# Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (PRODIGE 62-FFCD 1701-OESIRI)

David Tougeron, Laurent Mineur, Aziz Zaanan, Melissa Kadi, Catherine

Poisson Ligeza, Vincent Bourgeois, Jérôme Martin-Babau, Aurélie Fadin, Véronique Jestin Le Tallec, Valérie Ly Lebrun, et al.

► To cite this version:

David Tougeron, Laurent Mineur, Aziz Zaanan, Melissa Kadi, Catherine Poisson Ligeza, et al. Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (PRODIGE 62-FFCD 1701-OESIRI). European Journal of Cancer, 2025, 228, pp.115741. 10.1016/j.ejca.2025.115741. hal-05249822

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Clinical trial

<figure><img src="image_2.png" /></figure>

Nal-IRI/LV5-FU versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (PRODIGE 62-FFCD 1701-OESIRI)☆

David Tougeron<sup>a, *, e</sup>, Laurent Mineur<sup>b, e</sup>, Aziz Zaanan<sup>c</sup>, Melissa Kadi<sup>d, e</sup>, Catherine Poisson Ligeza<sup>e</sup>, Vincent Bourgeois<sup>f</sup>, Jérôme Martin-Babau<sup>g</sup>, Aurélie Fadin<sup>h</sup>, Véronique Jestin le Tallec<sup>i</sup>, Valérie Ly Lebrun<sup>j</sup>, Olivier Dubreuil<sup>k</sup>, Faiza Khemissa Akouz<sup>l</sup>, Elsa Thimonier<sup>m</sup>, Olivier Bouché<sup>n</sup>, Astrid Lièvre<sup>o</sup>, Frédéric Di Fiore<sup>p</sup>, Thierry Lecomte<sup>q</sup>, Côme Lepage<sup>d</sup>, Vincent Hautefeuille<sup>r, e</sup>, for the PRODIGE 62-FFCD 1701-OESIRI investigators/ collaborators<sup>1</sup>

ARTICLE INFO

Keywords:

Esophageal cancer

Irinotecan

Paclitaxel

Squamous cell carcinoma

ABSTRACT

**Background:** Metastatic esophageal squamous cell carcinoma (mESCC) patients with disease progression after platinum-based first-line chemotherapy (CT) +/- immune checkpoint inhibitors (ICI) may benefit from second-line CT, mostly based on paclitaxel and irinotecan, but no randomized trial has compared these regimens.

**Patients and methods:** PRODIGE 62-OESIRI is a multicenter, open-label, randomized phase II trial evaluating the efficacy and safety of nanoliposomal irinotecan (Nal-IRI) plus 5FU versus paclitaxel as second-line CT in mESCC. The primary endpoint was to achieve overall survival (OS) of 60 % at 9 months.

**Results:** Between March 2019 and July 2023, 106 pts were randomized. Median age was 65.6 years, 83.0 % men and 29.2 %/58.5 %/12.3 % of ECOG PS 0/1/2, respectively. As prior treatment, 48.6 % had chemoradiation, 41.9 % CT alone and 9.5 % CT plus ICI. OS at 9 months was 34.0 % [90 %CI: 22.9–46.5] and 39.2 % [90 %CI: 27.7–51.7] in the 5FU Nal-IRI and paclitaxel arms, respectively. The primary endpoint was not met. Median progression-free survival was 2.4 [95 %CI: 2.1–3.6] and 2.1 [95 %CI: 1.9–3.3] months, and median OS 7.1 [95 %CI: 5.2–8.3] and 6.6 [95 %CI: 4.8–10.3] months, respectively. Overall, 51.0 % and 38.5 % of patients experienced

<footnote><sup>a</sup> Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France</footnote>

<footnote><sup>b</sup> Liver and Gastro-intestinal Radiation Oncology unit, Institut du Cancer Provence Avignon Sainte Catherine, Avignon, France</footnote>

<footnote><sup>c</sup> Department of Digestive Oncology, Georges Pompidou European Hospital, AP-HP, Université Paris Cité, Paris Cancer Institute CARPEM, Paris, France</footnote>

<footnote><sup>d</sup> Fédération Francophone de Cancérologie Digestive, EPICAD INSERM LNC-UMR 1231, Bourgogne Franche-Comté University, Dijon, France</footnote>

<footnote><sup>e</sup> Department of Gastroenterology and Digestive Oncology, Saint Nazaire Centre, Saint Nazaire, France</footnote>

<footnote><sup>f</sup> Department of Gastroenterology and Digestive Oncology, Boulogne-sur-Mer Hospital, Boulogne-sur-Mer, France</footnote>

<footnote><sup>g</sup> Department of Gastroenterology and Digestive Oncology, Plérin Hospital, Plérin, France</footnote>

<footnote><sup>h</sup> Department of Gastroenterology, Beuvry Hospital, Beuvry, France</footnote>

<footnote><sup>i</sup> Department of Oncology, Pasteur Lanoze Hospital, Brest, France</footnote>

<footnote><sup>j</sup> Department of Oncology, Limoges University Hospital, Limoges, France</footnote>

<footnote><sup>k</sup> Department of Oncology, Diaconesses-Croix Simon Hospital, Paris, France</footnote>

<footnote><sup>l</sup> Department of Gastroenterology and Hepatology, Perpignan Hospital, Perpignan, France</footnote>

<footnote><sup>m</sup> Department of Gastroenterology, Annecy Hospital, Annecy, France</footnote>

<footnote><sup>n</sup> Department of Digestive Oncology, CHU Reims, Reims, France</footnote>

<footnote><sup>o</sup> Department of Gastroenterology, CHU Rennes, University of Rennes, INSERM U1242, Rennes, France</footnote>

<footnote><sup>p</sup> Normandy Univ, UNIROUEN, Rouen University Hospital, Department of Hepatogastroenterology, Rouen, France</footnote>

<footnote><sup>q</sup> Department of Gastroenterology and Hepatology, Tours University Hospital, Tours, France</footnote>

<footnote><sup>r</sup> Department of Hepatogastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France</footnote>

<footnote>* Trial registration NCT03719924</footnote>

<footnote>* Correspondence to: Department of Gastroenterology and Hepatology, Poitiers University Hospital, 2 rue de la Milétrie, Poitiers 86021, France.
E-mail address: david.tougeron@chu-poitiers.fr (D. Tougeron).
@david_tougeron (D. Tougeron)</footnote>

<footnote n="1">¹ See PRODIGE 62-FFCD 1701-OESIRI investigators/collaborators in supplementary appendix</footnote>
at least one grade 3–4 treatment-related adverse events (neuropathy: 2.0 vs. 7.7%, diarrhea: 16.3% vs. 0% and vomiting: 10.2 vs. 0%), in the 5FU Nal-IRI and paclitaxel arms, respectively. Treatment was discontinued for toxicity in 10.4% versus 3.9% in the 5FU Nal-IRI and paclitaxel arm, respectively.

