Nivolumab (Opdivo) is forging a new role in gastroesophageal cancers, according to results of 3 phase 3 clinical trials indicating that nivolumab as first-line therapy or adjuvant therapy can improve survival in patients with gastric and gastroesophageal junction (GEJ) cancer. These results are a “paradigm shift” for these patients, but questions remain, suggested several experts who discussed these results at the 2020 European Society for Medical Oncology (ESMO) virtual meeting.
Standard first-line chemotherapy in gastric and gastroesophageal cancers is associated with a median overall survival (OS) of <1 year. Immunotherapy is an active area of study in these cancers, with promising results seen with nivolumab in the first-line setting, particularly in patients with a combined positive score (CPS) of PD-L1 expression ≥5.
The CheckMate-649 Study
CheckMate-649 was the largest phase 3 clinical trial of nivolumab in this setting. The study enrolled 1581 treatment-naïve patients with unresectable, HER2-negative gastric cancer, GEJ cancer, or esophageal adenocarcinoma. Overall, 60% of the patients had PD-L1 expression. Patients were randomized in a 1:1 ratio to nivolumab plus ipilimumab (Yervoy); nivolumab plus oxaliplatin-based chemotherapy; or to chemotherapy alone.
At a median of 12 months of follow-up, nivolumab plus chemotherapy improved survival over chemotherapy alone. In patients with CPS ≥5, the median OS was 14 months with nivolumab plus chemotherapy versus 11.1 months with chemotherapy alone (P <.0001), a 21% improvement in survival. In patients with any level of PD-L1 expression (CPS ≥1), the median OS was 14.0 months versus 11.3 months, respectively (P = .0002), a 23% improvement in survival.
Progression-free survival (PFS) was significantly improved with nivolumab plus chemotherapy versus chemotherapy alone in patients with CPS ≥5, with a median of 7.7 months versus 6 months, respectively (P <.0001), an improvement of 32%. However, the PFS was not improved with the combination versus chemotherapy alone in patients with CPS ≥1.
In all, 36% of the patients who received the combination therapy had adverse events leading to treatment discontinuation versus 24% of those who received chemotherapy alone.
“These results are highly clinically meaningful, and nivolumab plus chemotherapy represents a new potential standard first-line treatment,” said lead author Markus Moehler, MD, PhD, Gastroenterology/Endosonography, Johannes-Gutenberg University Clinic, Mainz, Germany.
Salah-Eddin Al-Batran, MD, Director of GI Oncology, Krankenhaus Nordwest-University Cancer Centre, Frankfurt, Germany, commented on the study. “These results are practice-changing and are clearly significant,” Dr Al-Batran said, noting that he would have liked to see the results broken out by scores of CPS 1 to 4 and CPS 0.
“We have to be sure we do not inflate the results for all-comers by the very response group of high [PD-L1] expressers,” he continued.
The ATTRACTION-4 Study
The phase 3 ATTRACTION-4 clinical trial was conducted in Japan, Korea, and Taiwan, showing the opposite pattern of results regarding PFS and OS. Narikazu Boku, MD, PhD, Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan, was the lead investigator.
ATTRACTION-4 enrolled 724 treatment-naïve patients with HER2-negative gastric cancer or GEJ, and patients were randomized to nivolumab plus chemotherapy versus chemotherapy alone.
At a median follow-up of 11.6 months, nivolumab plus chemotherapy significantly improved PFS over chemotherapy alone, with a median of 10.5 months versus 8.3 months, respectively (P = .0007), an improvement of 32%. By contrast, the difference in OS did not reach statistical significance (17.5 months vs 17.2 months, respectively).
Formal discussant of these 2 studies, Elizabeth Smyth, MD, Consultant in Medical Oncology, Cambridge University Hospitals NHS Foundation Trust, England, pointed to several factors that could have influenced the OS in the ATTRACTION-4 study.
“PD-L1 status was assessed on tumor cells only, and there were no key end points based on PD-L1 status,” she explained. “Posttrial therapy could have affected overall survival results, as Asians typically receive more subsequent therapies than in other areas of the world.”
Nevertheless, Dr Smyth stated that CheckMate-649 and ATTRACTION-4 represent a “paradigm shift” in the treatment of gastroesophageal adenocarcinoma.
CheckMate-577 in the Adjuvant Setting
The results of the CheckMate-577 study suggested a role for nivolumab in the adjuvant setting in patients with resected esophageal or GEJ cancer after neoadjuvant chemoradiation. This study enrolled 794 patients from around the world and randomized them to adjuvant therapy with nivolumab versus placebo, after chemoradiation.
The median disease-free survival was 22.4 months with nivolumab versus 11 months with placebo (P = .0003).
“This is the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement in patients with esophageal cancer or gastroesophageal junction cancer following neoadjuvant chemoradiation,” said lead investigator Ronan J. Kelly, MD, MBA, Director of Oncology, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX. “These results represent the first advance in years for this group of patients, potentially establishing nivolumab as a new standard of care,” Dr Kelly added.
Treatment-related adverse events leading to treatment discontinuation were 9% with nivolumab versus 3% with placebo. No difference was seen between the treatment arms in patient-reported health status on the EQ-5D-3L visual analog scale, and both groups exhibited clinically meaningful improvements.
“This is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results are independent of PD-L1 status,” said formal discussant and President-Elect of ESMO, Andrés Cervantes, MD, PhD, Professor of Medicine, University of Valencia, Spain.
Dr Cervantes pointed out some flaws in the study design. For one, “preoperative chemoradiation is not a universally accepted standard of care in this setting,” he noted.
Disease-free survival is not a currently validated major end point in gastroesophageal cancers, and median follow-up was short. Also, the study was not stratified by esophageal squamous versus adenocarcinoma histology.