In Regard to “A Phase Ib Study of NUC‐1031 in Combination with Cisplatin for the First‐Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC‐08)”

Short abstract

This letter to the editor remarks on a recently published article on the use of NUC‐1031 and cisplatin for patients with biliary tract cancer and compares results of the landmark ABC‐02 trial.

We read with great interest the article published by McNamara et al. and commend the authors for bringing this interesting report to the field of systemic treatment of biliary tract cancer (BTC) [1]. Unfortunately, advanced BTC remains a highly lethal malignancy, showing a poor response to cytotoxic chemotherapy and dismal prognosis. Thus, the identification of more effective regimens represents an urgent need in this setting [2].

In The Oncologist, McNamara et al. reported the results of a phase Ib trial including 21 treatment‐naïve patients with advanced BTC, treated with NUC‐1031 and cisplatin [1]. Of note, the 33% of patients had an overall response, and median progression‐free survival and overall survival were 7.2 months and 9.6 months, respectively. Despite the small sample size, the authors confirmed that the combination of NUC‐1031 with cisplatin may show a potentially meaningful antitumor activity and a manageable safety profile in patients with advanced BTC.

We believe some elements deserve discussion. Interestingly enough, the combination of NUC‐1031 plus cisplatin showed a disease control rate similar to that of the reference doublet cisplatin‐gemcitabine in the landmark ABC‐02 trial (78% and 81.4%, respectively) [3]. In addition, the ABC‐08 trial comprised patients having received previous adjuvant chemotherapy including gemcitabine, and therefore, the study provides evidence supporting a possible role of NUC‐1031 (phosphoramidate transformation of gemcitabine) in this patient population. Moreover, cisplatin‐gemcitabine was given to two patients whose disease progressed on NUC‐1031 in combination with cisplatin, suggesting that advanced BTCs could be retreated with the standard‐of‐care doublet following the ABC‐08 experimental treatment.

In terms of safety, the combination therapy seems to have potentially important, but manageable, toxicities in what remains a palliative setting. Increased gamma‐glutamyltransferase, neutropenia, increased alanine aminotransferase, and fatigue were common, and nearly half of patients (n = 9) discontinued therapy because of toxicity. For example, of potential concern is the case of radiological pneumonitis (although on a background of longstanding fibrosis), which in our opinion should be monitored closely in future trials. In addition, it would be interesting to know if prophylaxis of chemotherapy‐induced neutropenia was allowed in this trial.

Lastly, the authors state that only 4 out of 21 patients had molecular testing in ABC‐08. In recent years, the identification of targets of relevance has changed the field of BTCs, and although several challenges remain, it would be important to assess NUC‐1031 plus cisplatin in a later‐line setting, or even in combination with targeted agents in patients harboring driver mutations.

Certainly, although caution should always be exercised when interpreting results from single‐arm, early‐phase trials without a comparator arm, results of the ABC‐08 study seem promising; thus, of great interest will be the results of the ongoing phase III NuTide:121 trial assessing NUC‐1031 in combination with cisplatin [4]. Today, 10 years after the publication of the ABC‐02 trial, the BTC medical community has an urgent need to improve outcomes for patients diagnosed with advanced disease [5]. Development of novel therapeutic approaches is needed, and the ABC‐08 has the potential to open a new chapter in this setting.

Disclosures

The authors indicated no financial relationships.