Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma: The AIO INTEGA Randomized Clinical Trial

Abstract

Importance: In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations.

Objective: To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA.

Design, setting, and participants: This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021.

Interventions: Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm).

Main outcomes and measures: The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm.

Results: A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment.

Conclusions and relevance: In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen.

Trial registration: ClinicalTrials.gov Identifier: NCT03409848.

Figure 1.. CONSORT Diagram of the INTEGA Trial

Figure 2.. Clinical Outcomes of Patients Treated in the INTEGA Trial

Overall (OS) (A) and progression-free survival (PFS) (B) are presented for the ipilimumab vs the FOLFOX arm. Duration of response (DOR) is shown in panel C. The waterfall plot (D) shows responses in individual patients in the intent-to-treat population (2 patients—1 in each arm—were allowed to continue in the trial based on clinical response and local treatment applied beside Response Evaluation Criteria in Solid Tumors progression). The key in panel D reports the ORRs. NA indicates not applicable; ORR, overall response rate.

Figure 3.. Mutational Profiling and Liquid Biopsy Disease Monitoring

A, Percentage of patients with genes with sequence variations at baseline in liquid biopsy circulating cell-free DNA (cfDNA) and in tumor tissue. Published data of the mutational landscape of driver genes in esophageal and gastric cancer were obtained from database cBioPortal.^, B and C, Overall survival (OS) and progression-free survival (PFS) of patients according to the level of cfDNA in blood after the first treatment cycle (2-3 weeks) vs baseline levels. Patients with increase in cfDNA concentration of greater than 20% (n = 21) were plotted vs patients showing cfDNA reduction or stability (n = 44). P values were calculated using log-rank test. Median survival is illustrated in months (vertical dashed lines); the horizontal dashed lines indicate the median of both curves. NA indicates not applicable.