Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

抗表皮生长因子受体 (EGFR) 单克隆抗体被批准用于治疗RAS野生型 (WT) 转移性结直肠癌 (mCRC)，但耐药突变的出现限制了其疗效。我们之前表明，在 EGFR 阻断期间出现在循环肿瘤 DNA (ctDNA) 中的RAS、BRAF和EGFR突变等位基因在停止治疗后会下降。我们假设监测血液中的耐药突变可以合理地指导随后的抗 EGFR 抗体治疗。我们在此报告 CHRONOS 的结果，这是一项开放标签、单臂 2 期临床试验，利用基于血液的RAS / BRAF / EGFR鉴定突变水平以定制帕尼单抗的无化疗抗 EGFR 再攻击（ClinicalTrials.gov：NCT03227926；EudraCT 2016-002597-12）。主要终点是客观反应率。次要终点是该策略的无进展生存期、总生存期、安全性和耐受性。在 CHRONOS 中，组织RAS患者先前使用基于抗 EGFR 的方案治疗后的 WT 肿瘤接受了基于 ctDNA 的介入性筛查。在 52 名患者中，16 名 (31%) 携带至少一种突变导致对抗 EGFR 治疗产生耐药性并被排除在外。达到了试验的主要终点；并且，在 27 名入组患者中，8 名 (30%) 实现了部分缓解和 17 名 (63%) 疾病控制，其中包括 2 名未经证实的缓解。这些临床结果优于标准三线治疗，表明介入性液体活检可以及时有效、安全地用于指导 mCRC 患者使用帕尼单抗进行抗 EGFR 再激发治疗。有必要进行更大规模的随机试验，以正式比较帕尼单抗再挑战与该患者环境中的标准护理疗法。