Benefit of both I-O/chemo combo and I-O/I-O combo over chemotherapy alone in oesophageal squamous cell cancer

First results of the randomised, phase 3 CheckMate 648 study demonstrated superior overall survival of first-line treatment with nivolumab plus ipilimumab or nivolumab plus chemotherapy versus chemotherapy alone.

Standard first-line chemotherapy for advanced or metastatic oesophageal squamous cell cancer (ESCC) results in poor overall survival [1]. Recently, first-line treatment with the PD-1 inhibitor nivolumab demonstrated superior overall survival versus chemotherapy in previously treated patients with ESCC in the ATTRACTION-3 trial (NCT02569242) [2].

The randomised, phase 3 CheckMate 648 trial (NCT03143153) explored the efficacy and safety of first-line treatment in ESCC with 2 combination therapies: nivolumab plus ipilimumab (I-O/I-O combo) and nivolumab plus chemotherapy (I-O/chemo combo). Enrolled were 970 patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC regardless of PD-L1 expression. Patients received either nivolumab (240 mg every 2 weeks) plus chemotherapy (fluorouracil plus cisplatin every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary endpoints for both comparisons were overall survival and progression-free survival in patients with tumour cell PD-L1 ≥1%. Secondary endpoints were overall and progression-free survival in all randomised patients. Dr Ian Chau (Royal Marsden Hospital, UK) presented the results of the first interim analysis at a minimum follow-up of 12.9 months [3].

Both the I-O/chemo combo and the I-O/I-O combo led to statistically significant improvement in overall survival versus chemotherapy alone. Median overall survival was 15.4 months, 13.7 months, and 9.1 months for treatment with I-O/chemo combo, I-O/I-O combo, and chemotherapy alone, respectively (see Figure). A statistically significant progression-free survival benefit was also observed for I-O/chemo combo versus chemotherapy alone, but this did not meet the prespecified boundary for significance for I-O/I-O combo versus chemotherapy alone. The objective response rate (per BICR) was 53% (I-O/chemo combo), 35% (I-O/I-O combo), and 20% (chemotherapy alone). The median duration of response was 8.4 months, 11.8 months, and 5.7 months for treatment with I-O/chemo combo, I-O/I-O combo, and chemotherapy alone, respectively. Secondary endpoint of overall survival was also met, showing clear superiority in all randomised patients regardless of PD-L1 expression. No new safety signals were identified for the combination treatments. In conclusion, nivolumab + chemotherapy and nivolumab + ipilimumab each represent a new potential standard of care for patients with advanced ESCC.

Figure: Interim overall survival data of CheckMate 648 for patients with PD-L1 ≥1% [3]

1. Moehler MH, et al. Ann Oncol. 2020;31(2):228-235.
2. Kato K, et al. Lancet Oncol. 2019;20:1506-1517.
3. 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. Abstract LBA4001, ASCO 2021 Virtual Meeting, 4–8 June.

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Posted on 12 August, 202127 March, 2024