*Conclusions:* PRODIGE 62-OESIRI trial showed low efficacy of paclitaxel and 5FU Nal-IRI in the 2nd line treatment of mESCC, though paclitaxel provided a better safety profile.

**Trial registration** NCT03719924

# 1. Introduction

The prognosis for metastatic esophageal cancer remains poor, with overall survival (OS) ranging from 3% to 10% at 5 years [1,2]. About 50% of patients diagnosed with ESCC have metastatic ESCC (mESCC) and about 50% of patients with initially local/loco-regional disease present disease recurrence after surgery or definitive chemoradiation.

Until recently, treatment of metastatic ESCC (mESCC) was based on palliative first-line chemotherapy with a doublet of fluoropyrimidine (5-fluorouracil (5FU) or capecitabine) plus a platinum salt (cisplatin or oxaliplatin) [3]. Some phase III trials demonstrated that the addition of anti-programmed cell death 1 (anti-PD1) monoclonal antibodies (immune checkpoint inhibitor, ICI) to platinum-based chemotherapy as the first-line treatment of PD-L1 positive advanced/metastatic ESCC improved efficacy according to tumor positive score (TPS), combined positive score (CPS) or tumor area positivity (TAP) [4–9].

No randomized trial has compared second-line chemotherapies in mESCC, and guidelines do not recommend a specific chemotherapy regimen [10–15]. Second-line chemotherapies have poor efficacy, but a Cochrane meta-analysis suggested that second-line chemotherapies as compared to best supportive care alone probably increase overall survival (OS) [12]. Median OS with second line chemotherapy (paclitaxel, docetaxel or irinotecan) ranged from 5 to 8 months [13–15]. Three phase III trials demonstrated better OS with second-line anti-PD1 than with chemotherapy [16–18]. Nevertheless, in all these studies, patients were ICI naïve, and today, in second-line settings, anti-PD1 alone is no longer used in patients who received first-line chemotherapy plus anti-PD1.

Nal-iri, is a nanoliposomal irinotecan increasing and prolonging intratumoral levels of both irinotecan and its active metabolite, already approved in metastatic pancreatic adenocarcinoma [19]. A phase II trial comparing nal-IRI to irinotecan and docetaxel in the second-line treatment of advanced esophago-gastric adenocarcinoma showed an objective response rate (ORR) of 13.6% of in the nal-IRI arm and 6.8% in the irinotecan arm [20].

There is no standard of care in second-line settings for mESCC, given the limited efficacy of chemotherapy regimens. Indeed, we conducted the PRODIGE 62-FFCD 1701-OESIRI randomized phase 2 trial to evaluate the efficacy and safety of 5FU Nal-IRI versus paclitaxel as the second-line therapy in patients with mESCC.

# 2. Patients and methods

## 2.1. Study design

The PRODIGE 62-FFCD 1701-OESIRI study is a randomized, open-label, multicenter, non-comparative, phase II study designed to evaluate the safety and efficacy of 5FU Nal-IRI versus paclitaxel as the second-line therapy in patients with mESCC [19]. This study was sponsored by the Fédération Francophone de Cancérologie Digestive (FFCD).

The PRODIGE 62-FFCD 1701-OESIRI trial was approved by the French healthcare authorities (Agence Nationale de Sécurité du Médicament et des Produits de Santé) and an independent ethics committee (Comité de Protection des Personnes Sud-Est IV, number 2017-004730-28 on October 15th, 2018). The study was conducted in accordance with the Declaration of Helsinki and International

Conference on Harmonization Good Clinical Practice Guidelines. Written informed consent was obtained from all patients before treatment.

## 2.2. Patients

The main inclusion criteria were patients aged 18 years or older, histologically proven mESCC, with progression or intolerance after first-line platinum-based chemotherapy. Patients with resectable disease treated with surgery and pre- or post-operative chemotherapy (alone or combined with radiotherapy) could be included if a metastatic recurrence occurred within 6 months after the end of treatment. In addition, patients with metastatic progression within 6 months after definitive chemoradiation were also eligible. Patients with or without measurable disease, according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, were eligible for the study. Patients had to have an Eastern Cooperative Oncology Group (ECOG) - Performance Status (PS) of 0, 1 or 2 and albumin ≥ 25 g/l (for all inclusion/non-inclusion criteria see Supplementary data).

## 2.3. Randomization

Patients were randomized using the minimization technique and a 1:1 ratio to receive 5FU plus Nal-IRI (5FU Nal-IRI arm) or paclitaxel (paclitaxel arm) and stratified on center and ECOG PS (0/1 versus 2).

The initial biological and clinical assessments (ECOG PS, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and OES18 questionnaires) were filled in within 2 weeks prior to randomization. Within 4 weeks prior to randomization, a CT-scan of the neck-thorax-abdomen-pelvis areas was done before enrollment.

## 2.4. Procedures

Patients received the 5FU Nal-IRI regimen with folinic acid 400 mg/m² in a 2-hour intravenous (IV) infusion, continuous 5FU 2400 mg/m² in a 46-hour IV infusion and nal-iri at 70 mg/m² in a 2-hour IV infusion, every 14 days. In the control arm, paclitaxel was administered at a dose of 80 mg/m² at day 1, day 8 and day 14 of a 28-day cycle. All toxicities requiring dose adjustment were evaluated according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 criteria.

