI to that of bevacizumab plus FOLFIRI. Investigators led by Julian Walter Holch, MD, of the Comprehensive Cancer Center of Munich, observed a significant improvement in median OS of 14.4 months with the cetuximab regimen. Specifically, median OS was 41.0 months with the addition of cetuximab versus 26.6 with the addition of bevacizumab to FOLFIRI (HR, 0.73; 95% CI, 0.61-0.87;P<.001) in patients with grade 2 through 3 Cet-ST. Among patients with grade 0 through 1 CET-ST, the median OS was comparable at 26.3 in the cetuximab arm versus 26.6 months in the bevacizumab arm (HR, 0.90; 95% CI, 0.67-1.21; P= .480).

The addition of cetuximab to FOLFIRI also showed an improvement in the response rate (odds ratio [OR], 2.25; 95% CI, 1.20-4.21;P= .013) and progression-free survival (PFS; HR, 0.86; 95% CI, 0.742-0.99;P= .037) in patients with Cet-ST grade ≥2 only. The addition of bevacizumab to FOLFIRI demonstrated superior early tumor shrinkage (ETS) and elicited deeper responses compared with the cetuximab/FOLFIRI arm, though.

The prognostic relevance of Cet-ST was analyzed in the study. Patients with Cet-ST grade 2 or 3 had better OS than those with Cet-ST grade 0 through 1. PFS was extended in patients with Cet-ST grade ≥2 at 13.6 months compared with patients with less severe toxicity who had only achieved a PFS of 10.3 months (HR, 0.63; 95% CI, 0.46-0.87;P= .005). Cet-ST grade ≥2 was also associated with an increase in overall response rate (ORR) among patients. The ORR observed was 78.7% versus 67.0% for patients with lower Cet-ST (P= .096), but the increase was not statistically significant. Similar to what was observed in the comparison of arms, the ETS was comparable between high- and low-grade Cet-ST groups at 69.7% versus 68.5%, respectively, as was the depth of response (DpR) at —52.7% and –47.5%.

In a multivariate Cox regression analysis, the relevance of Cet-ST and ETS were evaluated together. It was discovered in this analysis that Cet-ST was independently predictive of OS in the cetuximab-plus-FOLFIRI arm (HR, 0.65; 95% CI, 0.45-0.96;P= .003). In addition, ETS demonstrated independent predictive value for determining favorable OS in all evaluable patients (HR, 0.56; 95% CI, 0.42-0.74; P<.0001). Moreover, Holch et al found both parameters had relevance for primary tumor sidedness, which in left- versus right-sided tumors, had a hazard ratio of 0.67 (95% CI, 0.47-0.96; P= .01). Notably, patients with RAS WTand BRAF WT tumorshad comparable outcomes.

Based on a waterfall plot analysis, a shorter OS (15.1 months) was observed in patients in the cetuximab-plus-FOLFIRI arm who displayed Cet-ST grade 0 through 1 and ETS <20%. The other subgroups, however, reached a 30- to 40-month OS. It can be concluded, based on the results of the waterfall analysis, that Cet-ST grade 0 through 1 and ETS <20% in the cetuximab-plus-FOLFIRI group demonstrated inferior survival to patients in the bevacizumab-plus-FOLFIRI group with ETS <20%, the investigators noted.

FIRE-3 was a prospective, multicenter, open-label phase III study conducted in Germany. The primary end point of the study was ORR, and the secondary end points were median PFS, median OS, the secondary resection rate with curative intent, and safety/toxicity.

For the investigation of cetuximab plus FOLFIRI versus bevacizumab plus FOLFIRI, the investigators gathered retrospective data on Cet-ST which occurred during cycles 1 to 3 of treatment and the data were correlated with the efficacy end points.

The overall goal of the study was to extend the findings related to predictive and prognostic relevance of Cet-ST and ETS in patients with mCRC.

“The present analysis demonstrates that Cet-ST may predict the benefit from cetuximab-based first-line chemotherapy. Further, the analyses revealed a strong prognostic relevance of Cet-ST. Early development of Cet-ST grade ≥2 during the first 3 cycles of FOLFIRI/Cet was associated with superior clinical outcomes. Of note, both Cet-ST and ETS contained independent prognostic information in patients treated with FOLFIRI/Cet. Taken together, the presented results are hypothesis-generating and need to be validated in prospective clinical trials,” wrote Holch et al.


Holch JW, Held S, Stintzing S, et al. Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3trial FIRE-3 (AIO KRK0306).Ann Oncol. 2020:31(1);72-78. doi: 10.1016/j.annonc.2019.10.001.