Lessons learned: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity.
Background: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab.
Methods: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided.
Results: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018).
Conclusion: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
经验获取
• 使用厄洛替尼和帕尼单抗联合吉西他滨的表皮生长因子受体 (EGFR) 双重拮抗定向治疗优于吉西他滨和厄洛替尼，但由于吉西他滨单药治疗的作用有限，临床相关性尚不明确。
• 观察到接受 EGFR 双重拮抗定向治疗的患者的总生存期明显延长。
• EGFR 双重拮抗定向治疗导致毒性增加。
摘要
背景。吉西他滨对晚期胰腺癌患者有效。与单用吉西他滨相比，厄洛替尼，一种口服表皮生长因子受体 (EGFR) 抑制剂，和吉西他滨的联合用药稍微延长总生存期。中北癌症治疗组(现为肿瘤临床试验联盟的一部分)N064B试验比较了吉西他滨联合厄洛替尼对比吉西他滨加厄洛替尼和帕尼单抗联合进行 EGFR 抑制的疗效。
方法。患有转移性胰腺癌的入组患者随机分配至吉西他滨(1,000 mg/m 2， 在第 1、8 和 15 天用药，28 天为一周期)联合厄洛替尼(100 mg，每天口服)(A 组)或分配至同样联合用药再加上帕尼单抗(4 mg/kg，在第 1 天和第 15 天用药，28 天为一周期)(B 组)。该试验的主要终点为总生存期。次要终点包括无进展生存期、确诊的缓解率和毒性。使用单侧对数秩检验进行各组之间主要终点的比较，并且 p 值小于 0.20 被认为具有统计学显著性意义。用 Fisher 精确检验进行缓解率比较。所有其他报告的 p 值都是双侧的。
结果。共有 92 名患者随机分组，每组 46 名患者。A 组的中位总生存期为 4.2 个月，B 组为 8.3 个月 [风险比，0.817；95% 置信区间 (CI)，0.530‐1.260；p = 0.179 2]。A 组的无进展生存期为 2.0 个月，B 组为 3.6 个月(风险比，0.843；95% CI，0.555‐1.280；p = 0.419 0)。A 组有 8.7% 的患者出现了部分确认的缓解，而 B 组则为 6.5%(p = 0.999 9)。没有患者出现完全缓解。3 级或以上的非血液学毒性在 B 组患者中比在 A 组患者更常见(82.6 % vs. 52.2%；p = 0.001 8)。
结论。EGFR 双重拮抗定向治疗可使晚期胰腺癌患者的总生存期显著延长，但与毒性显著增加有关联。不推荐将 EGFR 双重拮抗定向治疗与单药吉西他滨用于进一步研究，因为单药吉西他滨不再被认为是其他适合的转移性胰腺癌患者的恰当治疗方法。
Trial registration: ClinicalTrials.gov NCT00550836.
© AlphaMed Press; the data published online to support this summary are the property of the authors.