An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas

Abstract

Background. The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC. Methods. This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m 2 of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing.Results. Twenty-three patients with a median age of 61 (range, 44-73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progressionfree survival was 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH. Conclusion. TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273. The Oncologist 2020;25:e782-e788 Implications for Practice: Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival of 4.3 (95% CI, 1.7-15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.

Systemic Treatment of Gastroenteropancreatic Neuroendocrine Carcinoma

“…Median PFS for second-line was 3.0 months and median OS 7.0 months, for third-line median PFS, and median OS was 2.5 and 6.2 months. Topoisomerase inhibitors were traditionally considered an alternative treatment strategy in small-cell lung cancer and was therefore subject to one prospective [55] and four retrospective [56][57][58][59] studies in NEC patients. Median PFS was about 2-4 months with a median OS of between 4 and 7 months and a RR between 19 and 40%.…”

Future therapeutic strategies in the treatment of extrapulmonary neuroendocrine carcinoma: a review

“…The phase II study of TLC388 HCl in the 2L management of NEC illustrates this point, with an ORR of 0%, disease control rate (DCR) of 15% and median PFS of 1.8 months. 26…”

Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma

“…To the author's knowledge, only one prospective phase II study of single-agent topoisomerase inhibitors in EP-PD-NEC has been published. In this study, 22 patients, over half of whom had a Ki-67 > 55%, were treated with a novel topoisomerase I inhibitor TLC388 at 40 mg/m 2 [43]. Disappointingly, no responses were seen, and PFS was only 1.8 months, despite the improved in vitro data showing higher rates of topoisomerase I inhibition when compared to topotecan [44].…”