Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular 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-type KRAS exon 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\u2009=\u2009160). 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 targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-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

Validity of Adolescent Diet Recall 48 Years Later

Few studies have evaluated the validity of adolescent diet recall after many decades. Between 1943 and 1970, yearly diet records were completed by parents of adolescents participating in an ongoing US study. In 2005–2006, study participants who had been 13–18 years of age when the diet records were collected were asked to complete a food frequency questionnaire regarding their adolescent diet. Food frequency questionnaires and diet records were available for 72 participants. The authors calculated Spearman correlation coefficients between food, food group, and nutrient intakes from the diet records and food frequency questionnaire and deattenuated them to account for the effects of within-person variation measured in the diet records on the association. The median deattenuated correlation for foods was 0.30, ranging from −0.53 for a beef, pork, or lamb sandwich to 0.99 for diet soda. The median deattenuated correlation for food groups was 0.31 (range: −0.48 for breads to 0.70 for hot beverages); for nutrient intakes, it was 0.25 (range: −0.08 for iron to 0.82 for vitamin B12). Some dietary factors were reasonably recalled 3–6 decades later. However, this food frequency questionnaire did not validly measure overall adolescent diet when completed by middle-aged and older adults on average 48 years after adolescence

Validity of Maternal Recall of Preschool Diet After 43 Years

Validation of early childhood diet recalls by surrogate responders decades later has not been possible because of a lack of diet records from the distant past. Between 1948 and 1970, parents of children participating in the Fels Longitudinal Study (Kettering, Ohio) completed a 7-day diet record for their children every year from birth to age 18 years. In 2005–2006, all surviving women (n = 59) with a child aged 3–5 years when diet records had been collected were asked to complete a 42-item food frequency questionnaire (FFQ) pertaining to 1 of their children's diets at age 3–5 years. One or more diet records were available for 48 children. The authors calculated Spearman correlation coefficients for correlations between food, food-group, and nutrient intakes from the diet records and the FFQ and deattenuated them to account for the effects of within-person variation in the diet records on the association. For foods, the median deattenuated correlation coefficient was 0.19 (range, −0.31 to 0.85); moderate-to-high correlations were found for some specific foods. Correlations for food groups were slightly higher (median, 0.27; range, −0.14 to 0.85). Correlations for nutrient intakes were consistently low (median, 0.06; range, −0.35 to 0.27). Overall, the FFQ did not validly reflect overall preschool diet when completed by mothers 4 decades later