Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy

Abstract

Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma, but long-term survival remains limited. In this study, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison with a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% confidence interval, 41%-71%) in the Ipi arm and 70% OS (95% confidence interval, 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analyses demonstrated elevated levels of normetanephrine, cortisol, and IL6 in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil to lymphocyte ratio that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low neutrophil to lymphocyte ratio characterized patients benefiting from immunotherapy and targeted therapy without the need for additional chemotherapy. These data suggest that patient selection based on inflammatory stress-driven immune changes could help customize first-line treatment in patients with advanced HER2-positive esophagogastric adenocarcinoma to potentially improve long-term survival.

Figure 1.

Low levels of systemic stress hormones are associated with long-term survival in the Ipi arm. A, Final OS is shown for the Ipi vs. FOLFOX arm. The number of patients at risk is indicated, and a log-rank test was performed to determine differences in the curves. B, Graphical abstract of the translational analysis. R and NR patients were defined based on the median OS. Serum samples from patients who had higher or lower than median survival in the Ipi arm were screened for metabolites using metabolomic screening (n = 8; random subset of all available patients from the Ipi arm; C) or cytokine/chemokine screening (n = 16; all available serum samples from the Ipi arm; D) as described in the “Materials and Methods” section. Metabolites with a P value < 0.1 are depicted. Fold change (FC) and t test calculations were performed as described in the “Materials and Methods” section.

Figure 2.

Peripheral immune composition in R and NR patients. Pretreatment immune composition and routine laboratory parameters that are potentially associated with response to immunotherapy are shown for R and NR patients in the Ipi (A) or FOLFOX (B) arm. R patients were defined by more than median OS in each arm. Each dot represents one patient. For the Ipi arm (n = 44), data were available for parameters, except for urea (43 values), neutrophils, and LDH (42 values each), and lymphocytes, NLR, and Mg²⁺ (41 values each). In the FOLFOX arm (n = 44), data were complete for most parameters, except for LDH (43 values) and Mg²⁺ (42 values). The median is indicated. C, The concentration of cortisol or normetanephrine was measured using LC-MS and was correlated with the NLR of the individual patient. Serum from 16 patients was analyzed. One sample was excluded because of an outlying NLR value, and two samples were missing an NLR value (n = 13 in the presented data). Each dot represents one patient. Values from two separate measurements were pooled. 95% CI is shown. D, Patients from the Ipi and FOLFOX arms were separated into NLR high (>5) and NLR low (NLR <5). Relative IL6 concentration as measured in Fig. 1D and Supplementary Fig. S2B was compared between NLR-high and NLR-low patients; N = 30 patients. Each dot represents one patient. Mean and upper SD are indicated. E, The NLR was defined per patient at time point pretreatment or cycle 4 of therapy. Each dot represents one patient. Values from similar patients are connected. P values (*, < 0.05; **, < 0.01; ***, < 0.001) were determined by the Mann–Whitney U test (A, B, and D), simple linear regression and Pearson R (C), or Wilcoxon paired-rank test (E). LDH, lactate dehydrogenase; WBC, white blood cells.

Figure 3.

Low NLR and HER2-3+ define patients with superior survival in the Ipi arm. A, HRs of indicated patient- or disease-specific parameters. Univariant (uv) Cox regression analysis was performed in the Ipi arm (n = 44 patients overall). Significant parameters with an HR different than 1 were further tested in a multivariant analysis (mv). OS is shown for patients selected by an NLR <5 (B) or CPS ≥1 + NLR <5 (C) alone or together with HER2-3+ within the Ipi and FOLFOX arms, respectively. The number of patients at risk is indicated. OS not reached is indicated as NR. P values (*, < 0.05; **, < 0.01) were determined by Cox regression analysis (A) or log-rank test (B and C). CEA, carcinoembryonic antigen; LDH, lactate dehydrogenase; WBC, white blood cells.