Importance Based on a small retrospective study, rechallenge with cetuximab-based therapy for patients withKRASwild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti–epidermal growth factor receptor–based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA). Objective To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients withRASandBRAFwild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy. Design, Setting, and Participants Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria includedRASandBRAFwild-type status on tissue samples; prior first-line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment. Interventions Biweekly cetuximab, 500 mg/m², plus irinotecan, 180 mg/m². Main Outcomes and Measures Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis,RASmutations in ctDNA. Results Twenty-eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%.RASmutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). NoRASmutations were detected in samples from patients who achieved confirmed partial response. Patients withRASwild-type ctDNA had significantly longer progression-free survival than those withRASmutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98;P = .03). Conclusions and Relevance This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients withRASandBRAFwild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation ofRASmutational status on ctDNA might be helpful in selecting candidate patients. Trial Registration ClinicalTrials.gov Identifier:NCT02296203

PD-L1 expression in tumour tissues is widely used to select patients to receive anti-PD-1/PD-L1 antibodies, but data are lacking on the correlation of plasma PD-L1 levels with the effect of treatments. To investigate the association between PD-L1 mRNA in plasma-derived exosomes and response to nivolumab and pembrolizumab in patients with melanoma (n=18) and NSCLC (n=8), blood was obtained at time point 0 and after 2 months. Exosomal PD-L1 mRNA was measured by digital droplet PCR. The mean±s.e.m. PD-L1 levels in patients with complete and partial responses were 830.4±231.3 and 242.5±82.5 copies per ml at time 0 vs 2 months, respectively (P=0.016). In patients with stable disease the mean±s.e.m. values were 298.8±97.2 vs 247.5±29.8 copies per ml (P=0.586), while in progressive disease, PD-L1 mRNA levels were 204.0±68.8 vs 416.0±87.8 copies per ml at time 0 vs 2 months, respectively (P=0.001). This study demonstrates that exosomal PD-L1 is significantly associated with response to treatment.

Aim: In the present study we conducted a systematic review and meta-analysis of published data to quantify the impact of the DPYD IVS14+1G>A and 2846A>T variants on the risk of fluoropyrimidine-related toxicities and to determine sensitivity and specificity testing for DPYD variants. Methods: Relevant studies were identified through PubMed and Web of Knowledge databases, studies included were those published up until to May 2012. Study quality was assessed according to the HuGENET guidelines and Strengthening the Reporting of Genetic Association (STREGA) recommendations. Results: Random-effects meta-analysis provided evidence that carriers of DPYD IVS14+1G>A are at higher risk of ≥3 degrees of overall grade toxicity, hematological toxicity, mucositis and diarrhea. In addition, a strong association was also found between carriers of the DPYD 2846T allele and overall grade ≥3 toxicity or grade ≥3 diarrhea. An inverse linear relationship was found in prospective studies between the odds ratio of DPYD IVS14+1...