Second-line chemotherapy in metastatic oesophageal squamous cell carcinoma: has PRODIGE 62-OESIRI closed the door on irinotecan?

The prognosis of metastatic oesophageal squamous cell carcinoma (mESCC) remains dismal despite meaningful advances in systemic therapy. The incorporation of immune checkpoint inhibitors (ICIs) into first-line platinum-based chemotherapy has modestly improved survival, but most patients ultimately progress (1-3). In this context, the second-line setting is characterised by short overall survival (OS), cumulative toxicity, and an absence of a clearly superior chemotherapy regimen.

In patients with mESCC who have progressed after first-line platinum/fluoropyrimidine chemotherapy and immunotherapy, taxane-based chemotherapy (paclitaxel or docetaxel) has historically been an accepted second-line option, yielding a median OS of roughly 6–8 months. However, in immunotherapy-naïve patients, phase III trials have demonstrated that programmed cell death protein 1 (PD-1) blockade surpasses taxane monotherapy. In the ATTRACTION-3 study, nivolumab prolonged OS to 10.9 vs. 8.5 months [hazard ratio (HR) 0.79] compared with investigator-choice taxane chemotherapy, establishing immunotherapy as a preferred option when accessible (4). Likewise, KEYNOTE-181 showed that in patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10, pembrolizumab improved OS compared with chemotherapy (9.3 vs. 6.7 months; HR 0.69) with fewer high-grade toxicities (5).

Single-agent taxane therapy remains commonly used, but real-world evidence highlights its limited impact. A U.S. analysis of older patients reported median OS of ~4.5 months for taxane monotherapy versus ~5.6 months for taxane-combination therapy and ~8.5 months for non-taxane regimens after failure of first-line platinum therapy (6). Weekly paclitaxel is commonly preferred over docetaxel due to tolerability and dose density, and is supported by randomised phase II evidence. In the OGSG 1201 trial, weekly paclitaxel significantly prolonged OS compared with three-weekly docetaxel in previously treated ESCC, reinforcing paclitaxel as a reasonable taxane backbone in this setting (7). By contrast, exploratory studies of taxane-based combinations—such as paclitaxel plus ramucirumab—have shown only numerical, non-statistically powered improvements, limiting their adoption (8). Another chemotherapy alternative is oral S-1, which, in a small Japanese series, produced a median OS of approximately 11 months, though the non-comparative design and small sample size restrict interpretability (9).

Overall, while taxane monotherapy offers practicality and familiarity, its modest efficacy underscores the need for more effective second-line strategies. To date, no purely chemotherapy-based regimen has clearly outperformed taxanes, and modern evidence supports immunotherapy as the preferred second-line option for eligible patients (4,5).

Tougeron et al. report the results of the PRODIGE 62-FFCD 1701-OESIRI trial, a multicentre phase II study that compares nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU) with weekly paclitaxel as second-line therapy for mESCC progressing after platinum-based chemotherapy with or without radiotherapy or immunotherapy (10). The trial addresses a relevant clinical question: can an optimised irinotecan formulation improve outcomes compared with paclitaxel, which has become an empiric standard in many centres?

The key message from PRODIGE 62-OESIRI is that both regimens have limited efficacy, and nal-IRI/5-FU did not demonstrate clinically meaningful improvement over weekly paclitaxel. Importantly, nal-IRI/5-FU was associated with higher toxicity and worse quality of life (QoL). In the setting of similar survival outcomes, these findings argue against nal-IRI/5-FU as a second-line strategy in unselected mESCC and prompt a reassessment of how and whether irinotecan should be positioned in this disease.

Study design and patient population

PRODIGE 62-OESIRI was an open-label, randomised, non-comparative phase II trial conducted across 43 French centres. Patients aged ≥18 years with histologically confirmed mESCC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, and progression or intolerance after first-line platinum-based chemotherapy (with or without radiotherapy or immune checkpoint inhibition) were eligible. Both synchronous and metachronous metastatic disease were allowed, as were patients who relapsed within 6 months of perioperative or definitive chemoradiation.

Patients were randomised 1:1 to receive:

• Nal-IRI + LV/5-FU: nal-IRI 70 mg/m² over 2 hours, folinic acid 400 mg/m², and 5-FU 2,400 mg/m² over 46 hours every 14 days.
• Paclitaxel: 80 mg/m² on days 1, 8, and 14 of a 28-day cycle.

Randomisation was stratified by centre and ECOG PS (0–1 vs. 2). The primary endpoint was OS at 9 months, with a prespecified target of 60% in each arm. Secondary endpoints included progression-free survival (PFS), median OS, objective response rate (ORR), safety, and QoL assessed using EORTC QLQ-C30 and OES18 questionnaires.

