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First-line immunotherapy-based therapy prolongs the survival of patients with advanced oesophageal squamous cell carcinoma

The phase III CheckMate 648 study evaluates the efficacy of nivolumab and ipilimumab (NIVO + IPI) or nivolumab combined with chemotherapy versus chemotherapy alone in patients with previously untreated advanced oesophageal squamous cell carcinoma. First results  presented at ASCO 2021 demonstrated superior overall survival for both regimens and indicate that NIVO + IPI and NIVO + chemo each represent a potential novel first-line treatment option for these patients.

The currently used standard first-line chemotherapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCC) is associated with a poor outcome, with a median overall survival (OS) of less than one year. In the ATTRACTION-3 trial, nivolumab monotherapy proved to be associated with a better OS in comparison to chemotherapy, in previously treated patients with advanced ESCC. Building on this success, the phase III CheckMate 648 study evaluates an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC.

CheckMate 648 study design

In CheckMate 648, 970 patients with previously untreated, unresectable, advanced ESCC were recruited, irrespective of their tumour PD-L1 expression levels. Patients were randomly allocated (1:1:1) into three groups. Group 1 assessed the addition of 240 mg nivolumab (NIVO) once every two weeks (Q2W) to chemotherapy (fluorouracil + cisplatin Q4W), while Group 2 received a chemotherapy-free treatment option of NIVO 3mg/kg Q2W + ipilimumab (IPI) 1mg/kg Q6W. Finally, Group 3 is a control arm in which patients receive chemotherapy (Q4W) alone. Primary endpoints for both comparisons are OS and progression-free survival (PFS) per blinded independent central review in patients with a tumour PD-L1 expression level of at least 1%. At the time of the presented analysis, patients were followed for a minimum of 12.9 months.

Superior overall survival with NIVO + chemotherapy

Baseline patient and disease characteristics were well balanced across the three treatment arms and were consistent for patients with and without a tumour cell PD-L level ≥ 1%. In total, 49% of patients had PD-L1 expression levels of 1% or more. For the first comparison of NIVO + chemo versus chemo alone, a statistically significant improvement in OS was observed in patients with tumour cell PD-L1 ≥1%. The median OS was 15.4 months for patients treated with NIVO + chemo and 9.1 months for patients receiving chemo alone (HR [99.5%CI]: 0.54 [0.37-0.80], p<0.0001). A similar trend was observed among all randomised patient population with a median OS of 13.2 and 10.7 months respectively (HR [99.1%CI]: 0.74 [0.58-0.96], p=0.0021). In addition, the PFS was significantly improved in the primary patient population of PD-L1 ≥1% (HR [95%CI]: 0.65 [0.46-0.92], p=0.0023). However, this was not the case in all randomised patients (HR [95%CI]: 0.81 [0.64-1.04], p=0.0355). The objective response rates (ORR) with NIVO + chemo were 53% vs. 20% with chemotherapy alone in patients with PD-L1 ≥1% (47% vs. 27% in all randomised patients).

Furthermore, in the second comparison of NIVO + IPI vs. chemo, a significant OS advantage was seen in favour of the immunotherapy-based regimen in the primary study population (13.7 vs. 9.1 months, HR [98.6%CI]: 0.64 [0.46-0.90], p=0.0010). This was also the case when looking at the entire randomised patient population (12.8 vs. 10.7 months, HR [98.2%CI]: 0.78 [0.62-0.98], p=0.0110). The primary endpoint of PFS per blinded independent central review (BICR) was not met in patients with tumour cell PD-L1 ≥1% (HR [95%CI]: 1.02 [0.73-1.43], p=0.8958) nor was this the case in all randomised patients (HR [95%CI]: 1.26 [1.04-1.52], p-value not tested). ORR with NIVO + IPI and chemotherapy were 35% and 20% for patients with tumour PD-L1 ≥1% and 28% and 27% in all randomised patients.

Side effects were different for patients treated with NIVO + IPI and those treated with chemotherapy with or without NIVO. The most common any-grade treatment related adverse events (TRAEs) (≥10%) for patients in the NIVO + chemo and chemo arms were nausea, decreased appetite and stomatitis. In contrast, for patients in the NIVO + IPI arm, these were rash, pruritus and hypothyroidism. Importantly, treatment-related deaths were low and similar among treatment arms (N= 5, N= 5 and N= 4 in NIVO + chemo, NIVO + IPI and chemo arms, respectively). The incidence of TRAEs in patients with tumour cell PD-L1 ≥1% was consistent with all treated patients across all arms.


Nivolumab is the first PD-1 inhibitor to demonstrate superior OS in combination with either chemotherapy or ipilimumab, in comparison to chemotherapy alone in previously untreated patients with advanced ESCC. No new safety signals were identified with NIVO + chemo or NIVO + IPI. As such, both NIVO + chemo and NIVO + IPI represent a new potential first-line standard of care for patients with advanced ESCC.


Chau I, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study. Presented at ASCO 2021; Abstract LBA4001.

Speaker Ian Chau

Ian Chau

Ian Chau, MD,Royal Marsden Hospital, London & Surrey, UK


See: Keyslides

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