Which Chemo-IO Combo Is Optimal in First-line Esophageal Cancer?

The review of 5 phase 3 randomized controlled trials found that overall, the combination treatments improved survival outcomes while eliciting more, but manageable, side effects.

As various immune-oncology combination treatments continue to be assessed in clinical trials for use in first-line advanced esophageal cancer, researchers of a meta-analysis published in International Immunopharmacology have found which combinations yield the strongest efficacy.

The review of 5 phase 3 randomized controlled trials found that overall, the combination treatments improved survival outcomes while eliciting more, but manageable, side effects. As a whole, adding a PD-1 inhibitor to chemotherapy was associated with improved overall survival (OS) (HR: 0.69, 95% CI: 0.62–0.76, P < .001), progression-free survival (PFS) (HR: 0.62, 95% CI: 0.55–0.70, P < .001) and objective response rate (ORR) (risk ratio [RR]: 1.41, 95% CI: 1.23–1.62, P < .001) among the 3000 patients included in the studies.

While PD- 1/PD-L1 inhibitors have emerged as promising treatments in esophageal cancer—pembrolizumab is currently approved in the second-line setting—preliminary data suggest that combining PD-1 inhibitors with chemotherapy may have a synergistic effect. To date, there have been no head-to-head comparisons of different chemo-immunotherapy combinations in the first-line setting.

Across the combinations,toripalimab plus chemotherapy (tori-chemo) yielded the strongest OS results relative to chemotherapy (HR: 0.58, 95% CI: 0.43-0.78) followed by sintilimab plus chemotherapy (sinti-chemo) (HR: 0.63, 95% CI: 0.51-0.78) and camrelizumab plus chemotherapy (camre-chemo) (HR: 0.70, 95% CI: 0.56-0.88).

Sinti-chemo and camre-chemo were associated with the most improved PFS relative to chemotherapy (HR: 0.56, 95% CI: 0.46-0.68). Notably, nivolumab plus chemotherapy (nivo-chemo) demonstrated significantly shorter PFS than tori-chemo (HR: 0.72, 95% CI: 0.51-1.00), sinti-chemo (HR: 0.69, 95% CI: 0.51-0.94) and camre-chemo (HR: 0.69, 95% CI: 0.51-0.94).

Subgroup analyses found significantly improved OS among patients with PD-L1 tumor-positive score (TPS) ≥ 10% and longer PFS among patients with PD-L1 combined positive score (CPS) ≥ 10.

“This led us to consider which method of assessing PD-L1 expression had better prognostic value in esophageal cancer. At present, it is still controversial, with some studies using TPS and others using CPS,” explained the researchers. “Based on our analysis, PD-L1 TPS may be more meaningful in OS and PD-L1 CPS probably more predictive in PFS for advanced esophageal cancer patients who used IO-chemotherapy combination as first-line treatment. Further studies are still needed to explore the association between PD-L1 expression and the efficacy of PD-1 inhibitors.”

Highest ORR compared with chemotherapy was seen with nivo-chemo (RR: 1.73, 95% CI:1.40-2.14), followed by pembrolizumab plus chemotherapy (pembro-chemo) (RR:1.54,95%CI:1.27-1.87) and sinti-chemo (RR:1.47, 95% CI: 1.28-1.70). Camre-chemo had the lower ORR rate among the combinations.

The chemo-immunotherapy combinations were associated with an increase in serious adverse events (AEs) (pooled RR: 1.36, 95% CI: 1.15-1.61, P < .001) and treatment discontinuation due to AEs (pooled RR: 1.82, 95% CI: 1.55-2.14, P < .001). Among the combinations, camre-chemo and pembro-chemo were associated with relatively lower grade ≥3 AEs.

Immune-mediated AEs of any grade (pooled RR: 2.01, 95% CI: 1.35-2.98, P = .001) and immune-mediated AEs of grade ≥3 (pooled RR: 2.33, 95% CI: 1.36-3.97, P = .002) were both higher with chemo-immunotherapy combinations.


Li Z, Sun Y, Lai M, Zhou Y, Qiu M. Efficacy and safety of PD-1 inhibitors combined with chemotherapy as first-line therapy for advanced esophageal cancer: A systematic review and network meta-analysis. Int Immunopharmacol. Published online April 20, 2022. doi:10.1016/j.intimp.2022.108790