Between March 2019 and July 2023, 106 patients were randomised; 101 received at least one dose of study treatment and formed the modified intention-to-treat (mITT) population (50 in the nal-IRI/5-FU arm and 51 in the paclitaxel arm). Baseline characteristics were well balanced: the median age was 66 years, 83% were men, and most had ECOG PS 0–1. Lymph nodes (68%), lungs (54%), and liver (25%) were the most frequent metastatic sites, and nearly 80% had one or two metastatic sites. Only 14% had previously received an ICI, reflecting evolving first-line standards during the accrual period. Importantly, prior ICI exposure was balanced between the two arms, but the small overall proportion limits generalisability to contemporary post-chemo-immunotherapy populations.

Efficacy: limited benefit with either regimen

The primary endpoint was not met. OS at 9 months was 34.0% [90% confidence interval (CI): 22.9–46.5%] in the nal-IRI/5-FU arm and 39.2% (90% CI: 27.7–51.7%) in the paclitaxel arm, well below the targeted 60% for both regimens. Median PFS and OS were similarly modest:

• Median PFS: 2.4 months (95% CI: 2.1–3.6) with nal-IRI/5-FU vs. 2.1 months (95% CI: 1.9–3.3) with paclitaxel.
• Median OS: 7.1 months (95% CI: 5.2–8.3) vs. 6.6 months (95% CI: 4.8–10.3), respectively.

ORR and disease control rates (DCR) were numerically higher with nal-IRI/5-FU (ORR 22.9% vs. 15.7%; DCR 45.8% vs. 37.3%), but these differences did not translate into improved PFS or OS and should be interpreted cautiously given the phase II, non-comparative design.

A concise summary of key efficacy outcomes is presented in Table 1.

No subgroup analysis identified a subset clearly benefiting from either regimen. In multivariate analysis in the pooled population, liver metastases and ECOG PS 2 were independently associated with worse OS, emphasising the impact of disease burden and performance status on prognosis.

From a clinical perspective, these survival outcomes are concordant with prior second-line trials in mESCC, where median OS typically ranges from 5 to 8 months (4-8). Rather than representing a breakthrough, PRODIGE 62-OESIRI confirms the limited efficacy of conventional cytotoxic chemotherapy in this setting.

Toxicity and QoL: the decisive differences

In the absence of clear efficacy separation, safety and QoL become critical determinants of clinical value. Here, the contrast between regimens is clinically meaningful.

Grade 3–4 treatment-related adverse events (AEs) were more frequent with nal-IRI/5-FU (53.1%) than with paclitaxel (38.5%). The nal-IRI/5-FU regimen was associated with a characteristic irinotecan-related toxicity profile, including:

• Grade 3–4 diarrhoea: 16.3% vs. 0%;
• Grade 3–4 vomiting: 10.2% vs. 0%;
• Higher rates of severe fatigue and anorexia.

Paclitaxel, conversely, produced more haematological and neurological AEs (e.g., leucopenia, lymphopenia, and neuropathy), but with lower rates of severe gastrointestinal toxicity.

Crucially, two treatment-related deaths (4.1%) occurred in the nal-IRI/5-FU arm (one related to diarrhoea and one to pneumopathy), whereas none occurred in the paclitaxel arm. Treatment discontinuation due to toxicity was also higher with nal-IRI/5-FU (10.4% vs. 3.9%).

Quality-of-life data reinforce this conclusion. A greater proportion of patients treated with nal-IRI/5-FU experienced clinically meaningful deterioration (loss ≥5 points) in global health status on the QLQ-C30 (52.4% vs. 34.8%), as well as declines in physical, role, emotional, cognitive, and social functioning. On the oesophageal-specific QLQ-OES18, more patients in the nal-IRI/5-FU arm had worsening dysphagia, eating difficulties, reflux, and pain.

Taken together, the toxicity and QoL findings suggest that nal-IRI/5-FU adds burden without delivering compensatory benefit. In a disease where median survival is measured in months, this trade-off is difficult to justify. Given the non-comparative design, these data should be interpreted as indicating a more favourable tolerability/QoL profile for paclitaxel rather than proof of superiority in efficacy.

Positioning PRODIGE 62-OESIRI in the therapeutic landscape

How should clinicians integrate these data into practice?

Weekly paclitaxel remains a reasonable second-line chemotherapy option

While the trial was not designed for formal head-to-head comparisons, the similar survival outcomes and more favourable tolerability/QoL profile support weekly paclitaxel as a pragmatic chemotherapy backbone for fit patients requiring second-line treatment. This aligns with other randomised phase II data supporting weekly paclitaxel over docetaxel (OGSG 1201) (7). Given the non-comparative phase II design, the results support weekly paclitaxel as a reasonable chemotherapy backbone with a more favourable tolerability and QoL profile than nal-IRI/5-FU, rather than establishing formal superiority.

