Lessons learned: RAS- or BRAF-mutated metastatic colorectal cancers (mCRCs) progressing after first-line treatment have a poor prognosis.European and U.S. guidelines include the multikinase inhibitor regorafenib as a standard option for second-line therapy and beyond, based on the results of the randomized phase III CORRECT trial demonstrating improvement in survival.Although stopped prematurely for failing to accrue, the PREVIUM trial, the first prospective interventional study exploring regorafenib as second-line treatment for patients with mCRC bearing RAS or BRAF mutations, failed to demonstrate clinical activity in the population analyzed.
Background: Patients with RAS- or BRAF-mutated (mut) metastatic colorectal cancer (mCRC) progressing on first-line bevacizumab plus 5-FU/irinotecan/oxaliplatin (FOLFOXIRI) have a poor prognosis. We aimed to assess the efficacy and safety of regorafenib in this population.
Methods: Regorafenib was administered daily for 3 weeks of each 4-week cycle until disease progression or other reason. The primary endpoint was 6-month progression-free survival (PFS).
Results: KRAS, NRAS, or BRAF was mutated in mCRC samples in 60%, 20%, and 13% of patients, respectively. Median time from initial diagnosis of metastases to the start of regorafenib and treatment duration was 13.8 months and 7 weeks, respectively. Reasons for discontinuation included disease progression (80%), investigator decision (13%), and adverse events (AEs; 7%). Seven patients (47%) required dose reduction, mostly for asthenia (43%). The most common regorafenib-related grade 3 AEs were asthenia (33%), dysphonia (13%), and hypertension (13%) (Table 1). There were no grade 4 toxicities. No patient was progression-free at 6 months. Median PFS, time to progression (TTP), and overall survival (OS) were 2.2, 2.0, and 3.3 months, respectively.
Conclusion: Although stopped prematurely for failing to accrue, in the population analyzed, regorafenib failed to demonstrate clinical activity in KRAS- or BRAF-mutated mCRC with progression following first-line with FOLFOXIRI plus bevacizumab, although tolerability was acceptable. Our trial suggests that exploring regorafenib efficacy in an earlier line of therapy should not be undertaken without better population refinement.
经验获取
• 一线治疗后进展的 RAS 或 BRAF 基因突变转移性结直肠癌 (mCRC) 预后不良。
• 欧洲和美国的指南将多激酶抑制剂瑞格非尼作为二线治疗及后线治疗的标准选择,是根据随机III期CORRECT试验证实生存期改善的结果。
• 虽然因招募失败而提早结束,但PREVIUM 试验是首个前瞻性干预研究探索瑞格非尼作为二线治疗 RAS 或 BRAF 基因突变的 mCRC 患者,未能对分析人群取得临床活性。
摘要
背景。贝伐珠单抗 + 5‐FU/伊立替康/奥沙利铂 (FOLFOXIRI) 一线治疗后病情进展的 RAS 或 BRAF 基因突变 (mut) 转移性结直肠癌 (mCRC) 患者预后差。我们旨在评估瑞格非尼对该人群的有效性和安全性。
方法。瑞格非尼每天一次,连续给药 3 周,每 4 周为一个周期,直到患者病情出现进展或存在其他原因。主要终点是 6 个月无进展生存期 (PFS)。
结果。分别有 60%、20% 和 13% 的患者的 mCRC 样本出现 KRAS、NRAS 或 BRAF 基因突变。从转移的初始诊断到开始使用瑞格非尼和持续治疗的中位时间分别为 13.8 个月和 7 周。停药的原因包括病情进展 (80%)、研究者决定 (13%) 和不良事件 (AE;7%)。七名患者 (47%) 需要减少剂量,主要是因为身体虚弱 (43%)。最常见的瑞格非尼相关的 3 级 AE 是身体虚弱 (33%)、发声困难 (13%) 和高血压 (13%)(表 1)。未出现 4 级毒性。没有患者在 6 个月时病情无进展。中位PFS、至进展时间 (TTP) 和总生存期 (OS) 分别为 2.2、2.0 和 3.3 个月。
结论。虽然在招募失败的情况下提早结束,但在所分析的人群中,未证实瑞格非尼对 FOLFOXIRI + 贝伐珠单抗一线治疗后病情进展的 KRAS 或 BRAF 基因突变 mCRC 患者具有临床活性,尽管耐受性尚可。我们的试验表明,如果没有进行更好的人群细化,则不应在较早期的治疗中探索瑞格非尼的有效性。
Trial registration: ClinicalTrials.gov NCT02175654.
© AlphaMed Press; the data published online to support this summary is the property of the authors.