Patients withor gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.
However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.
The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.
Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.
Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.
The new results come from the largest phase 3 trial of its kind to date,, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.
Among these patients, 60% had a PD-L1 CPS ≥5.
Patients were randomly assigned to one of three treatment groups: Nivolumab plus(Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.
Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.
In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).
The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).
PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).
The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.
At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.
These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.
“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”
“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”
Surprisingly, the results from, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.
This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.
Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).
In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).
Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.
Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.
Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.