Patients were evaluated every 8 weeks using clinical examinations, and laboratory and morphological assessments until progression [19].

## 2.5. Study objectives

The primary endpoint was the percentage of patients alive at 9 months (OS at 9 months). OS was defined as the time from randomization to death from any cause. Patients alive were censored on the date of last news.

Secondary endpoints included PFS, OS, best response rate (complete response or partial response according to RECIST 1.1 criteria), safety profile (according to NCI-CTCAE v4.0 criteria) and quality of life (QoL).

## 2.6. Sample size and statistical considerations

The hypotheses were H₀: 40% of patients alive at 9 months was not
<figure><img src="image_3.png" /><figcaption>Fig. 1. CONSORT diagram. mITT: modified intention-to-treat population.</figcaption></figure>

acceptable, and H₁: 60% of patients alive at 9 months was expected. With a risk α (one-sided) of 5%, a power of 85% and according to the binomial exact method, 50 evaluable patients per arm were needed. Assuming 5% of non-evaluable or lost to follow-up patients, 53 patients per arm were included (for a total of 106 patients).

Analyses of primary and secondary efficacy endpoints were conducted on the modified intention-to-treat population (mITT population), i.e. all patients who had received at least one dose of treatment in the study, regardless of their eligibility criteria. Safety analyses were conducted on all patients receiving at least one dose of treatment and according to the treatment received (safety population) (Figure 1).

Quantitative variables are described with means, medians, standard deviations (SD) or interquartile ranges (IQR). Qualitative variables are described as frequencies and percentages. For quantitative variables, baseline characteristics of treatment arms were compared using a Student or Wilcoxon test, and for qualitative variables a chi² test or a Fisher exact test was used.

For the primary endpoint, a one-sided 90 % confidence interval (CI) was calculated. Survival criteria were estimated using the Kaplan-Meier method and described by medians and their two-sided 95 % CI. For exploratory purposes, univariate and multivariate analyses were done using a Cox model. Variables with p-value less than 0.15 in univariate analysis were included in the multivariate model.

Follow-up duration was estimated by the reverse Kaplan-Meier method. SAS software 9.4 (SAS Institute, Cary, NC) was used for all statistical analyses.

# 3. Results

## 3.1. Patients

Between March 7th, 2019 and July 5th, 2023, 106 patients in 43 centers were randomized (ITT population) and 101 patients received at least one dose of the treatment (mITT population). One patient randomized in the 5FU Nal-IRI arm received the paclitaxel treatment and was analyzed in the paclitaxel arm for safety analyses (safety population) (Figure 1).

The median age was 66.0 years, 18 patients (17.0 %) were women and most patients had an ECOG PS at 0 (29.7 %) or 1 (58.4 %) (Table 1).

(Supp Table 1). Patients were mostly treated with chemotherapy (40.0 %) or chemotherapy plus radiation (46.0 %), and 14.0 % had received an immune checkpoint inhibitor before inclusion.

At inclusion, the most frequent metastatic sites were lymph nodes (68.0 %), lung (54.0 %) and liver (25.0 %). Most patients had only one (45.0 %) or two (36.0 %) metastatic sites. All baseline characteristics were balanced across the treatment groups.

## 3.2. Treatment and response rate

The median follow-up was 7.1 [IQR 4.8–10.1] months in the 5FU Nal-IRI arm and 6.6 [IQR 4.0–11.6] months in the paclitaxel arm. At the time of the analysis (March 29th, 2024), 48 patients had definitively discontinued 5FU Nal-IRI treatment and 51 patients had discontinued paclitaxel treatment. The most common reason for treatment discontinuation in both groups was disease progression (81.2 % and 88.2 %, respectively) (Figure 1).

Median duration of treatment was 1.5 [IQR 1.2–3.7] and 1.9 [IQR 1.4–3.8] months in the 5FU Nal-IRI and paclitaxel arms, respectively. The overall response rate (ORR) (22.9 % in the 5FU Nal-IRI arm and 15.7 % in the paclitaxel arm) and disease control rate (DCR) (45.8 % and 37.3 %) in the two arms were not different. Median DoR was 3.6 [IQR 1.9–5.3] months in the 5FU Nal-IRI arm and 3.4 [IQR 2.0–6.7] months in the paclitaxel arm. Most patients received a third-line treatment (55.1 % in the 5FU Nal-IRI arm and 61.5 % in the paclitaxel arm).

## 3.3. Outcome and survival

Median PFS was 2.4 [95 % CI 2.1–3.6] and 2.1 [95 % CI 1.9–3.3] months in the 5FU Nal-IRI and paclitaxel arms, respectively (Figure 2). Three-month and six-month PFS rates were 42.0 % [95 % CI 28.3–55.1] and 18.0 % [95 % CI 8.9–29.7], and 37.2 % [95 % CI 24.3–50.2] and 13.7 % [95 % CI 6.0–5.9] in the 5FU Nal-IRI and paclitaxel arms, respectively.

Most patients had died (90.0 % in the 5FU Nal-IRI arm and 94.1 % in the paclitaxel arm). Most deaths were related to disease progression (75.6 % and 85.4 % in the 5FU Nal-IRI and paclitaxel arms, respectively). Regarding the primary objective, OS at 9 months (primary endpoint) was 34.0 % [90 % CI 22.9–46.5] versus 39.2 % [90 % CI
<table><caption>**Table 1**

