A preplanned analysis of ctDNA found that a subpopulation of mCRC patients with acquired anti-EGFR resistance were sensitive to treatment with Sym004.
In a recent phase II study published in JAMA Oncology, Sym004, a mixture of two nonoverlapping monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), did not improve overall survival compared with physician choice of therapy in patients with metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR therapy. However, the authors observed a clinically meaningful survival benefit in select patients and concluded that the study results warrant further investigation.
“In a hypothesis generating analysis, ctDNA profiling identified a subset of patients (clonal RAS, BRAF, and EGFR ECD WT) that gained clinically meaningful benefit from therapy with Sym004,” wrote Clara Montagut, MD, of Hospital del Mar, Barcelona, Spain, and colleagues. “These findings provide the rationale for a prospective clinical validation of Sym004 efficacy in a molecularly defined subgroup of patients for whom prior anti-EGFR therapy had failed.”
According to the study, patients with colorectal cancer who acquire resistance to EGFR inhibitors frequently have RAS or EGFR extracellular domain mutations. However, some patients refractory to EGFR inhibitors retain tumor EGFR dependency that can potentially be targeted by agents like Sym004.
“Sym004 is a mixture of 2mAbs that target nonoverlapping epitopes on domain III with more efficient mediated down-modulation and subsequent degradation of cell-surface EGFR than the clinically approved antibodies cetuximab and panitumumab, leading to more complete and durable pathway inhibition,” the researchers wrote.
This study enrolled 254 patients with wild-type KRAS exon 2 disease refractory to standard chemotherapy and with acquired resistance to EGFR inhibitors. Patients were randomly assigned to Sym004 at a dosage of 12 mg/kg per week (arm A), Sym004 at 9 mg/kg per week (arm B), or investigator’s choice of therapy.
There was no significant difference in overall survival between the study arms, with a median of 7.9 months in arm A, 10.3 months in arm B, and 9.6 months in arm C.
“Currently, trifluridine/tipiracil (TAS-102) and regorafenib are the only treatment options for last-line mCRC, based on an increase in median overall survival in randomized clinical trials,” the researchers wrote. “While patients in the control arms in these 2 earlier studies received placebo, those in the present Sym004 study had a potentially active control arm, in which patients were able to receive capecitabine (68 patients), fluorouracil (13 patients), or best supportive care (4 patients). It is therefore plausible that a potential benefit of Sym004 in the ITT population was masked by a control arm in which most patients received an active treatment.”
However, a preplanned analysis of ctDNA found “high intrapatient heterogeneity” and showed that a subpopulation of patients had disease sensitive to treatment with Sym004.
A subgroup analysis of patients defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) found improved overall survival in patients treated with Sym004 (arm B) compared with investigator’s choice (arm C). The median overall survival was 12.8 months vs 7.3 months, respectively, leading the authors to conclude that “prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted.”