Clinical trialPhase 3Oesophageal cancer

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer

N Engl J Med · 2021794 patients

Kelly RJ, Ajani JA, Kuzdzal J, et al. N Engl J Med. 2021. 384:1191-1203

Study type: Clinical trial
Study name: CheckMate 577
Phase: Phase 3
Design: Global, double-blind, placebo-controlled randomised trial (2:1)
Sample size: 794 patients
Source: N Engl J Med · 2021
Trial registration: NCT02743494

In plain words

If some cancer cells are still seen in the surgical specimen after chemoradiotherapy and surgery for oesophageal cancer, the risk of the cancer coming back is higher. In this study, one year of immunotherapy with nivolumab after surgery nearly doubled the time without the cancer coming back (about 22 months versus 11 months). Most patients did not have serious side effects, but you should talk with your treatment team about the possible side effects of immunotherapy.

Key results

22.4 vs 11.0 months

Median disease-free survival

HR 0.69 (96.4% CI 0.56–0.86); P<0.001; median follow-up 24.4 months

13% vs 6%

Treatment-related grade 3 or 4 adverse events

71 of 532 vs 15 of 260 patients

9% vs 3%

Discontinuation due to treatment-related adverse events

Drugs in this study:Carboplatin (Paraplatin)Nivolumab (Opdivo)Paclitaxel (Taxol)

Dose and schedule cards

Adjuvant nivolumab (CheckMate 577 trial)

Oesophageal or gastroesophageal junction cancer (squamous cell carcinoma or adenocarcinoma) with residual pathologic disease after neoadjuvant chemoradiotherapy and complete (R0) resection; in the trial, randomisation 4 to 16 weeks after surgeryOn the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

Drug	Dose	Route	Schedule
Weeks 1–16
Nivolumab	240 mg	IV (30 minutes)	Every 2 weeks
From Week 17
Nivolumab	480 mg	IV (30 minutes)	Every 4 weeks

Cycle length: Every 14 days for the first 16 weeks, then every 28 days
Duration: 1 year in total (or until recurrence or unacceptable toxicity)

Schedule from the trial and the FDA label; the label allows 240 mg every 2 weeks or 480 mg every 4 weeks throughout the 1-year course.

On the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

CROSS

Resectable oesophageal cancer, before oesophagectomyCycle length: WeeklyOn the page “CROSS regimen: chemoradiotherapy before oesophageal surgery”

Resectable oesophageal cancer, before oesophagectomy

Drug	Dose	Route	Schedule
Carboplatin	AUC 2	IV	Days 1, 8, 15, 22 and 29
Paclitaxel	50 mg/m²	IV	Days 1, 8, 15, 22 and 29
Radiotherapy	41.4 Gy in 23 fractions		5 days a week, concurrent

Cycle length: Weekly
Duration: 5 weeks; surgery about 4 to 6 weeks after completion

Doses as in the CROSS study. Adjuvant nivolumab: 240 mg every 2 weeks for 16 weeks, then 480 mg every 4 weeks up to one year.

On the page “CROSS regimen: chemoradiotherapy before oesophageal surgery”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab (532 patients)

Nivolumab 240 mg IV every 2 weeks for 16 weeks, then 480 mg every 4 weeks (from week 17); maximum treatment duration 1 year.

2Placebo (262 patients)

Matching placebo on the same schedule; maximum 1 year.

Source of the regimen details: Doses confirmed from the abstract of the published paper and the Clinical Studies section of the FDA label for nivolumab (CHECKMATE-577).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with stage II or III oesophageal or gastro-oesophageal junction cancer who had undergone complete (R0) resection after neoadjuvant chemoradiotherapy but had residual pathological disease in the surgical specimen (that is, they had not achieved a pathological complete response). Both histological types (squamous and adenocarcinoma) were included.

Endpoints

Primary endpoint: disease-free survival (DFS). Key secondary endpoint: overall survival (still immature in this report).

Safety and side effects

Treatment-related grade 3 or 4 adverse events occurred in 13% of the nivolumab group and 6% of the placebo group. 9% of the nivolumab group and 3% of the placebo group discontinued treatment because of treatment-related adverse events.

Clinical significance and place in guidelines

Based on this trial, nivolumab has been approved by the FDA for adjuvant treatment of completely resected oesophageal or gastro-oesophageal junction cancer with residual pathological disease after neoadjuvant chemoradiotherapy (current OPDIVO label, section 1.13). This treatment is specific to patients who have followed the CROSS pathway (chemoradiotherapy followed by surgery); the data cannot be directly generalised to patients receiving perioperative FLOT chemotherapy.

Limitations

At the time of publication, overall survival data were immature and were not reported in this paper; only patients who had received preoperative chemoradiotherapy were enrolled (not perioperative chemotherapy); patients with a pathological complete response were not enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.