Patient and tumor characteristics.</caption><thead><tr><th>Variables</th><th>All patients*<br>(n=101)</th><th>5FU nal-iri<br>arm (n=50)</th><th>Paclitaxel<br>arm (n=51)</th></tr></thead><tbody><tr><td>Age (years, median, range)</td><td>66.0 [60.0-<br>71.5]</td><td>66.9 [42.3-<br>82.1]</td><td>65.1 [46.9-<br>82.0]</td></tr><tr><td>Female (n, %)</td><td>18 (17.0%)</td><td>7 (14.0%)</td><td>11 (21.6%)</td></tr><tr><td>ECOG PS (n, %)</td><td></td><td></td><td></td></tr><tr><td>0</td><td>30 (29.7%)</td><td>20 (40.0%)</td><td>10 (19.6%)</td></tr><tr><td>1</td><td>59 (58.4%)</td><td>24 (48.0%)</td><td>35 (68.6%)</td></tr><tr><td>2</td><td>12 (11.9%)</td><td>6 (12.0%)</td><td>6 (11.8%)</td></tr><tr><td>Body Mass Index (kg/m²,<br>median, range)</td><td>21.4 [13.9-<br>40.5]</td><td>22.1 [14.4-<br>39.5]</td><td>20.8 [13.9-<br>40.5]</td></tr><tr><td>BMI (class)</td><td></td><td></td><td></td></tr><tr><td>&lt;25kg/m²</td><td>76 (75.2%)</td><td>37 (74.0%)</td><td>39 (76.5%)</td></tr><tr><td>&gt;=25 kg/m²</td><td>25 (24.8%)</td><td>13 (26.0%)</td><td>12 (23.5%)</td></tr><tr><td>Primary tumor site (n, %)</td><td></td><td></td><td></td></tr><tr><td>Upper third</td><td>31 (31.0%)</td><td>14 (28.6%)</td><td>17 (33.3%)</td></tr><tr><td>Middle third</td><td>40 (40.0%)</td><td>19 (38.8%)</td><td>21 (41.2%)</td></tr><tr><td>Lower third</td><td>29 (29.0%)</td><td>16 (32.7%)</td><td>13 (25.5%)</td></tr><tr><td>Unknown</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Tumor grade (n, %)</td><td></td><td></td><td></td></tr><tr><td>Well differentiated</td><td>30 (32.2%)</td><td>15 (32.6%)</td><td>15 (31.9%)</td></tr><tr><td>Moderately differentiated</td><td>40 (44.1%)</td><td>21 (45.7%)</td><td>20 (42.6%)</td></tr><tr><td>Poorly differentiated</td><td>22 (23.7%)</td><td>10 (21.7%)</td><td>12 (25.5%)</td></tr><tr><td>Unknown</td><td>8</td><td>4</td><td>4</td></tr><tr><td>Prior treatment (n, %)</td><td></td><td></td><td></td></tr><tr><td>Chemotherapy alone</td><td>40 (40.0%)</td><td>21 (42.9%)</td><td>19 (37.2%)</td></tr><tr><td>Chemoradiation alone</td><td>46 (46.0%)</td><td>22 (44.9%)</td><td>24 (47.1%)</td></tr><tr><td>Chemotherapy/chemoradiation<br>plus immunotherapy</td><td>14 (14.0%)</td><td>6 (12.2%)</td><td>8 (15.7%)</td></tr><tr><td>Unknown</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Time between tumor diagnosis<br>and randomization (months,<br>median, range)</td><td>8.9 [3.9-<br>62.9]</td><td>8.3 [3.9-<br>62.9]</td><td>9.3 [3.3-<br>68.5]</td></tr><tr><td>Duration of first-line treatment<br>(months, median, range)</td><td>2.8 [0.2-<br>25.9]</td><td>2.8 [0.9-<br>25.9]</td><td>2.9 [0.2-<br>18.8]</td></tr><tr><td>Time to metastatic disease (n,<br>%)</td><td></td><td></td><td></td></tr><tr><td>Metachronous</td><td>38 (38.0%)</td><td>15 (30.6%)</td><td>23 (45.1%)</td></tr><tr><td>Synchronous</td><td>62 (62.0%)</td><td>34 (69.4%)</td><td>28 (54.9%)</td></tr><tr><td>Unknown</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Resection of primary tumor (n,<br>%)</td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>7 (70.0%)</td><td>3 (6.1%)</td><td>4 (7.8%)</td></tr><tr><td>No</td><td>93 (93.0%)</td><td>46 (93.9%)</td><td>47 (92.2%)</td></tr><tr><td>Unknown</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Number of metastatic sites at<br>inclusion (n, %)</td><td></td><td></td><td></td></tr><tr><td>1</td><td>45 (45.0%)</td><td>21 (42.9%)</td><td>24 (47.1%)</td></tr><tr><td>2</td><td>36 (36.0%)</td><td>17 (34.7%)</td><td>19 (37.3%)</td></tr><tr><td>3 and more</td><td>19 (19.0%)</td><td>11 (22.4%)</td><td>8 (15.6%)</td></tr><tr><td>Unknown</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Site of metastases at inclusion<br>(n, %)</td><td></td><td></td><td></td></tr><tr><td>Liver</td><td>25 (25.0%)</td><td>15 (30.6%)</td><td>10 (19.6%)</td></tr><tr><td>Lung</td><td>54 (54.0%)</td><td>25 (51.0%)</td><td>29 (56.8%)</td></tr><tr><td>Peritoneal carcinomatosis</td><td>1 (1.0%)</td><td>0</td><td>1 (2.0%)</td></tr><tr><td>Lymph nodes</td><td>68 (68.0%)</td><td>36 (73.5%)</td><td>32 (62.7%)</td></tr><tr><td>Lactate dehydrogenase (IU,<br>median, range)</td><td>198.0<br>[120.0-<br>6118.0]</td><td>196.0<br>[120.0-<br>535.0]</td><td>204.0<br>[133.0-<br>6118.0]</td></tr><tr><td>Albuminemia (g/l, median,<br>range)</td><td>38.0 [35.0-<br>41.0]</td><td>37.1 [27.0-<br>45.5]</td><td>38.1 [23.1-<br>46.9]</td></tr><tr><td>Albuminemia</td><td></td><td></td><td></td></tr><tr><td>&lt;35 g/L</td><td>24 (23.8%)</td><td>13 (26.0%)</td><td>11 (21.6%)</td></tr><tr><td>&gt;= 35/L</td><td>77 (76.2%)</td><td>37 (74.0%)</td><td>40 (78.4%)</td></tr></tbody></table>

ECOG PS: Eastern Cooperative Oncology Group performance status

*Patient and tumor characteristics in modified intention-to-treat population (n=101)

27.7–51.7] in the 5FU Nal-IRI and paclitaxel arms, respectively. The primary endpoint was not met. Median OS was 7.1 [95 % CI 5.2–8.3] and 6.6 [95 % CI 4.8–10.3] months in the 5FU Nal-IRI and paclitaxel arms, respectively (Figure 3). Twelve-month OS was 15.4 % [95 % CI 6.7–27.4] in the 5FU Nal-IRI arm and 26.7 % [95 % CI 15.3–39.4] in the

paclitaxel arm.

