medwireNews: Treatment-naïve EGFR-mutant non-small-cell lung cancer (NSCLC) patients are unlikely to benefit from the addition of cetuximab to afatinib, results suggest.
“Given that afatinib [plus] cetuximab is active in a subset of patients after progressive disease from EGFR TKIs [tyrosine kinase inhibitors], it appears likely that failure of the combination as initial therapy in our trial reflects differences in the biology of treatment-naïve disease compared with that of acquired resistance,” explain Sarah Goldberg (Yale School of Medicine, New Haven, Connecticut, USA) and colleagues.
The phase 2 SWOG S1403 study comprised 168 EGFR–TKI-naïve patients aged a median of 66 years (66% female) with stage IV or recurrent NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation.
There was no significant difference in progression-free survival (PFS) between the 83 patients who were randomly assigned to receive cetuximab 500 mg/m2 every 2 weeks plus afatinib 40 mg daily and the 85 patients who received afatinib alone, at a median of 11.9 and 13.4 months, respectively.
The combination and afatinib alone treatment groups were also comparable with regard to other endpoints, including response rate (67 vs 74%) and overall survival (OS; 2-year rates of 67 vs 70%).
Goldberg et al highlight that patients harboring exon 19 deletions had longer PFS and OS than those with L858R mutations, but “[t]here was no difference in PFS or OS between the two treatment arms” by mutation subtype.
In all, the combination therapy led to significantly more patients having a grade 3 or worse treatment-related adverse event, at a rate of 72% versus 40% with afatinib alone, the most frequent of which were acneiform rash (27 vs 2%), diarrhea (15 vs 20%), and maculopapular rash (13 vs 0%).
More patients taking cetuximab with afatinib versus alone reduced their dose of afatinib to 30 mg (56.7 vs 26.2%), but reductions to 20 mg occurred at similar rates between the treatment groups (13.6 vs 16.7%).
A total of 30% of patients in the combination arm discontinued cetuximab due to toxicity, while the rates of adverse event-related trial discontinuation were 14% and 11% in the combination and afatinib alone arms, respectively.
One treatment-related death occurred during the course of the study; it was related to the combination treatment and due to pneumonitis.
Goldberg and fellow investigators say: “Why this combination, which is active in the resistance setting, failed in the first-line setting is unclear.”
Nevertheless, they believe that “there may be subsets of patients in whom this combination is worthy of further study.”
Goldberg et al conclude in the Journal of Clinical Oncology: “There is currently no role for the combination of afatinib and cetuximab in patients with treatment-naïve EGFR-mutated NSCLC; however, further investigation into more tolerable combinations of EGFR TKIs with EGFR antibodies is warranted.”
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