Erratum: Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients

Importance Rechallenge therapy with anti–epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractoryRASwild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti–EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting. Objective To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab. Design, Setting, and Participants This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients withRASWT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) forKRAS, NRAS, BRAF,andEGFR-S492Rmutation analysis was done. Interventions Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m²and, subsequently, 250 mg/m²weekly) until disease progression or unacceptable toxic effects. Main Outcomes and Measures The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Results Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF,andEGFR-S492Rvariations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients withRAS/BRAFWT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90;P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) inRAS/BRAFWT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75;P = .004). Conclusions and Relevance The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy inRAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit. Trial Registration ClinicalTrials.gov Identifier:NCT04561336

At the TOPAZ-1 (NCT03875235) primary analysis, durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in advanced biliary tract cancer (aBTC). We report updated exploratory analyses of OS and safety, characterisation of extended long-term survivors (eLTS), and subsequent anticancer therapy (SAT) use. Participants with aBTC received durvalumab+GemCis or placebo+GemCis every 3 weeks (≤8 cycles), then durvalumab or placebo monotherapy every 4 weeks until progressive disease or other discontinuation criteria were met. OS and serious adverse events (SAEs) were assessed in the full analysis and safety analysis sets (FAS/SAS), respectively. eLTS outcomes were assessed (FAS participants alive ≥30 months after randomisation). 685 participants were randomised: durvalumab+GemCis (n = 341); placebo+GemCis (n = 344). After a median 41.3 (95% confidence interval [CI] 39.3-44.1) months' follow-up in all participants, median OS (95% CI) for durvalumab+GemCis versus placebo+GemCis was 12.9 (11.6-14.1) versus 11.3 (10.1-12.5) months (hazard ratio, 0.74 [95% CI 0.63-0.87]); 36-month OS rate was 14.6% versus 6.9%, respectively. In participants who achieved disease control (566/685; 82.6%), the 36-month OS rate was higher for durvalumab+GemCis (17.0%) versus placebo+GemCis (7.6%). Overall, 12.8% were eLTS, with more eLTS in the durvalumab+GemCis (17.0%) versus placebo+GemCis (8.7%) arms; eLTS included all clinically relevant subgroups. Durvalumab+GemCis improved OS regardless of SAT use. In eLTS, SAEs were comparable between arms and less frequent than in the full SAS. Survival benefit and manageable safety continued with durvalumab+GemCis versus placebo+GemCis approximately 3 years after the last participant was randomised. All clinically relevant subgroups were represented in eLTS, supporting standard-of-care status for durvalumab+GemCis in aBTC. The TOPAZ-1 study found that treatment with durvalumab plus gemcitabine and cisplatin (chemotherapy, also known as GemCis), helped people with advanced biliary tract cancer (BTC) to live longer on average than those treated with a placebo plus GemCis. The latest results from TOPAZ-1 showed that these benefits continued for over 3 years in participants treated with durvalumab plus GemCis and side effects continued to be manageable. At an updated analysis, carried out 3 years after the last participant started the study, twice as many participants treated with durvalumab plus GemCis were alive compared to those treated with placebo plus GemCis. Results also showed that the positive effect of durvalumab plus GemCis compared with placebo plus GemCis was not affected by the use of other therapies some participants received after they finished the study treatment. These results continue to support durvalumab plus GemCis as a standard first-line treatment for people with advanced BTC. ClinicalTrials.gov Identifier: NCT03875235; https://clinicaltrials.gov/study/NCT03875235.