Nivolumab vs Chemotherapy in Advanced Esophageal Cancer

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Nivolumab improved overall survival compared with chemotherapy in previously treated patients with esophageal squamous cell carcinoma in the final analysis of the phase III ATTRACTION-3 study. The data were presented at the European Society for Medical Oncology (ESMO) Congress 2019 Presidential Symposium1 and concurrently published in The Lancet Oncology.2

Patients receiving the checkpoint inhibitor had a 23% reduction in the risk of death and an 18-month survival rate of 31%, vs 21% with chemotherapy, according to Byoung Chul Cho, MD, PhD, of Yonsei Cancer Center, Seoul, Korea.

Overall survival consistently favored nivolumab vs chemotherapy across multiple prespecified subgroups, including tumor PD-L1 expression.
— Byoung Chul Cho, MD, PhD

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“Today is an important day for our patients who are eagerly waiting for an effective therapy,” Dr. Cho commented. “Nivolu-mab is the first immune checkpoint inhibitor to demonstrate a statistically significant and clinically meaningful improvement in overall survival vs chemotherapy in previously treated advanced esophageal squamous cell carcinoma, and it represents a potential new standard second-line treatment option.”


The ATTRACTION-3 study enrolled 419 patients (90% male, 96% Asian) with unresectable advanced or recurrent esophageal squamous cell carcinoma who were refractory to or intolerant of one prior fluoropyrimidine/platinum-based regimen. Patients were randomly assigned to nivolumab at 240 mg every 2 weeks or investigator’s choice of taxane chemotherapy (docetaxel at 75 mg/m2 every 3 weeks or paclitaxel at 100 mg/m2 every week for 6 weeks on, 1 week off). The primary endpoint was overall survival.

The median duration of treatment was 2.6 months in both arms. The median relative dose intensity was 100% in the nivolumab arm and 81% in the chemotherapy arm.

Overall Survival Benefit

At a minimum follow-up of 17.6 months, the median overall survival was 10.9 months with nivolumab and 8.4 months with chemotherapy (hazard ratio [HR] = 0.77; P = .019), with survival rates of 47% and 34%, respectively, at 12 months, and 31% and 21% at 18 months. A survival benefit was observed regardless of programmed cell death ligand 1 (PD-L1) expression, Dr. Cho reported.

“Overall survival consistently favored nivolumab vs chemotherapy across multiple prespecified subgroups, including tumor PD-L1 expression,” he said, although the hazard ratio for patients with ≥ 1% expression was 0.69 (95% confidence interval [CI] = 0.51–0.94) and 0.84 (95% CI = 0.62–1.14) for those with PD-L1 expression < 1%. Although only 18 non-Asians were enrolled in ATTRACTION-3, the overall survival benefit with nivolumab was consistent in this subgroup.


  • The phase III randomized ATTRACTION-3 trial evaluated nivolumab as second-line treatment, vs chemotherapy, in patients with advanced esophageal squamous cell carcinoma.
  • In the final analysis, nivolumab reduced the risk of death by 23% (P = .019), without improving response rates or progression-free survival.
  • Nivolumab had a better safety profile and was associated with improved quality of life.
  • Nivolumab joins pembrolizumab in showing a benefit in this patient population; investigators maintain that checkpoint inhibitors should be the new second-line standard of care.

Interestingly, the improvement in median overall survival occurred despite a nearly identical objective response rate between the two treatment arms (33% with nivolumab and 34% with chemotherapy, with complete responses in 1% of each arm) and a progression-free survival that numerically favored chemotherapy (1.7 months with nivolumab and 3.4 months with docetaxel or paclitaxel [HR = 1.08, 95% CI = 0.87–1.34]). At 12 months, 12% of the nivolumab arm had not experienced disease progression, compared with 7% of the chemotherapy arm. But responses occurred sooner with nivolumab and were “substantially more durable,” he added. The median duration of response was 6.9 months and 3.9 months, respectively, with ongoing responses in 21% and 6%.

Treatment-related adverse events were observed in 95% of the chemotherapy arm vs 66% of the nivolumab arm, and the incidence of grade 3 or 4 treatment-related adverse events was more than three times lower (18% vs 63%) with the checkpoint inhibitor.

Grade 3 or 4 endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin toxicities were uncommon in either arm. Endocrine disorders of any grade occurred more frequently in the nivolumab arm (11% vs < 1%). In an exploratory analysis, health-related quality of life was significantly improved with nivolumab. 

DISCLOSURE: Dr. Cho has received honoraria from or advised/consulted for Novartis, Bayer, AstraZeneca, the Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, BMS, Pfizer, Eli Lilly, Janssen, and Takeda; served on the speakers bureau for Novartis; received royalties from Champions Oncology; held stock in TheraCanVac; and received research funding from many of the above-listed companies.


1. Cho BC, Kato K, Takahashi M, et al: Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): The phase 3 ATTRACTION-3 study. ESMO Congress 2019. Abstract LBA11. Presented September 30, 2019.

2. Kato K, Cho BC, Takahashi M, et al: Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:1506-1517, 2019.

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