Nal-IRI/5-FU should not be adopted as a standard second-line regimen in unselected mESCC

PRODIGE 62-OESIRI does not support nal-IRI/5-FU in this setting due to higher toxicity and worse QoL without clear efficacy gain. However, it is important to distinguish between nal-IRI/5-FU and irinotecan monotherapy. Irinotecan alone may remain a reasonable alternative in selected patients with contraindications to taxanes, although robust contemporary data (particularly post-ICI) are limited. In the absence of compelling biomarker-driven rationale, future development of irinotecan-containing combinations in mESCC does not seem justified.

Careful patient selection is essential

The identification of liver metastases and ECOG PS 2 as adverse prognostic factors suggests that some patients may derive little net benefit from second-line chemotherapy. In individuals with poor PS and/or liver-dominant disease burden, best supportive care and early palliative care integration may be more appropriate than further cytotoxic therapy. These findings merit validation in larger cohorts, particularly in post-ICI populations.

Expectation management is crucial

With a median PFS around 2–3 months, second-line chemotherapy should be framed as palliative, with clearly stated goals focusing on symptom control and modest survival prolongation. Shared decision-making is particularly important when treatment may worsen QoL.

These practice-oriented implications are summarised in Table 2.

Limitations and generalisability

Several limitations should be acknowledged. The non-comparative phase II design means the study is not powered for formal head-to-head statistical comparisons between arms, although the overlapping survival outcomes and clear toxicity/QoL differences provide useful qualitative guidance.

A major limitation is that only 14% of patients had received prior immune checkpoint inhibition. As first-line chemo-immunotherapy becomes routine, the real-world second-line population will increasingly comprise ICI-pretreated patients. Prior ICI exposure may be associated with improved subsequent chemotherapy responsiveness, and therefore, the magnitude and pattern of chemotherapy benefit in contemporary post-ICI practice may differ from that observed in PRODIGE 62-OESIRI. While prior ICI exposure was balanced between arms, the small overall number limits the ability to draw firm conclusions in this subgroup.

Finally, PD-L1 status and other biomarkers were not collected. Although these have not been shown to predict chemotherapy benefit in mESCC, biomarker annotation will be essential for the development of future targeted strategies.

Future directions

Perhaps the most important message of PRODIGE 62-OESIRI is that conventional cytotoxic strategies in second-line mESCC have largely reached their limits. Median OS remains under 8 months, and QoL is frequently compromised. Incremental modifications of chemotherapy backbones are unlikely to yield transformative benefits.

Future research should therefore prioritise:

• Antibody-drug conjugates (ADCs) and novel payload delivery. Importantly, PRODIGE 62-OESIRI does not invalidate topoisomerase I inhibition as a therapeutic concept in ESCC; rather, it questions the value of nal-IRI/5-FU in unselected patients. Several ADCs with topoisomerase I inhibitor payloads are being evaluated in ESCC. Early clinical data suggest activity with anti-B7-H3 deruxtecan (ifinatamab deruxtecan or I-DXd) in unselected ESCC in later-line settings based on phase I/II studies (11,12). A phase III global randomized trial (IDeate-Esophageal01) is currently recruiting to evaluate ifinatamab deruxtecan versus physician’s choice chemotherapy in patients with advanced or metastatic ESCC following progression on platinum-based chemotherapy and ICIs (13). These approaches raise the possibility that topo-I inhibition may be effective when delivered via an ADC platform and guided by appropriate targets/biomarkers.
• Angiogenesis inhibition and rational combinations. Small studies of angiogenesis inhibitors (e.g., anlotinib, apatinib) suggest potential activity in previously treated ESCC and warrant further study, particularly in combination with immunotherapy or other novel agents (14-18).
• Patient-reported outcomes and supportive care integration. Given short survival and high symptom burden, QoL and functional measures should be integrated as key endpoints to ensure that any survival gains are not achieved at the cost of unacceptable toxicity.
• Prognostic and predictive models. Tools incorporating disease burden (including liver metastases), PS, and symptom metrics may help identify patients most likely to benefit from second-line therapy versus best supportive care.

Conclusions

Tougeron and colleagues are to be commended for completing a multicentre trial in a difficult and often understudied disease context. PRODIGE 62-FFCD 1701-OESIRI demonstrates that nal-IRI plus 5-FU does not provide a clinically meaningful benefit over weekly paclitaxel in second-line mESCC and is associated with greater toxicity and QoL deterioration. Based on these data, nal-IRI/5-FU should not be adopted as a standard second-line treatment in unselected mESCC.

Weekly paclitaxel remains a reasonable chemotherapy backbone for selected patients; however, its modest efficacy underscores the urgent need for biology-driven approaches, including ADCs and targeted strategies, and for care models that place patient experience and QoL at the centre of decision-making.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article has undergone external peer review.

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-36/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-36/coif). The author has no conflicts of interest to declare.

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