Adjuvant Nivolumab Significantly Improves DFS in Resected Esophageal or GEJ Cancer

Nivolumab (Opdivo), following neoadjuvant chemoradiation and complete surgical resection, resulted in a statistically significant improvement in disease-free survival (DFS) in patients with resected esophageal or gastroesophageal junction (GEJ) cancer, meeting the primary end point of the phase 3 CheckMate-577 trial (NCT02743494).¹

Moreover, the safety profile of nivolumab proved to be consistent with what has been demonstrated in previous studies.

“Approximately 50% of patients with esophageal or gastroesophageal junction cancer who undergo neoadjuvant chemoradiation therapy followed by tumor resection will have disease recurrence within 4 years,” Ronan J. Kelly, MD, director of the Charles A. Sammons Cancer Center at Baylor University Medical Center, stated in a press release.

“Medical oncologists have had limited to no treatment options to offer [patients with] esophageal cancer who undergo neoadjuvant chemoradiation therapy followed by surgery and fail to demonstrate a pathologic complete response (pCR),” Kelly added. “For the first time, we have a potential therapeutic option with nivolumab in the adjuvant setting for these patients.”

Chemoradiation followed by surgical resection is the current standard of care for this patient population, and 3- to 5-year survival rates following chemoradiation typically range from 30% to 40%.^2,3 Notably, the majority of patients, or 70%, will not achieve a pCR following resection.^4,5 As such, the median OS in these patients is typically less than 2 years.⁶ There is no postoperative adjuvant standard of care after chemoradiation and resection.

In the multicenter, double-blind, phase 3 CheckMate-577 trial, investigators set out to evaluate whether adjuvant nivolumab would improve overall survival (OS), DFS, or both when compared with placebo in patients with resected esophageal or GEJ cancer.^7,8

To be eligible for enrollment, patients had to have been diagnosed with stage II/III carcinoma of the esophagus or GEJ, have completed preoperative treatment with chemoradiation followed by surgery, and have been diagnosed with residual pathologic disease after having been surgically rendered disease free with negative margins after complete resection.

Patients with a diagnosis of cervical esophageal carcinoma or a diagnosis of stage IV resectable disease were not eligible for participation on the trial. Moreover, patients who did not receive concurrent chemoradiation before surgery and those who had received an attenuated vaccine within 30 days of the first treatment, were also not permitted for inclusion.

In the trial, patients were randomized to receive either nivolumab at 240 mg via intravenous infusion biweekly for the duration of 16 weeks followed by nivolumab at 480 mg every 4 weeks until progressive disease or intolerable toxicity, or placebo.

The primary end point of the trial was DFS of adjuvant nivolumab in patients with resected esophageal or GEJ cancer who had received previous chemoradiation followed by surgery, with a time frame of about 58 months after the first patient underwent randomization. Key secondary end points of the trial included OS of adjuvant nivolumab in this patient population, with a time frame of about 77 months following randomization, and the OS rate at 1, 2, and 3 years.

Enrollment was planned for 160 study sites throughout 27 countries including France, Germany, Belgium, the United Kingdom, Italy, Poland, Romania, Spain, Czech Republic, Hungary, Ireland, the Netherlands, Switzerland, Denmark, Israel, Russia, Canada, the United States, Japan, Taiwan, the Republic of Korea, Mexico, Puerto Rico, Brazil, Argentina, Peru, and Australia.

“[Nivolumab] is the first and only therapy to improve DFS, along with a manageable safety profile, for patients with esophageal or GEJ cancer following neoadjuvant chemoradiation therapy and surgery,” Ian M. Waxman, MD, development lead of Gastrointestinal Cancers at Bristol Myers Squibb (BMS), added in the release. “The results from CheckMate-577 are immensely important for physicians and patients and have the potential to establish [nivolumab] as a new standard of care. We plan to provide our data to health authorities worldwide with the goal of bringing [nivolumab] as an adjuvant therapy to these patients with high unmet need.”

BMS plans to complete a full evaluation of the available data from CheckMate-577 and to work with investigators to present the results at an upcoming medical meeting. Additionally, the pharmaceutical company will discuss these data with health authorities.

CheckMate-577 will continue as planned to allow for future examination of OS in these patients receiving adjuvant nivolumab, which is the secondary end point of the trial.

References

1. CheckMate-577, a phase 3 trial evaluating Opdivo (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer, meets primary endpoint of disease-free survival. News release. Bristol Myers Squibb. August 11, 2020. Accessed August 11, 2020. https://bit.ly/3itpX7K.
2. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11-20. doi:10.1056/NEJMoa055531
3. Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol. 2014;32(23):241602422. doi:10.1200/JCO.2013.53.6532
4. Reynolds JV, Muldoon C, Hollywood D, et al. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg. 2007;245(5):707-716. doi:10.1097/01.sla.0000254367.15810.38
5. Ordu AD, Nieder C, Geinitz H, et al. Association between radiation dose and pathological complete response after preoperative radiochemotherapy in esophageal squamous cell cancer. Anticancer Res. 2014;34(12):7255-7261. https://bit.ly/31F9QgM.
6. Kim JY, Nelson RA, Kim J, et al. How well does pathologic stage predict survival for esophageal adenocarcinoma after neoadjuvant therapy? J Thorac Dis. 2015;7(4):734-739. doi:10.3978/j.issn.2072-1439.2015.04.30
7. An investigational immuno-therapy study of nivolumab or placebo in participants with resected esophageal or gastroesophageal junction cancer (CheckMate 577). ClinicalTrials.gov. Updatedd June 9, 2020. Accessed August 11, 2020.
8. CheckMate 577: a randomized, double-blind, phase 3 study of nivolumab (nivo) or placebo in patients (pts) with resected lower esophageal (e) or gastroesophageal junction (GEJ) cancer. J Clin Oncol. 2017;35(suppl 4s):TPS212. doi:10.1200/JCO.2017.35.4_suppl.TPS212