First results of the randomized, phase 3 CheckMate 648 study demonstrate 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 a 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 [2]. The randomized, phase 3 Checkmate 648 trial explored the efficacy and safety of first-line treatment in ESCC with two combination therapies: nivolumab plus ipilimumab (I-O/I-O combo) and nivolumab plus chemotherapy (I-O/chemo combo). A total of 970 patients with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Patients received either nivolumab (240 mg Q2W) plus chemotherapy (fluorouracil plus cisplatin Q4W), nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W), or chemotherapy alone.

Primary endpoints for both comparisons were overall survival and progression-free survival in patients with tumor cell PD-L1 ≥1%. Dr Ian Chau (Royal Marsden Hospital, UK) presented the results of the first interim analysis of CheckMate 648 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. Statistically significant progression-free survival benefit was also observed for I-O/chemo combo versus chemotherapy alone but 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). 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. No new safety signals were identified for I-O/chemo combo and/or I-O/I-O combo. “Nivolumab is the first PD1 inhibitor to demonstrate superior overall survival and durable responses in combination with either chemotherapy of ipilimumab versus chemotherapy alone, in previously untreated patients with advanced ESCC, and therefore represents a potential new first-line treatment option,” concluded Dr Chau.

  1. Moehler M, 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. ASCO 2021 Virtual Meeting, abstract LBA4001.

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