No subgroup of either arm seemed to have a better PFS or OS (Supp Figure 1 and 2). In the overall population in univariate and multivariate analyses, the only factor associated with worse PFS was the presence of liver metastases (Supp Table 2). In multivariate analysis, the presence of liver metastases and ECOG PS 2 were associated with worse OS (Table 2).

### 3.4. Safety

Doses were reduced for toxicity in 77.8 % for the 5FU Nal-IRI arm and 83.3 % for the paclitaxel arm. Treatment was delayed for toxicity in 48.4 % and 46.9 % in the 5FU Nal-IRI and paclitaxel arms, respectively. Five (10.4 %) patients in the 5FU Nal-IRI arm and two (3.9 %) patients in the paclitaxel arm definitively stopped treatment due to treatment-related AEs.

Grade 3 and more AEs related to the treatment were observed in 26 (53.1 %) patients in 5FU Nal-IRI arm and in 20 (38.5 %) patients in the paclitaxel arm (diarrhea: 16.3 % versus 0 %, fatigue: 14.3 % versus 3.8 %, vomiting: 10.2 % versus 0 % anorexia: 8.2 % versus 3.8 %, lymphopenia: 8.2 % versus 13.5 %, leucopenia: 6.1 % versus 15.4 % and neuropathy 2.0 % versus 7.7 %) in the 5FU Nal-IRI and paclitaxel arms, respectively (Table 3). Two toxic deaths (4.1 %) were considered related to the treatment in the 5FU Nal-IRI arm (one diarrhea and one pneumopathy) and none in the paclitaxel arm.

### 3.5. Quality of life

More patients in the 5FU Nal-IRI arm than in the paclitaxel arm experienced a deterioration in QoL (loss of more than 5 points in the global health score of the EORTC QLQC30 scale) (52.4 % versus 34.8 %) (Supp Figure 3). More patients in the 5FU Nal-IRI arm than in the paclitaxel arm experienced a deterioration in EORTC QLQC30 functional and symptom scales, including physical functioning (loss of more than 5 points for 71.4 % of patients in 5FU Nal-IRI arm and 54.2 % in the paclitaxel arm), role functioning (71.4 % versus 45.8 %), emotions (42.9 % versus 33.3 %), cognitive functioning (42.9 % versus 29.2 %) and social functioning (33.3 % versus 16.7 %) (Supp Figure 3). For the QLQ-OES18, more patients in the 5FU Nal-IRI arm experienced a deterioration in most scales (loss of more than 5 points), including dysphagia (70.0 % of patients in 5FU Nal-IRI arm and 27.3 % in the paclitaxel arm), eating (84.2 % versus 27.3 %), reflux (40.0 % versus 13.0 %) and pain (35.0 % versus 13.0 %) (Supp Figure 4).

## 4. Discussion

To our knowledge, PRODIGE 62-FFCD 1701-OESIRI is the first trial to evaluate an irinotecan-based regimen versus a taxane for patients with mESCC in a second-line setting, for which treatment options are limited.

The primary endpoint was not met since the 90 % confidence interval of OS at 9 months did not include 60 %. Nine-month OS was 34.0 % [90 % CI 22.9–46.5] versus 39.2 % [90 % CI 27.7–51.7] in the 5FU Nal-IRI and paclitaxel arms, respectively. The primary endpoint of obtaining OS of 60 % at 9 months was probably too ambitious. In addition, the results for secondary endpoints were also poor, including the short PFS (2.4 and 2.1 months) in the two arms. Even though these results are discouraging, they are in accordance with or a little better than published data from previous chemotherapy trials, which reported median PFS of about 2 months and median OS of about 6 months [13–15]. Nevertheless, the PRODIGE 62-FFCD 1701-OESIRI trial showed the lack of efficacy of 5FU Nal-IRI in mESCC and more broadly of irinotecan and its derivatives, suggesting that irinotecan-based chemotherapy should not be included in future combinations deemed suitable for evaluation.

No subgroup of either arm had better PFS or OS. In multivariate
<figure><img src="image_4.png" /><figcaption>Fig. 2. Progression-free survival, mITT: modified intention-to-treat population.</figcaption></figure>

analyses, the presence of liver metastases was associated with worse PFS and the presence of liver metastases and ECOG PS 2 were associated with worse OS. To our knowledge, no trial has evaluated prognostic factors in mESCC treated with second-line chemotherapy. A few studies have investigated prognostic factors in mESCC patients in first line, and found that a poor ECOG PS, age and number of metastases were associated with a poor prognosis [21,22]. These criteria could help physicians decide whether or not to propose 2nd line chemotherapy, given the limited survival increase in mESCC patients.

The safety profile of paclitaxel is in accordance with previously published series with 38.5 % of grade 3/4 AE, mainly lymphopenia, leucopenia and neuropathy. In the ATTRACTION-3 and RAMOS trials, chemotherapy (paclitaxel or docetaxel) was associated with 27-41 % of grade 3/4 AE [16,23]. In PRODIGE 62-FFCD 1701-OESIRI, the safety profile of 5FU Nal-IRI was as expected, with 53.1 % of grade ≥ 3 AEs, including diarrhea (16.3 %), asthenia (14.3 %) and vomiting (10.2 %). These data are in accordance with grade ≥ 3 AE rates for an irinotecan-based regimen in other tumors, like gastric tumors [24,25]. Finally, 5FU Nal-IRI, that is a doublet chemotherapy, led to more grade ≥ 3 AEs than did paclitaxel monotherapy, especially for digestive toxicity. In addition, 5FU Nal-IRI was associated with two treatment-related deaths. More patients in the 5FU Nal-IRI arm than in the paclitaxel arm experienced a deterioration in QoL with QLQC30 (52.4 % versus 34.8 %). Moreover, a greater proportion of patients in the 5FU Nal-IRI arm than in the paclitaxel arm experienced a deterioration in most items of the EORTC QLQC30 functional and symptom scales as well as the QLQ-OES18 items.

