FDA Approves Adjuvant Nivolumab for Resected Esophageal or GEJ Cancer

FDA

The FDA has approved nivolumab (Opdivo) for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease, in patients have received neoadjuvant chemoradiotherapy.¹

The regulatory decision is based on data from the phase 3 CheckMate-577 trial (NCT027434940), which showed that adjuvant nivolumab doubled the median disease-free survival (DFS) compared with placebo, at 22.4 months (95% CI, 16.6-34.0) vs 11.0 months (95% CI, 8.3-14.3), respectively. This translated to a 31% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.69; 95% CI, 0.56-0.85; P = .0003).^2,3

“Locally advanced esophageal and GEJ cancers are aggressive tumor types that often require multiple approaches to address the disease, including chemotherapy, radiation and surgery,” Ronan J. Kelly MD, MBA, director, Baylor Scott & White Charles A. Sammons Cancer Center, and W.W. Caruth Jr. Endowed Chair of Immunology at Baylor University Medical Center, stated in a press release. “Even after neoadjuvant chemoradiotherapy followed by surgery, there may be a high risk of recurrence for patients who do not achieve a pathologic complete response. In the CheckMate-577 trial, we saw a doubling in median DFS compared to placebo, which suggests that [nivolumab] could become a new standard of care for these patients. This is exciting news, providing renewed hope.”

For the double-blind, placebo-controlled, phase 3 trial, investigators enrolled patients with stage II/II esophageal or GEJ cancer, adenocarcinoma, or squamous cell carcinoma. To be eligible for enrollment, patients had to have received neoadjuvant chemoradiation, undergone surgical resection, and had residual pathologic disease; they also needed to have an ECOG performance score of 0 or 1.

Stratification factors included histology (squamous vs adenocarcinoma), pathologic lymph node status ( ≥ypN1 vs ypN0), and PD-L1 expression (≥1% vs <1%).

A total of 794 patients were randomized 2:1 to 240 mg of nivolumab once every 2 weeks for 16 weeks followed by 480 mg once every 4 weeks (n = 532) or placebo once every 2 weeks for 16 weeks and then once every 4 weeks (n = 262). Participants received treatment for up to 1 year.

The primary end point of the trial was DFS, while important secondary end points comprised overall survival (OS), as well as OS rates at 1, 2, and 3 years.

The median age of study participants was 61.5 years, and the majority were male. Fifty-nine percent of patients had an ECOG performance status of 0, while 41% had a status of 1. Moreover, 36% of patients had stage II disease at the time of initial diagnosis, while 64% had stage III disease. With regard to tumor location, 59.5% had esophageal cancer and 40.5% had GEJ cancer. Twenty-nine percent of patients had squamous cell carcinoma, while 71% had adenocarcinoma.

Moreover, 17% of patients in the nivolumab arm had a PD-L1 expression of 1% or greater and 70% had an expression of less than 1%; these rates were 15% and 75%, respectively, in the placebo arms.

The median duration of treatment in the investigative arm was 10.1 months compared with 9.0 months in the placebo arm. Ninety-four percent of patients on the investigational arm discontinued treatment compared with 93% of those on the control arm.

The most frequently cited reason for discontinuation in those who received adjuvant nivolumab was treatment completion (43%); this was followed by progressive disease (28%), treatment-related toxicities (11%), adverse effects (AEs) not associated with the treatment (3%), patient decision (8%), and other (2%).

Eighty-six percent of patients who received the immunotherapy had a relative dose intensity of 90% or greater.

Data from an exploratory analysis that was done in 563 patients with adenocarcinoma (70.9%) showed that the median DFS with nivolumab was 19.4 months (95% CI, 15.9-29.4) vs 11.1 months (95% CI, 8.3-16.8) with placebo (unstratified HR 0.75; 95% CI, 0.59-0.96). Among 230 patients with squamous cell carcinoma (29%), the median DFS with nivolumab was 29.7 months (95% CI, 14.4–not evaluable) vs 11.0 months (95% CI, 7.6-17.8) with placebo (unstratified HR 0.61; 95% CI, 0.42-0.88).

Regarding safety, 96% of patients who received nivolumab experienced any-grade AEs with 34% grade 3 or 4 in severity. Seventy-one percent of patients reported any-grade treatment-related AEs (TRAEs) and 13% were grade 3 or 4. However, nivolumab was found to be well tolerated overall with the majority of TRAEs only grade 1 or 2 in severity. Commonly reported TRAEs in the investigational arm included fatigue (17%), diarrhea (17%), pruritis (10%), and rash (10%).

Seventeen percent of patients who received the immunotherapy experienced any-grade endocrine TRAEs, 17% had gastrointestinal, 9% had hepatic, 4% had pulmonary, 1% had renal, and 24% had skin toxicities.

The majority of the select TRAEs were grade 1 or 2 in the nivolumab arm and 1% or less of patients experienced grade 3 or 4 toxicities. Notably, no grade 5 select toxicities associated with treatment were experienced. The most frequently reported grade 3/4 TRAEs reported with nivolumab included pneumonitis (n = 4) and rash (n = 4).

Nivolumab has the following Warnings and Precautions associated with it: severe and fatal immune-mediated adverse effects such as pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis and renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse effects.

The agent has also had infusion-related reactions, associated complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. Moreover, increased mortality has been observed in patients with multiple myeloma when nivolumab is added to a thalidomide analogue and dexamethasone; this is not recommended outside of controlled clinical trials.

References

1. US Food and Drug Administration approves Opdivo (nivolumab) as adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer in patients who have received neoadjuvant chemoradiotherapy. News release. Bristol Myers Squibb. May 20, 2021. Accessed May 20, 2021. https://bit.ly/3bFlde8
2. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer following neoadjuvant chemoradiation therapy: first results of the CheckMate 577 study. Ann Oncol. 2020;31(suppl 4):S1193-S1194.
3. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021-384(13):1191-1203. doi: 10.1056/NEJMoa2032125