Jorien B E Janssen, Kirti K Iyer, Sophie L Gerritse, Eline Janssen, Elske C Gootjes, Mariette Labots, Tineke E Buffart, Miriam L Wumkes, Joeri A J Douma, Mirte M Streppel, Laurien M Buffart, Marianne A Jonker, Erik van den Hombergh, Nielka P van Erp, Jan Paul Medema, Daniele V F Tauriello, Dennis Poel, Henk M W Verheul
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引用次数: 0
Abstract
Background: Patients with metastatic colorectal cancer often have poor or short responses to currently available therapies. Drug repurposing with alternative dosing schedules may offer unexpected clinical benefit, even for agents that previously failed for this indication.
Methods: We explored a high-dose treatment strategy for sunitinib, assessing its potential for both cancer cell killing and inducing immunogenic cell death in patient-derived tumour organoids (PDTOs) of metastatic colorectal cancer (mCRC). In a randomized clinical trial, we studied the efficacy of high-dose intermittent sunitinib (700 mg once every 2 weeks) in patients with advanced CRC compared to standard therapy with trifluridine/tipiracil. The primary outcome measure was progression-free survival (PFS); secondary outcomes included overall survival, safety and tolerability, quality of life, and exploratory biomarker analyses.
Results: While high, intermittent dosing was found to effectively kill PDTOs in vitro, no support for immunogenic cell death was found. In our clinical trial, among a total of 63 evaluable patients, median PFS was 2.8 months (95% CI 0.9-4.7) for the investigation arm compared to 1.9 months (95% CI 1.6-2.3) for the trifluridine/tipiracil group (p = 0.78, HR 1.22; 95% CI 0.73-2.04). The trial was halted prematurely due to toxicities: in particular, hemorrhage, fever and gastrointestinal adverse events.
Conclusion: High-dose intermittent sunitinib treatment did not improve PFS for patients with heavily pretreated mCRC compared to standard 3rd or 4th-line treatment with trifluridine/tipiracil, whereas significant toxicity was observed. In addition, this approach provoked no relevant immunological responses in vitro, discouraging further research for potential combinations with immunotherapeutics.
背景：转移性结直肠癌患者对现有治疗方法的反应通常较差或较短。采用替代给药方案重新使用药物可能会带来意想不到的临床益处，即使对于以前未能适应该适应症的药物也是如此。方法：我们探索了舒尼替尼的高剂量治疗策略，评估了其在转移性结直肠癌（mCRC）患者源性肿瘤类器官（PDTOs）中杀死癌细胞和诱导免疫原性细胞死亡的潜力。在一项随机临床试验中，我们研究了高剂量间歇性舒尼替尼（700 mg，每2周1次）在晚期结直肠癌患者中的疗效，并与trifluridine/tipiracil标准治疗进行了比较。主要结局指标为无进展生存期（PFS）；次要结局包括总生存期、安全性和耐受性、生活质量和探索性生物标志物分析。结果：虽然发现高剂量、间歇性给药可有效杀死体外pdto，但未发现支持免疫原性细胞死亡。在我们的临床试验中，在总共63例可评估的患者中，调查组的中位PFS为2.8个月（95% CI 0.9-4.7），而trifluridine/tipiracil组的中位PFS为1.9个月（95% CI 1.6-2.3） （p = 0.78, HR 1.22; 95% CI 0.73-2.04）。由于毒性，特别是出血、发热和胃肠道不良事件，该试验过早停止。结论：与标准的三线或四线trifluridine/tipiracil治疗相比，大剂量间歇性舒尼替尼治疗并没有改善重度预处理mCRC患者的PFS，而观察到明显的毒性。此外，这种方法在体外没有引起相关的免疫反应，阻碍了与免疫疗法潜在联合的进一步研究。标识符:NCT03909724。
期刊介绍：
The Oncologist® is dedicated to translating the latest research developments into the best multidimensional care for cancer patients. Thus, The Oncologist is committed to helping physicians excel in this ever-expanding environment through the publication of timely reviews, original studies, and commentaries on important developments. We believe that the practice of oncology requires both an understanding of a range of disciplines encompassing basic science related to cancer, translational research, and clinical practice, but also the socioeconomic and psychosocial factors that determine access to care and quality of life and function following cancer treatment.
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