1. Overall survival rate at 12 months for the FOLFOX arm and ipilimumab arm was 70% and 57%, respectively.
2. Incidence of adverse events of grades 3 or higher was similar in each group, with a higher incidence of autoimmune events in the ipilimumab arm and a higher incidence of neuropathy in the FOLFOX arm.
Evidence Rating Level: 1 (Excellent)
Study Rundown: In ERBB2-positive esophagogastric adenocarcinoma (EGA), the standard of care is chemotherapy plus trastuzumab. While the addition of immune checkpoint inhibitors has improved outcomes in select ERBB2-negative EGA, their efficacy in ERBB2-positive EGA awaits verification. Another PD-1 inhibitor regimen has preliminary evidence of efficacy in ERBB2-postitive gastric cancer. This study investigated the efficacy of FOLFOX vs. ipilimumab in ERBB2-positive EGA with background nivolumab use. Patients were randomly assigned to receive either FOLFOX or ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 inhibitor), in combination with nivolumab (an anti-programmed death 1 antibody) and trastuzumab (an ERBB2 antibody). In the FOLFOX group, the overall survival (OS) at 12 months was longer, the median progression-free survival (PFS) was longer, and the objective response rate (ORR) was higher. Baseline quality of life was similar in both groups, but the FOLFOX arm showed a clinically relevant improvement in the first four months when compared to baseline. Adverse events of grades 3 or higher occurred similarly in each group and both groups had expected safety profiles. In the ipilimumab arm, there was a higher incidence of autoimmune events, whereas in the FOLFOX group there was a higher incidence of neuropathy and hematological events. Liquid biopsy was performed and circulating cell-free DNA (cf-DNA) was measured, whereby early cf-DNA increase was a strong predictor of shorter PFS and OS. As such, early monitoring of cf-DNA may allow for immediate determination of the efficacy of treatment. Limitations to this study are its small sample size and that it used historical controls for comparisons to the current standard of care and makes cross-trial comparisons difficult. The strengths of this study are that it has limited bias given its design and that it highlighted that a chemotherapy backbone is crucial in unselected ERBB2-postive patients. Overall, the addition of a PD-1 inhibitor to standard trastuzumab plus chemotherapy is a viable option to evaluate in phase 3 studies.
Click to read the study in JAMA Oncology
In-Depth [randomized control trial]: This multicenter phase II trial in Germany randomly assigned 88 patients with ERBB2-positive EGA to receive either FOLFOX or ipilimumab, both in combination with nivolumab and trastuzumab; 44 in the FOLFOX arm and 44 in the ipilimumab arm. The OS after 12 months was 70% (95% confidence interval [CI], 54% to 81%) for the FOLFOX arm and 57% for the ipilimumab arm (95% CI, 41% to 71%). Median PFS was 10.7 months (95% CI, 6.6 to 13.1) for the FOLFOX arm and 3.2 months (95% CI, 2.0 to 6.5) for the ipilimumab arm. ORR was 56% and 32% for the FOLFOX arm and ipilimumab arm, respectively. Adverse events of grades 3 or higher occurred in 88% of patients in the FOLFOX arm and 82% in the ipilimumab arm. Most frequent adverse events in the FOLFOX arm were leukopenia (23%), infection (16%), fatigue (14%), and neuropathy (11%). Most frequent treatment-related adverse events in the ipilimumab arm were anemia (11%), infection (11%), and diarrhea (14%). Liquid biopsy revealed that in one-third of patients, cf-DNA levels increased by more than 20% after the first treatment cycle of 2-3 weeks. This early cf-DNA increase had a strong correlation to shorter PFS and OS. Overall, this study highlights the potential of a chemotherapy backbone, ERRB2 directed therapy and chemotherapy as the possible next standard of care in ERRB2 positive gastric cancer pending further confirmatory studies.
Image: PD
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