Confirmed superiority for nivolumab-based combination therapy over chemotherapy alone in previously untreated patients with advanced oesophageal cancer

Standard first-line chemotherapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCC) results in a poor median overall survival (OS) of less than one year. In CheckMate 648, nivolumab (NIVO) combined with either chemotherapy (chemo), or ipilimumab (IPI) were compared to chemotherapy alone in previously untreated patients with advanced oesophageal squamous cell carcinoma (ESCC). Interestingly, both NIVO-based treatment regimens induced a superior OS benefit compared to chemotherapy alone in this setting.

The standard first-line (1L) chemotherapy for patients with advanced or metastatic ESCC results in a poor median overall survival (OS) of less than a year. In the CheckMate 648 trial, NIVO + chemo and NIVO + IPI demonstrated significant OS benefit and more durable responses compared to chemotherapy in previously untreated patients with advanced ESCC. Based on these results, NIVO + chemo and NIVO + IPI are now approved in the EU, US, and Japan as new 1L standard standard-of-care treatments for these patients. During ESMO World Congress on Gastrointestinal Cancer 2022, the expanded efficacy and safety results from the primary analysis of CheckMate 648 were presented.

Study design

The global, open-label, randomised phase 3 CheckMate 648 trial enrolled patients with unresectable, advanced, recurrent or metastatic ESCC. Patients had to have an ECOG PS 0-1, have measurable disease and were not allowed to have received prior systemic treatment for advanced disease. Patients (n=970) were randomised 1:1:1 to NIVO (240mg Q2W) + chemo (Q4W) (n=321), NIVO (3mg/kg Q2W) + IPI (1mg/kg, Q6W) (n=325), or chemotherapy alone (Q4W) (n=324). The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS) in participants with a tumour cell PD-L1 expression of ≥1%. Secondary endpoints included OS and PFS in all patients, and the ORR in patients with a tumour cell PD-L1 expression ≥1% and in all randomised patients. Exploratory endpoints included progression-free survival on subsequent therapy (PFS2), duration of response (DoR), and safety.

Results

At data cutoff (January 2021), the minimum follow-up was 12.9 months. At this time point, the OS was significantly longer with NIVO + chemo than with chemotherapy alone in patients with a tumour-cell PD-L1 ≥1% (median OS: 15.4 vs. 9.1 months, HR[99.5%CI]: 0.54[0.37-0.80]; p<0.001). The OS was also significantly superior with NIVO + CHEMO vs. chemo in the overall population  (median OS: 13.2 vs. 10.7 months, HR[99.1%CI]:0.74[0.58-0.96], P=0.002). In the subgroup analysis of all PD-L1 expression subgroups, HRs were all favouring NIVO + chemo vs. chemo across all PD-L1 expression subgroups.  The largest magnitude of benefit was observed in patients with a tumour cell PD-L1 expression of ≥1%. A larger proportion of responders who received NIVO + chemo vs. chemo had a DoR ≥12 months. This was true among all randomised patients (39 vs. 23%)  and in patients with tumour cell PD-L1 ≥ 1% (40 vs. 13%) and < 1% (38 vs. 27%). For all randomised patients, the median PFS was 11.0 vs. 7.9 months in the NIVO + chemo vs. chemo group.  

In the NIVO+ IPI and chemo arms, the median OS was reported at 13.7 and 9.1 months, respectively,  in patients with tumour cell PD-L1 ≥1% (HR[98.6%CI]:0.64[0.46-0.90]; p=0.0010]. In all randomised patients, the median OS was 12.8 vs. 10.7 months with NIVO + IPI and chemo (HR[98.2%CI]: 0.78[0.62-0.98]; p=0.0110]), respectively . In an analysis in function of PD-L1 expression, HRs were all favouring NIVO + IPI over chemo across all PD PD-L1 expression subgroups, except for patients with a CPS <1 (HR =1). The largest magnitude of benefit was observed in patients with tumour cell PD-L1 expression of ≥1%. As with NIVO + chemo, a larger proportion of responders who received NIVO + IPI vs. chemotherapy had a DoR ≥ 12 months (48 vs. 23% among all randomised patients; 49 vs. 13% in PD-L1 ≥1% patients  and 47 vs. 27% in PD-L1 < 1% patients). For all randomised patients, the median PFS was 9.7 vs. 7.9 months with NIVO + IPI vs. chemo group (HR[95%CI]: 0.74[0.62-0.88]).  

Grade 3/4 treatment‐related adverse events (TRAEs) with potential immunologic aetiology occurred in ≤ 2% of patients treated with NIVO + chemo and in ≤ 6% of the patients treated with NIVO + IPI. The majority of non-endocrine TRAEs with potential immunologic aetiology with NIVO + chemo and NIVO + IPI resolved (57-91% and  63-95%) with a median time to resolution of 1.5-17.1 and 2.9-12.1 weeks, respectively.

Conclusion

Both NIVO + chemo and NIVO+IPI induced a superior OS benefit over chemotherapy alone in previously untreated patients with advanced ESCC, both in patients with tumour cell  PD-L1 expression ≥1% as in all randomised patients. A larger proportion of responders had prolonged DoR (≥ 12 months) with NIVO + chemo or NIVO + IPI vs. chemotherapy. TRAEs with potential immunologic aetiology resolved in most patients in both NIVO + chemo or NIVO + IPI arms. These results further support NIVO + chemo and NIVO + IPI as new 1L standard-of -care options for patients with advanced ESCC.

Reference

Chau I, Ajani JA, Doki Y, et al. Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): expanded efficacy and safety analyses from CheckMate 648. Presented at ESMO World Congress on Gastrointestinal Cancer; Abstract O-3.