FOLFOX Plus Trastuzumab and Nivolumab Demonstrated Promising Efficacy in ERBB2+ Esophagogastric Adenocarcinoma

Although trastuzumab (Herceptin), nivolumab (Opdivo), and ipilimumab (Yervoy) demonstrated comparable overall survival (OS), trastuzumab and nivolumab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) yielded improved efficacy in patients with ERBB2-positive esophagogastric adenocarcinoma, according to findings from the phase 2 AIO INTEGA trial (NCT03409848).

Investigators reported that the 12-month overall survival (OS) rate in the FOLFOX arm was 70% (95% CI, 54%-81%) compared with 57% (95% CI, 41%-71%) in the ipilimumab arm. The median progression-free survival (PFS) was 10.7 months (95% CI, 6.6-13.1) in the FOLFOX arm compared with 3.2 months (95% CI, 2.0-6.5) in the ipilimumab group. The overall response rates in the 2 respective groups were 56% and 32%, with median duration of response of 9.2 months (95% CI, 8.1-13.5) and 5.8 months (95% CI, 2.4–not estimable).

“In this randomized clinical trial, the addition of nivolumab to trastuzumab and chemotherapy in first-line ERBB2-positive EGA resulted in long PFS and OS and should be further developed in a phase 3 trial. The chemotherapy backbone is needed and should not be replaced by ipilimumab in an unselected ERBB2-positive patient population,” the study authors wrote.

The trial included patients who were 18 years or older with pathologically confirmed ERBB2-positive, inoperable, locally advanced or metastatic disease. Patients also needed to have untreated metastatic disease. Previous adjuvant and/or neoadjuvant therapies were allowed provided that they were completed a minimum of 3 months before randomization. Other inclusion criteria included an ECOG performance status of 0 to 2 and adequate hematologic, hepatic, and kidney function.

Patients were randomly assigned 1:1 to receive 6 mg/kg of trastuzumab, 1 mg/kg of nivolumab, and 3 mg/kg of ipilimumab every 3 weeks for 4 cycles followed by 4 mg/kg of trastuzumab and 240 mg of nivolumab every 2 weeks; or 4 mg/kg of intravenous trastuzumab, 240 mg of nivolumab, and modified FOLFOX6, consisting of 85 mg/m² of oxaliplatin, 400 mg/m² of fluorouracil, 400 mg of folinic acid, and 2400 mg/m² of fluorouracil, every 2 weeks.

A total of 97 patients were assessed, of whom 88 underwent randomization. The median patient age was 61 years. Moreover, 61% and 39% of patients had an ECOG performance status of 0 or 1, respectively. Thirty percent of patients received prior perioperative chemotherapy. The study’s median follow-up was 14.3 months.

Additional findings from the study indicated that although quality of life was comparable between arms, the FOLFOX arm experienced a clinically relevant improvement vs baseline in the first 4 months of treatment.

In terms of safety, 82% of patients in the ipilimumab arm and 88% in the FOLFOX arm experienced grade 3 or higher adverse effects (AEs). The most common high-grade AEs in the control group were diarrhea (14%), anemia (11%), infection (11%), and autoimmune hepatitis (9%). In the experimental group, the most common high-grade AEs were leukopenia (23%), infection (16%), fatigue (14%), and neuropathy (11%).

Serious AEs occurred in 77% and 65% of patients in the ipilimumab and FOLFOX arms, respectively. A total of 47 patients discontinued treatment due to disease progression or death, including 27 patients in the ipilimumab arm and 20 in the FOLFOX arm.

Reference

Stein A, Paschold L, Tintelnot J, et al. Efficacy of ipilimumab vs FOLFOX in combination with nivolumab and trastuzumab in patients with previously untreated ERBB2-positive esophagogastric adenocarcinoma. JAMA Oncol. Published online June 23, 2022. doi:10.1001/jamaoncol.2022.2228