One limitation of the study is that few patients received a first-line treatment with ICI (14.0 %). Nevertheless, there are no data suggesting that first-line treatment with an ICI in mESCC could influence the efficacy of second-line chemotherapy. In the same way, TPS and CPS PD-L1 status were not available, but these scores are not associated with chemotherapy efficacy [26]. The main strength is that we conducted a second-line trial in a population of 106 Caucasian mESCC patients. No large randomized trial has ever been conducted in a second-line setting of mESCC in Europe. Of note, the randomized phase II RAMOS trial in the same setting comparing paclitaxel/ramucirumab versus paclitaxel included only 21

patients and failed to enroll the planned 186 patients, due to slow accrual [23]. It should be noted that few targeted therapies are being evaluated as the second-line in mESCC, given the absence of a targetable molecular alteration. Nevertheless, some phase II trials with new therapies/combinations including trifluridine/tipiracil, palbociclib, afatinib, fruquintinib, S-1 and ifinatamab deruxtecan are ongoing.

## 5. Conclusions

To conclude the PRODIGE 62-FFCD 1701-OESIRI trial showed low efficacy of chemotherapy with either paclitaxel or 5FU Nal-IRI in the 2nd-line treatment of mESCC. Nevertheless, paclitaxel alone provided a better safety profile and a lesser deterioration of QoL. Consequently, the future development of irinotecan-based strategies is not appropriate in mESCC patients. These results support active research for new strategies in the 2nd-line treatment for mESCC patients, who have a very poor
<figure><img src="image_5.png" /><figcaption>Fig. 3. Overall survival, mITT: modified intention-to-treat population.</figcaption></figure>
<table><caption>**Table 2**
Univariate and multivariate analysis of predictive factors for overall survival.</caption><thead><tr><th></th><th></th><th>Events/ n (%)</th><th>Univariate analysisHazard ratio [95 %CI] p-value</th><th>Multivariate analysis Hazard ratio [95 %CI] p-value</th></tr></thead><tbody><tr><td rowspan="2">Arm</td><td>Arm A - Nal-IRI plus LV5FU</td><td>45/50 (90.0)</td><td>Reference</td><td></td></tr><tr><td>Arm B - Paclitaxel</td><td>48/51 (94.1)</td><td>0.87 [0.57;1.31] - p = 0.504</td><td></td></tr><tr><td rowspan="2">Sex</td><td>Female</td><td>14/18 (77.8)</td><td>0.78 [0.44;1.38] - p = 0.391</td><td></td></tr><tr><td>Male</td><td>79/83 (95.2)</td><td>Reference</td><td></td></tr><tr><td rowspan="2">Age (years)</td><td>&lt; 65 years</td><td>43/48 (89.6)</td><td>0.66 [0.43;1.01] - p = 0.054</td><td>0.69 [0.44;1.07] - p = 0.096</td></tr><tr><td>&gt; =65 years</td><td>50/53 (94.3)</td><td>Reference</td><td>Reference</td></tr><tr><td rowspan="3">ECOG PS</td><td>0</td><td>25/30 (83.3)</td><td>Reference</td><td>Reference</td></tr><tr><td>1</td><td>57/59 (96.6)</td><td>1.56 [0.97;2.5] - p = 0.066</td><td>1.31 [0.8;2.14] - p = 0.290</td></tr><tr><td>2</td><td>11/12 (91.7)</td><td>2.74 [1.33;5.64] - p = 0.006</td><td>2.31 [1.08;4.93] - p = 0.030</td></tr><tr><td rowspan="3">Primary tumor site</td><td>Lower third</td><td>27/29 (93.1)</td><td>1.33 [0.8;2.19] - p = 0.270</td><td></td></tr><tr><td>Middle third</td><td>36/40 (90.0)</td><td>Reference</td><td></td></tr><tr><td>Upper third</td><td>29/31 (93.6)</td><td>1.08 [0.65;1.78] - p = 0.777</td><td></td></tr><tr><td rowspan="3">Tumor grade</td><td>Well differentiated</td><td>27/30 (90.0)</td><td>Reference</td><td></td></tr><tr><td>Moderately differentiated</td><td>39/41 (95.1)</td><td>1.31 [0.8;2.15] - p = 0.290</td><td></td></tr><tr><td>Poorly differentiated</td><td>19/22 (86.4)</td><td>0.82 [0.45;1.49] - p = 0.520</td><td></td></tr><tr><td rowspan="2">Time to metastasis</td><td>Metachronous</td><td>37/38 (97.4)</td><td>Reference</td><td></td></tr><tr><td>Synchronous</td><td>55/62 (88.7)</td><td>0.89 [0.58;1.35] - p = 0.584</td><td></td></tr><tr><td rowspan="3">Prior treatment</td><td>Chemoradiotherapy alone</td><td>44/47 (93.6)</td><td>0.87 [0.56;1.36] - p = 0.547</td><td></td></tr><tr><td>Chemotherapy alone</td><td>37/39 (97.9)</td><td>Reference</td><td></td></tr><tr><td>Chemotherapy/chemoradiation plus immunotherapy</td><td>11/14 (78.6)</td><td>0.70 [0.36;1.38] - p = 0.303</td><td></td></tr><tr><td rowspan="2">Time between tumor diagnosis and raandomization</td><td>&lt; 9 months</td><td>47/51 (92.2)</td><td>Reference</td><td></td></tr><tr><td>&gt; =9 months</td><td>46/50 (92)</td><td>0.87 [0.58;1.31] - p = 0.508</td><td></td></tr><tr><td rowspan="3">Number of metastatic sites</td><td>1</td><td>41/45 (91.1)</td><td>Reference</td><td></td></tr><tr><td>2</td><td>34/36 (94.4)</td><td>1.16 [0.73;1.84] - p = 0.527</td><td></td></tr><tr><td>3 or more</td><td>17/19 (89.5)</td><td>1.60 [0.91;2.84] - p = 0.105</td><td></td></tr><tr><td rowspan="2">Liver metastases at inclusion</td><td>No</td><td>69/76 (90.8)</td><td>Reference</td><td>Reference</td></tr><tr><td>Yes</td><td>24/25 (96)</td><td>1.71 [1.07;2.73] - p = 0.026</td><td>1.64 [1.02;2.64] - p = 0.041</td></tr><tr><td rowspan="2">Lung metastases at inclusion</td><td>No</td><td>44/47(93.6)</td><td>Reference</td><td></td></tr><tr><td>Yes</td><td>49/54 (90.7)</td><td>0.84 [0.56;1.26] - p = 0.406</td><td></td></tr><tr><td rowspan="2">Node metastases at inclusion</td><td>No</td><td>31/33 (93.9)</td><td>Reference</td><td></td></tr><tr><td>Yes</td><td>62/68 (91.2)</td><td>1.11 [0.72;1.72] - p = 0.635</td><td></td></tr><tr><td rowspan="2">BMI</td><td>&lt; 25 kg/m²</td><td>68/76 (89.5)</td><td>Reference</td><td></td></tr><tr><td>&gt; =25 kg/m²</td><td>25/25 (100)</td><td>0.93 [0.58;1.47] - p = 0.751</td><td></td></tr><tr><td rowspan="2">Albumin</td><td>&lt; 35 g/L</td><td>22/24 (91.7)</td><td>Reference</td><td>Reference</td></tr><tr><td>&gt; =35 g/L</td><td>71/77 (92.2)</td><td>0.50 [0.3;0.82] - p = 0.006</td><td>0.61 [0.36;1.03] - p = 0.066</td></tr></tbody></table>

