Switching from cetuximab to bevacizumab associated with acceptable survival, reduced derm toxicity in mCRC

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab leads to acceptable survival outcomes and a reduction in severe dermatological toxicities in patients with RAS wild-type (RASwt) metastatic colorectal cancer (mCRC), according to the results of a single-arm phase II HYBRID trial.

Adding an anti–epidermal growth factor receptor (EGFR) antibody, such as cetuximab or panitumumab, to standard first‐line chemotherapy produces earlier and deeper tumour response compared with that obtained with an anti–vascular endothelial growth factor (VEGF) antibody, such as bevacizumab, in patients with RASwt mCRC. [Int J Color Dis 2017;32:1179‐1190] However, anti-EGFR antibody therapy is associated with dermatologic toxicities, such as acneiform rash, dry skin, and paronychia, and cetuximab‐containing first‐line regimens have been reported to be more detrimental to the quality of life vs bevacizumab‐containing regimens. [Clin Colorectal Cancer 2018;17:85‐96; J Natl Compr Cancer Netw 2009;7(Suppl 1):S5‐S21; J Clin Oncol 2013;31(15_suppl):3611]

Present study evaluated whether switching first‐line treatment with FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab would offer survival benefit and minimize dermatological toxicity, depending on early tumour shrinkage (ETS) observed with cetuximab. ETS was defined as ≥20 percent radiologically assessed reduction in the sum of the largest diameters of all target lesions 8 weeks after FOLFIRI plus cetuximab initiation. [Cancer Med 2024;13:e7107]

It was intended that patients who did not achieve ETS at 8 weeks (n=7) would immediately switch to FOLFIRI plus bevacizumab. Only two of the seven patients without ETS switched to FOLFIRI plus bevacizumab at 8 weeks, whereas the remaining five patients without ETS could not switch to FOLFIRI plus bevacizumab because of toxicities (n=3), early disease progression (n=1), and patient request (n=1). Patients who achieved ETS (n=22) continued FOLFIRI plus cetuximab for a total of 16 weeks after treatment initiation, followed by switch to FOLFIRI plus bevacizumab (n=17). The remaining five patients with ETS did not switch to FOLFIRI plus bevacizumab because of conversion surgery (n=4) or disease progression (n=1), which occurred during the first 8 weeks following induction treatment.

Median PFS and OS were 13.4 months and 34.7 months, respectively. Patients with ETS had significantly longer median PFS (14.2 months vs 6.1 months; p<0.01) and OS (not reached vs 13.3 months; p<0.01) than those without. In two patients without ETS who switched to FOLFIRI plus bevacizumab at 8 weeks, PFS and OS were 9.1 months and 18.2 months, respectively, in one patient, and 8.6 months and 13.5 months, respectively, in the other patient.

The most frequent grade ≥3 adverse event (AE) across all patients was neutropenia (60 percent). Six patients (20 percent) developed grade ≥3 paronychia, with no other grade ≥3 dermatologic toxicities reported. All grade ≥3 paronychia improved to grade ≤2 by 18 weeks after treatment initiation.

The frequencies of grade 2 acneiform rash, dry skin, and pruritus were 20 percent, 20 percent, and 7 percent, respectively. Grade 2 acneiform rash and dry skin improved to grade 1 or 0 by 24 weeks after treatment initiation, and grade 2 pruritus improved to grade 1 or 0 by 6 weeks after treatment initiation. The rate of major AEs did not increase after the switch, except for grade ≥3 hypertension, which was reported in 16 percent of patients who switched to bevacizumab.

“In summary, the potential benefits of the novel first‐line treatment strategy, involving an early switch from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on ETS, may offer acceptable efficacy and potentially reduce cetuximab‐induced dermatologic toxicities in patients with RASwt mCRC,” concluded the researchers. “However, planned patient accrual could not be completed for this study, hence its findings remain exploratory due to the insufficient statistical power and warrant further validation.”