A combination of the PD-1 inhibitor nivolumab (Opdivo) plus trastuzumab and chemotherapy (mFOLFOX6) was effective as first-line therapy for patients with HER2 (ERBB2)-positive esophagogastric adenocarcinoma, according to results from the randomized AIO INTEGA trial.
This combination improved 12-month overall survival (OS) compared with the chemotherapy-free combination of nivolumab, trastuzumab, and ipilimumab (Yervoy), with rates of 70% (95% CI 54-81) versus 57% (95% CI 41-71).
That randomized comparison among 88 patients with a median follow-up of 14.3 months, was shored up by a significant benefit of the nivolumab-trastuzumab-chemotherapy combination compared with historical controls on the combination of trastuzumab and chemotherapy alone in the ToGA trial, with a median OS of 21.8 versus 14.2 to 16 months.
“The high efficacy warrants further randomized evaluation of the addition of a programmed cell death 1 inhibitor to standard trastuzumab and chemotherapy in ERBB2-positive [esophagogastric adenocarcinoma] EGA,” suggested Alexander Stein, MD, of the University Cancer Center Hamburg in Germany, and colleagues in JAMA Oncology.
However, the ipilimumab arm of the trial wasn’t better than the trastuzumab- and chemotherapy-treated historical controls, although within the same numerical range (median OS of 16.4 months). “Chemotherapy should not be replaced by ipilimumab in an unselected ERBB2-positive population,” the authors said.
In a commentary accompanying the study, Monica Patel, MD, and Nataliya Uboha, MD, PhD, both of the University of Wisconsin-Madison, wrote that AIO INTEGA “contributes to the growing evidence that immune checkpoint inhibitors have a role in the management of advanced ERBB2-positive EGA” and that the results underscore the importance of chemotherapy during the first-line treatment of advanced esophagogastric adenocarcinoma.
The trial’s secondary endpoints showed a median progression-free survival (PFS) of 3.2 (95% CI 2.0-6.5) versus 10.7 (95% CI 6.6-13.1) months, a median duration of response of 5.8 (95% CI 2.4-not estimable) versus 9.2 (95% CI 8.1-13.5) months, and an overall response rate (ORR) of 32% versus 56% in the ipilimumab arm versus the mFOLFOX6 arm, respectively.
Thus, the FOLFOX arm demonstrated improved PFS and ORR compared with the ToGA regimen (PFS of 6.7 to 7 months, and an ORR of 47% t0 48%), while the chemotherapy-free regimen in the ipilimumab group resulted in lower PFS and ORR compared with the traditional standard therapy.
The overall incidence of grade 3 or greater adverse events (AEs) was comparable in both arms, with treatment-related grade 3 or greater AEs and serious AEs occurring in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm.
The most frequently observed treatment-related AEs in the ipilimumab arm were anemia, infection, and diarrhea, while the most frequent AEs in the FOLFOX arm were leukopenia, infection, fatigue, and neuropathy. Grade 3 or greater autoimmune disorders occurred in less than 10% in the ipilimumab arm and was rarely seen in the FOLFOX arm. In the ipilimumab arm, nine patients (21%) discontinued treatment owing to an AE, compared with seven patients (16%) in the FOLFOX arm.
Baseline quality of life, according to the EORTC QLQ-C30 global health score, was similar between the randomized groups.
The AIO INTEGA trial was a phase II multicenter, outpatient, randomized clinical trial conducted between March 2018 and May 2020 across 21 German sites. It enrolled patients with previously untreated, metastatic HER2-positive esophagogastric adenocarcinoma and adequate organ function who were eligible for immunotherapy. Most patients were male; the median age was 61. Baseline ECOG performance status was 0 in 61% of patients and 1 in 39%.
Patients randomized to the ipilimumab arm received trastuzumab at 6 mg/kg (loading dose 8 mg/kg), nivolumab at 1 mg/kg, and ipilimumab at 3 mg/kg, every 3 weeks for a total of 12 weeks. From week 13, patients received trastuzumab at 4 mg/kg and nivolumab at 240 mg, every 2 weeks.
Patients in the FOLFOX arm received trastuzumab at 4 mg/kg intravenously (loading dose 6 mg/kg) along with nivolumab at 240 mg and mFOLFOX6 every 2 weeks.
Treatment was administered until progression by RECIST v1.1 criteria, intolerable toxic effects, withdrawal of consent, or secondary resection. Nivolumab treatment was limited to a maximum of 12 months in both arms.
The study was supported by Bristol Myers Squibb (BMS).
Stein reported grants from BMS during the conduct of the study along with institutional fees for advisory boards from BMS and Merck Sharp & Dohme outside the submitted work.
Co-authors reported multiple relationships with industry.
Uboha reported personal advisory board fees from AstraZeneca, Pfizer, Astellas, Taiho, QED, and Incyte; research support grants from Ipsen, Taiho, EMD Serono, Helsinn, and Boston Gene; and long position holdings with Natera and Exact Sciences outside the submitted work.