Françoise Desseigne, Klaus Koefoed, Mikkel W. Pedersen, Rodrigo Dienstmann, C. Ding, Thomas Tuxen Poulsen, Trine Lindsted, Joana Vidal, Jenifer Clausell-Tormos, Michael M. Grandal, Salvatore Siena, Ana Rovira, Giulia Siravegna, Francisco J. Sánchez-Martín, Giuseppe Rospo, Guillem Argiles, Antonio Cubillo, Alberto Bardelli, Cristina Nadal, Michael Kragh, Clara Montagut, Ivan D. Horak, Lucjan Wyrwicz, Mikhail Dvorkin, Joan Albanell, Scott Kopetz, Guglielmo Fumi, Paul Nadler, Fortunato Ciardiello, Ramon Salazar, Josep Tabernero, Vittorina Zagonel, Montagut, Clara, Argilés, Guillem, Ciardiello, Fortunato, Poulsen, Thomas T, Dienstmann, Rodrigo, Kragh, Michael, Kopetz, Scott, Lindsted, Trine, Ding, Cliff, Vidal, Joana, Clausell-Tormos, Jenifer, Siravegna, Giulia, Sánchez-Martín, Francisco J, Koefoed, Klau, Pedersen, Mikkel W, Grandal, Michael M, Dvorkin, Mikhail, Wyrwicz, Lucjan, Rovira, Ana, Cubillo, Antonio, Salazar, Ramon, Desseigne, Françoise, Nadal, Cristina, Albanell, Joan, Zagonel, Vittorina, Siena, Salvatore, Fumi, Guglielmo, Rospo, Giuseppe, Nadler, Paul, Horak, Ivan D, Bardelli, Alberto, and Tabernero, Josep
Importance Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due toRASandEGFRextracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR–refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. Objective To determine if continuous blockade of EGFR by Sym004 has survival benefit. Design, Setting, and Participants Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator’s choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-typeKRASexon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. Interventions Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator’s choice of treatment (arm C). Main Outcomes and Measures Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. Results A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targetedEGFRECD-mutated cancer cells, and a decrease inEGFRECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients withEGFRECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFRECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). Conclusions and Relevance Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. Trial Registration clinicaltrialsregister.eu Identifier:2013-003829-29