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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 , 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 .

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 , 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.

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