Targeting HER2: precision oncology for colorectal cancer.

www.thelancet.com/oncology Vol 17 June 2016 685 Advanced colorectal cancer still has a poor prognosis and more active drugs are urgently needed. HER2 was investi gated as a target in colorectal cancer in two early trials of trastuzumab plus chemotherapy as fi rst, second or third line therapy, which produced interesting but confl icting results. In The Lancet Oncology, Andrea Sartore-Bianchi and colleagues present the results of the HERACLES trial, the fi rst phase 2 trial in patients with refractory colorectal cancer and HER2 amplifi cation or overexpression. They tested the rationally selected combination of trastuzumab plus lapatinib, which preclinical data suggested as having promising activity in patient-derived xenografts of HER2-amplifi ed metastatic colorectal cancer. Sartore-Bianchi and colleagues screened 914 patients who were refractory to chemotherapy and had KRAS wild-type colorectal carcinoma, identifying 46 patients as having HER2-positive disease, and enrolling 27 eligible patients into the study. Eight (30%) patients achieved objective responses—the highest proportion ever reported in treat ment-refractory patients. One (4%) patient achieved a complete response; 20 (74%) achieved either a complete response, partial response, or stable disease; median response duration was 9·5 months, median progression-free survival was 5·2 months (95% CI 4–8); and median overall survival was 11·5 months (95% CI 8–17). In this heavily pretreated population, these outcome data are extraordinary, and they show the relevance of HER2 as a target in the treatment of colorectal cancer. These results represent a breakthrough, even though they apply only to a small subgroup of patients. The results are in line with data from the MyPathway basket trial, which included refractory patients with expression of an identifi ed druggable target (HER2, BRAF, EGFR, or hedgehog). 13 patients with colorectal cancer were given trastuzumab (targeting HER2) plus pertuzumab (targeting the dimerisation domain of HER2, thus inhibiting the HER2–HER3-dimerisation and HER2-activation), with similar results to those of HERACLES (table). Together, the results from HERACLES and MyPathway support preclinical data showing that the inhibition of HER2 with trastuzumab plus either lapatinib or pertuzumab is superior to combination with standard chemotherapy (table). What do these results mean in routine clinical practice? Despite the small number of patients, these data defi ne a new standard of routine therapy for patients with HER2 amplifi cation or overexpression. Data from HERACLES and MyPathway suggest that the combination of anti-HER2 (trastuzumab or lapatinib) plus either anti HER2–3 (pertuzumab) or anti-HER1/ EGFR (lapatinib) is a valid approach for colorectal cancer. However, several questions remain. First, beyond the problems of registration and reimbursement for this novel treatment, a question exists as to which combination should be used. HERACLES and MyPathway included diff erent populations of patients: in MyPathway, patients were not selected by KRAS mutation status (although it can be anticipated that all included patients with RAS wild-type tumours had been refractory to EGFR-targeting antibodies), whereas in HERACLES, all patients had KRAS wild-type tumours, based on Targeting HER2: precision oncology for colorectal cancer