Nivolumab Improves OS in Advanced Esophageal Cancer

In the phase III ATTRACTION-3 study, nivolumab prolonged overall survival compared with chemotherapy in patients with previously treated advanced esophageal squamous cell carcinoma, according to findings presented at the 2019 ESMO Congress.

Byoung Chul Cho, MD, PhD

In the phase III ATTRACTION-3 study, nivolumab prolonged overall survival compared with chemotherapy in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC), according to findings presented at the 2019 ESMO Congress.

At a minimum follow-up of 17.6 months, the median OS improved from 8.4 months in patients randomized to chemotherapy to 10.9 months in those randomized to nivolumab, corresponding to a significant 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.62-0.96;P= .019).

The OS benefit with nivolumab was evident regardless of PD-L1 expression.

As such, "nivolumab represents a potential new standard second-line treatment option for patients with advanced ESCC," said Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Seoul, Korea.

"Today is an important day for our patients who are eagerly waiting for an effective therapy."

In the 419-patient study, 31% of patients in the nivolumab arm were alive at 18 months compared with 21% in the arm that received docetaxel or paclitaxel. At 12 months, 47% and 34%, respectively, were alive.

The improvement in median OS occurred despite a nearly identical objective response rate (ORR) between the 2 treatment arms and a progression-free survival (PFS) that favored chemotherapy. The ORR was 33% in the nivolumab arm and 34% in the chemotherapy arm, and the median PFS rates were 1.7 months and 3.4 months (HR, 1.08; 95% CI, 0.87-1.34), respectively.

Metastatic esophageal cancer has a poor prognosis. The 5-year relative survival rate is ≤8%. ESCC is the dominant histologic subtype, accounting for approximately 90% of all esophageal cancer worldwide. Current chemotherapy options in the second-line setting offer poor long-term survival and are associated with toxicity.

ATTRACTION-3 builds on the phase II ATTRACTION-1 study that showed that nivolumab had promising antitumor activity with a manageable safety profile with advanced ESCC refractory to or intolerant of standard chemotherapies.2

ATTRACTION-3 enrolled 419 patients with unresectable advanced or recurrent ESCC refractory to or intolerant of 1 prior fluoropyrimidine/platinum-based chemotherapy. They were randomized in a 1:1 ratio to nivolumab at 240 mg intravenously every 2 weeks, or investigator’s choice of taxane chemotherapy that consisted of either docetaxel at 75 mg/m2intravenously every 3 weeks, or paclitaxel at 100 mg/m2intravenously every week for 6 weeks, then 1 week off.

The primary endpoint was OS. The data cutoff for this analysis was November 2018. Of the 419 patients randomized, 417 received at least one dose of their assigned treatment.

Baseline characteristics were well balanced between the 2 arms. Nearly 90% of the patients were male and 96% were Asian. Patients were split evenly between an ECOG performance status of 0 or 1. About half of patients had prior surgery and about 70% had prior radiotherapy. Approximately half of patients had tumor PD-L1 expression ≥1%. About 85% of patients were current or former smokers.

The median duration of treatment was 2.6 months in either arm. The median relative dose intensity was 100% in the nivolumab arm and 81% in the chemotherapy arm. More than 90% in either arm discontinued treatment, with the most common reason being disease progression (64% in the nivolumab arm and 66% in the chemotherapy arm).

"OS consistently favored nivolumab versus chemotherapy across multiple prespecified subgroups, including tumor PD-L1 expression," said Cho.

The best overall response was a complete response in 1% in each arm (P= .63), a partial response in 19% of the nivolumab arm and 20% of the chemotherapy arm, and stable disease in 18% and 41%, respectively. The disease control rate was 37% in the nivolumab group and 63% in the chemotherapy group.

The median time to response was 2.6 months in the nivolumab arm and 1.5 months in the chemotherapy arm. "However, responses were substantially more durable with nivolumab compared to chemotherapy," Cho said, with a median duration of response of 6.9 months and 3.9 months, respectively. Some 21% of patients in the nivolumab arm have ongoing responses, compared with 6% in the chemotherapy arm.

Exploratory analyses revealed a significant overall improvement in health-related quality of life with nivolumab versus chemotherapy using the EQ-5D-3L Visual Analog Scale.

Grade 3/4 treatment-related adverse events (TRAEs) occurred at a rate that was more than 3 times lower with nivolumab, and TRAEs occurred at a rate that was less than half in the nivolumab group compared with chemotherapy (18% vs 63%). The most common TRAEs with nivolumab were rash (n = 11), diarrhea (n = 11), and fatigue (n = 7), compared with alopecia (n = 47), a decline in neutrophil count (n = 37), a decline in white blood cell count (n = 35), decreased appetite (n = 27), anemia (n = 24), peripheral sensory neuropathy (n = 23), malaise (n = 22), fatigue (n = 21), and neutropenia (n = 19) in the chemotherapy arm. Endocrine disorders of any grade occurred more frequently in the nivolumab arm (11% vs <1%).

When taken together with findings from the KEYNOTE-181 pembrolizumab study, which was conducted in patients with either advanced/metastatic ESCC or adenocarcinoma, the findings from ATTRACTION-3 demonstrate a consistent beneficial OS effect of PD-1 antibody therapy in advanced ESCC, said invited discussant Ian Chau, MD, and shifts the treatment paradigm of this disease.

In KEYNOTE-181, pembrolizumab showed a significant OS benefit versus chemotherapy as second-line treatment in patients with esophageal cancer with a PD-L1 combined positive score (CPS) ≥10. In the intent-to-treat population in KEYNOTE-181, a “directionally favorable” but nonsignificant OS benefit was observed with pembrolizumab, said Chau, consultant medical oncologist, The Royal Marsden Hospital, London and Surrey, United Kingdom.

The KEYNOTE-181 trial resulted in the FDA approval of pembrolizumab for patients with recurrent, locally advanced ormetastaticESCC whose tumors express PD-L1 (CPS ≥10).

Although only 18 white patients were enrolled in ATTRACTION-3, the OS benefit with nivolumab was consistent in this subgroup, noted Chau.


  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. Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.
  2. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial.Lancet Oncol. 2017;18:631-639.