ECOG PS: Eastern Cooperative Oncology Group performance status

prognosis, and the use of paclitaxel in the control arm.

### CRediT authorship contribution statement

David Tougeron: Writing – original draft, Writing – review & editing, Resources, Supervision, Project administration, Methodology, Conceptualization, Investigation, Formal analysis, Data curation. Laurent Mineur: Writing – review & editing, Investigation, Resources. Aziz Zaanan: Writing – review & editing, Investigation, Resources. Melissa Kadi: Methodology, Conceptualization, Formal analysis, Data curation. Catherine Poisson Ligeza: Writing – review & editing, Investigation, Resources. Vincent Bourgeois: Writing – review & editing, Inv. Jestin le Tallec: Writing – review & editing, Investigation, Resources. Valérie Ly Lebrun: Writing – review & editing, Investigation, Resources. Aurélie Fadin: Writing – review & editing, Investigation, Resources. Olivier Dubreuil: Writing – review & editing, Investigation, Resources. Faiza Khemissa Akouz: Writing – review & editing, Investigation, Resources. Elsa Thimonier: Writing – review & editing, Investigation, Resources. Olivier Bouché: Writing – review & editing, Investigation, Resources. Astrid Lièvre: Writing – review & editing, Investigation, Resources. Frédéric Di Fiore: Writing – review & editing, Investigation, Resources. Thierry Lecomte: Writing – review & editing, Investigation, Resources. Côme Lepage: Writing – review & editing, Investigation, Resources, Project administration. Vincent Hautefeuille: Writing – original draft, Writing – review & editing, Resources, Conceptualization, Investigation.

### Funding

The FFCD is the sponsor of the PRODIGE 62-FFCD 1701-OESIRI trial.

Servier provided financial support for the trial. FFCD funded a part of the trial and the biobank. Servier provided the study drug. Servier has no role in the design, conduct, analysis, or publication of the study.

### Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

DT reports receiving consulting or advisory board fees from Astra Zeneca, Sanofi, Amgen, MSD, BMS, Roche, Servier, Pierre Fabre, Merck, Astellas, Takeda; receiving research funding from Pierre Fabre and Sandoz. LM reports receiving consulting or advisory board fees from BMS, GSK travel and congress registration from Merck, Amgen, and research funding from Sanofi and Biocon. AZ reports receiving consulting or advisory board fees from Amgen, Astellas, Merck, Roche, Sanofi, Servier, Baxter, MSD, BMS, Pierre Fabre, Havas Life, Alira Health, Zymeworks, Daiichi Sankyo and Astra Zeneca. VB reports receiving consulting or advisory board fees from Pierre Fabre, Servier, receiving research funding from Servier and Astra Zeneca. VJLE reports receiving consulting or advisory board fees from Amgen, Novartis, Merck, Pierre Fabre, Accord, Astra Zeneca and MSD. OD reports receiving consulting or advisory board fees from Deciphera, Merck-Serono, Sanofi, Servier, Novartis, MSD, BMS, Pierre Fabre, and Astra Zeneca. FKA reports receiving consulting or advisory board fees from Roche, Sanofi, Servier, Fresenius Kabi, MSD, and Astra Zeneca. OB reports receiving consulting or advisory board fees from Amgen, Astellas, BMS, Deciphera, Merck, Pierre Fabre, Servier, Takeda, and MSD. AL reports honoraria for lectures from Amgen, Astellas, Astra-Zeneca, BMS, Esteve, MSD, Pierre Fabre, Servier and Viatris; honoraria for consulting/advisory
<table><caption>**Table 3**
Treatment-related adverse events*.</caption><thead><tr><th rowspan="2">n, %</th><th colspan="2">5FU nal-iri arm (n = 49)</th><th colspan="2">Paclitaxel arm(n = 52)</th></tr><tr><th>Grade 1-2</th><th>Grade 3-4-5</th><th>Grade 1-2</th><th>Grade 3-4-5</th></tr></thead><tbody><tr><td><strong>Patients with at least one adverse event</strong></td><td><strong>43</strong><br>(87.8 %)</td><td><strong>26</strong><br>(53.1 %)</td><td><strong>49</strong><br>(94.2 %)</td><td><strong>20</strong><br>(38.5 %)</td></tr><tr><td>Diarrhea</td><td>25<br>(51.0 %)</td><td>8<br>(16.3 %)</td><td>14<br>(26.9 %)</td><td>0</td></tr><tr><td>Nausea</td><td>24<br>(49.0 %)</td><td>1<br>(2.0 %)</td><td>13<br>(25.0 %)</td><td>0</td></tr><tr><td>Fatigue</td><td>21<br>(42.9 %)</td><td>7<br>(14.3 %)</td><td>32<br>(61.5 %)</td><td>2 (3.8 %)</td></tr><tr><td>Anemia</td><td>18<br>(36.7 %)</td><td>3<br>(6.1 %)</td><td>28<br>(53.8 %)</td><td>1 (1.9 %)</td></tr><tr><td>White blood cell decrease</td><td>12<br>(24.5 %)</td><td>3<br>(6.1 %)</td><td>9<br>(17.3 %)</td><td>8<br>(15.4 %)</td></tr><tr><td>Vomiting</td><td>9<br>(18.4 %)</td><td>5<br>(10.2 %)</td><td>7<br>(13.5 %)</td><td>0</td></tr><tr><td>Anorexia</td><td>9<br>(18.4 %)</td><td>4<br>(8.2 %)</td><td>4<br>(7.7 %)</td><td>2 (3.8 %)</td></tr><tr><td>Stomatitis</td><td>9<br>(18.4 %)</td><td>0</td><td>7<br>(13.5 %)</td><td>0</td></tr><tr><td>GGT increase</td><td>8<br>(16.3 %)</td><td>0</td><td>8<br>(15.4 %)</td><td>1 (1.9 %)</td></tr><tr><td>Neuropathy</td><td>7<br>(14.2 %)</td><td>1<br>(2.0 %)</td><td>19<br>(36.5 %)</td><td>4<br>(7.7 %)</td></tr><tr><td>Platelet count decrease</td><td>6<br>(12.2 %)</td><td>0</td><td>8<br>(15.4 %)</td><td>0</td></tr><tr><td>Alopecia</td><td>6<br>(12.2 %)</td><td>0</td><td>15<br>(28.8)</td><td>1 (1.9 %)</td></tr><tr><td>Abdominal pain</td><td>6<br>(12.2 %)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>AST increase</td><td>4<br>(8.2 %)</td><td>0</td><td>9<br>(17.3 %)</td><td>0</td></tr><tr><td>Hyponatremia</td><td>4<br>(8.2 %)</td><td>1<br>(2.0 %)</td><td>3<br>(5.8 %)</td><td>0</td></tr><tr><td>Lymphocyte count decrease</td><td>3<br>(6.1 %)</td><td>4<br>(8.2 %)</td><td>11<br>(21.2 %)</td><td>7<br>(13.5 %)</td></tr><tr><td>Dyspnea</td><td>2<br>(4.1 %)</td><td>1<br>(2.0 %)</td><td>3<br>(5.8 %)</td><td>1<br>(1.9 %)</td></tr><tr><td>Pulmonary infection</td><td>1<br>(2.0 %)</td><td>2<br>(4.1 %)</td><td>0</td><td>0</td></tr><tr><td>Acute kidney injury</td><td>2<br>(4.1 %)</td><td>1<br>(2.0 %)</td><td>0</td><td>0</td></tr><tr><td>Fall</td><td>0</td><td>1<br>(2.0 %)</td><td>0</td><td>0</td></tr><tr><td>Acute respiratory distress syndrome</td><td>0</td><td>1<br>(2.0 %)</td><td>0</td><td>0</td></tr><tr><td>Sepsis</td><td>0</td><td>1<br>(2.0 %)</td><td>0</td><td>0</td></tr><tr><td>Hypertension</td><td>0</td><td>0</td><td>0</td><td>1 (1.9 %)</td></tr><tr><td>Hypophosphatemia</td><td>0</td><td>0</td><td>2<br>(3.8 %)</td><td>1<br>(1.9 %)</td></tr></tbody></table>

*all grade 3/4/5 adverse events are reported and only those in 10 % or more of treated patients for grade 1/2 were reported
The total number of adverse events could be superior to the total number of patients since some patients could have more than one adverse event.
AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase

relationship from Astellas, Bayer, BMS, Servier and Takeda; received travel (or congress registration) support from Bayer, Esteve, Ipsen, Pierre Fabre, Servier, Viatris; received research funding from Bayer, Lilly, FDF reports receiving consulting or advisory board fees from Amgen, Astra Zeneca, Bayer, BMS, Janssen, Incyte, Merck, MSD, Novartis, Pierre Fabre, Roche, Sandoz, Sanofi, Servier, Takeda, and Viatris. TL reports receiving consulting or advisory board fees from Servier, Pierre Fabre, Merck Serono, BMS, MSD, Astra Zeneca, AAA, Sanofi and research funding from Pierre Fabre and Leo Pharma. CL reports receiving consulting or advisory board fees from Amgen, Novartis, Pierre Fabre, Ipsen, Abbvie, Deciphera. VH reports honoraria for consulting or advisory board for AdAcAp/Novartis, Deciphera, Esteve, Ipsen, Merck, MSD, Pierre Fabre, Servier

All remaining authors have declared no conflicts of interest.

## Acknowledgement

We thank all physicians who are participating in the PRODIGE 62-FFCD 1701-OESIRI trial. We also thank all members of the

cooperative PRODIGE group (FFCD – UNICANCER GI – GERCOR) for their contribution and participation in the present trial, especially Daniel Gonzalez, Lila Gaba, and Charles Fuchey (the PRODIGE 62-FFCD 1701-OESIRI team). Finally, we thank the “Ligue Nationale Contre le Cancer” for their support.

## Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.ejca.2025.115741.

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