Adjuvant Nivolumab Approved in Europe for Select Esophageal or GEJ Cancers

The European Commission has approved nivolumab (Opdivo) for use as an adjuvant treatment in adult patients with esophageal or gastroesophageal junction (GEJ) cancer who have residual pathologic disease after neoadjuvant chemoradiation.¹

The approval was supported by data from the phase 3 CheckMate-577 trial (NCT02743494), which demonstrated that adjuvant nivolumab resulted in a median disease-free survival (DFS) of 22.4 months (95% CI, 16.6-34.0) vs 11.0 months (95% CI, 8.3-14.3) with placebo (HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003).² Notably, the DFS benefit was observed across several subgroups.

“We have demonstrated that the use of immunotherapy in earlier stages of cancer has the potential to prevent recurrence for certain patients,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb (BMS), stated in a press release. “BMS was the first company to bring checkpoint inhibitors into the adjuvant setting for the treatment of patients with melanoma, and we are pleased to the first to bring adjuvant therapy to patients win the European Union with esophageal or GEJ cancers who continue to face a high unmet need.”

In the global, double-blind, placebo-controlled phase 3 CheckMate-577 trial, investigators set out to evaluate an immune checkpoint inhibitor in the adjuvant setting after tri-modality treatment.

To be eligible for enrollment, patients needed to have stage II or III esophageal cancer or GEJ cancer, either adenocarcinoma or squamous cell carcinoma, and have received neoadjuvant chemoradiation and surgical resection. Patients also needed to have residual pathologic disease and an ECOG performance status of 0 or 1.

A total of 794 patients were enrolled to the study and they were randomized 2:1 to receive either nivolumab at 240 mg every 2 weeks for 16 weeks and then at 480 mg every 4 weeks (n = 532) or placebo (n = 262). Patients were stratified based on histology (squamous vs adenocarcinoma), pathologic lymph node status (≥ypN1 vs ypN0), and PD-L1 expression on tumor cells (≥1% vs <1%). Treatment was administered for the duration of 1 year.

The primary end point of the trial was DFS, and secondary end points included overall survival (OS), and OS rates at 1, 2, and 3 years. Exploratory end points comprised distant metastasis-free survival (DMFS), progression-free survival 2 (PFS2), safety, and quality of life (QoL).

The median age of study participants was 61.5 years, 84.5% were male, 81.5% were White, and 59% had an ECOG performance status of 0. Moreover, 64% of patients had stage III disease at the time of the initial diagnosis. More patients had esophageal cancer than GEJ cancer, at 59.5% and 40.5%, respectively. Regarding histology, 29% had squamous cell carcinoma and 71%

had adenocarcinoma. The pathologic lymph node status was ≥ypN1 in 57.5% of patients. Sixteen percent of patients had a PD-L1 tumor cell expression of ≥1% and 72.5% had expression of <1%.

Additional data indicated that the DMFS achieved with nivolumab was 28.3 months (95% CI, 21.3–not evaluable [NE]) vs 17.6 months (95% CI, 12.5-25.4) with placebo (HR, 0.74; 95% CI, 0.60-0.92). The PFS2 had not been reached (95% CI, 34.0–NE) in the investigative arm vs 32.1 months (95% CI, 24.2–NE) in the placebo arm (HR, 0.77; 95% CI, 0.60-0.99).

Moreover, QoL, based on the FACT-E G7 demonstrated improvements for both arms while on treatment, and a maintenance of QoL after treatment has stopped. QoL, based on the esophageal cancer subscale of FACT-E ECS, demonstrated improvements for both arms while receiving treatment and a maintenance QoL after treatment was stopped.

Nivolumab was found to be well tolerated, with the majority of treatment-related adverse effects (TRAEs) being just grade 1 or 2 in severity. Any-grade and grade 3 or 4 serious TRAEs were reported in 8% and 5%, respectively, of those on the investigative arm; these rates were 3% and 1%, respectively. Grade 3 or 4 TRAEs resulted in discontinuation in 5% of those who received nivolumab vs 3% of those who were given placebo.

Most of the select TRAEs were grade 1 or 2. Grade 3 or 4 TRAEs occurred in at least 1% of patients in the investigative arm, and no grade 5 select TRAEs were reported. Notably, select TRAEs in the nivolumab arm occurred early, with a median time to onset of 6 to 13 weeks, and resolved in the majority of patients (range, 65%-100% across organ categories) with the use of established management strategies. The median time to resolution ranged from 3 to 21 weeks.

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) as adjuvant treatment for esophageal or gastroesophageal junction cancer patients with residual pathologic disease following chemoradiotherapy. News release. Bristol Myers Squibb. July 30, 2021. Accessed July 30, 2021. https://bit.ly/3A6efJh
2. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): expanded efficacy and safety analyses from CheckMate 577. J Clin Oncol. 2021;39(suppl 15):4003. doi:10.1200/JCO.2021.39.15_suppl.4003