Abstract
Purpose
The C-reactive protein–albumin–lymphocyte (CALLY) index is a novel immuno-nutritional marker in various cancers. We investigated its prognostic value in patients with unresectable or recurrent gastric cancer who were treated with nivolumab monotherapy.
Materials and Methods
This multicenter retrospective study included 126 patients treated with third- or later-line nivolumab monotherapy. The CALLY index was calculated as (Albumin × Lymphocyte Count)/(C-Reactive Protein × 104) and dichotomized at 1.08. The operating characteristics of this cutoff were evaluated using receiver operating characteristic analysis for 1-year overall survival (OS). OS and progression-free survival (PFS) were evaluated.
Results
The CALLY-low group exhibited a significantly shorter median OS (164 vs. 377 days; P=0.004) and median PFS (56 vs. 104 days; P<0.001) than the CALLY-high group. In multivariable models from which posttreatment immune-related adverse events were excluded, the CALLY index was an independent prognostic factor for both OS (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.31–3.21; P=0.002) and PFS (HR, 2.00; 95% CI, 1.33–3.02; P<0.001) after adjustment for clinically relevant factors.
Conclusions
The pretreatment CALLY index was an independent prognostic biomarker for both OS and PFS in patients with unresectable or recurrent gastric cancer receiving third- or later-line nivolumab monotherapy. By integrating the C-reactive protein levels, albumin levels, and lymphocyte counts, the CALLY index may serve as a practical tool for pretreatment risk stratification in this setting.
Keywords: Biomarkers, Immune checkpoint inhibitors, Nivolumab, Prognosis, Stomach neoplasms
INTRODUCTION
Gastric cancer remains a major global health burden despite improvements in incidence, mortality, and survival [1,2,3,4]. Increasingly, biomarker-guided systemic treatment incorporates human epidermal growth factor receptor 2 (HER2) status, mismatch repair (MMR)/microsatellite instability (MSI) status, and the programmed death-ligand 1 (PD-L1) combined positive score, while the Epstein–Barr virus status has also been associated with sensitivity to immune checkpoint inhibitors (ICIs) [5,6,7]. Nivolumab monotherapy is a guideline-listed later-line option for use in selected patients after failure of at least 2 systemic regimens [8,9]. First-line anti-programmed cell death protein 1 (PD-1) antibody plus chemotherapy is now an established biomarker-informed treatment option, supported by phase 3 trials of nivolumab and pembrolizumab and additional phase 3 evidence for tislelizumab [7,10,11,12,13]. However, a defined subset of patients continues to receive nivolumab monotherapy after multiple regimen failure despite modest response rates and heterogeneous outcomes. Therefore, practical pretreatment markers for risk stratification are needed in this setting.
The clinical outcomes during ICI therapy are influenced by both tumor biology and host immuno-nutritional status. Tumor-based biomarkers are used to inform treatment selection, whereas host-status markers may provide complementary prognostic information about baseline vulnerability rather than predict nivolumab-specific benefit. The prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein-to-albumin ratio (CAR) have been investigated as prognostic markers in gastric cancer, and the baseline inflammatory burden has also been associated with outcomes during therapy with ICIs [14,15,16,17]. However, these indices do not simultaneously capture inflammation, nutrition, and immune competence.
The C-reactive protein–albumin–lymphocyte (CALLY) index is an emerging immuno-nutritional biomarker that integrates systemic inflammation, nutritional status, and immune competence into a single composite measure. The CALLY index has demonstrated prognostic relevance in hepatocellular carcinoma and colorectal cancer [18,19], and recent systematic reviews and meta-analyses across digestive system cancers, as well as gastric cancer cohorts after gastrectomy, have consistently shown that a lower CALLY index is associated with worse survival outcomes [20,21,22]. Nevertheless, the prognostic utility of the pretreatment CALLY index has not been well established in patients with unresectable or recurrent gastric cancer treated with nivolumab. Therefore, we conducted a multicenter retrospective study to evaluate the prognostic value of the pretreatment CALLY index in patients with unresectable or recurrent gastric cancer treated with third- or later-line nivolumab monotherapy. We aimed to determine whether the CALLY index could serve as a practical, integrated biomarker for pretreatment risk stratification in this patient population.
MATERIALS AND METHODS
Study design and patients
This multicenter retrospective observational study was conducted at 3 hospitals affiliated with The Jikei University School of Medicine. A total of 185 patients with unresectable or recurrent gastric cancer were initially screened according to the general eligibility criteria at these institutions. Of these, 58 patients were excluded because they had received nivolumab-based combination therapy. Among the remaining 127 patients who received nivolumab monotherapy, 1 patient was further excluded because nivolumab was administered as first-line treatment due to advanced age. Ultimately, 126 patients with histologically confirmed unresectable or recurrent gastric cancer, including gastroesophageal junction adenocarcinoma, who received nivolumab monotherapy as third- or later-line treatment between July 2017 and November 2023 were included in the final retrospective analysis. Third- or later-line nivolumab monotherapy was defined as nivolumab administered after at least 2 systemic chemotherapy regimens.
The main eligibility criteria were as follows: (1) age ≥20 years; (2) an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2; and (3) the availability of blood test data required to calculate the CALLY index before the initial administration of nivolumab, including data for the levels of C-reactive protein and serum albumin, and total lymphocyte count. The main exclusion criteria were as follows: (1) presence of other active malignancies; (2) uncontrolled infection before nivolumab initiation; and (3) insufficient clinical data. This study was approved by the Ethics Committee of The Jikei University School of Medicine (approval number 34-147) and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained using an opt-out approach.
Data collection and variables
The clinical data of eligible patients were retrospectively collected from the medical records of each institution. The baseline clinicopathological variables for which data were collected included age, sex, ECOG PS, body mass index, tumor size, tumor location at the esophagogastric junction, histological type, Borrmann type, HER2 status, number of metastatic organs, presence of peritoneal metastasis, presence of distant lymph node metastasis, serum tumor marker (carcinoembryonic antigen and carbohydrate antigen 19-9 [CA19-9]) levels, number of chemotherapy regimens administered before nivolumab therapy, history of gastrectomy, and history of resection of recurrent lesions. For postoperative recurrence, tumor size was defined as the maximum diameter of the primary tumor in the resected pathological specimen; for disease that was initially unresectable, tumor size was defined as the longest diameter of the primary tumor, in millimeters, measured endoscopically or radiologically before initiation of nivolumab therapy. Histology was classified according to the predominant type in the Japanese classification of gastric carcinoma: papillary and tubular adenocarcinomas were classified as differentiated, whereas poorly differentiated adenocarcinomas and signet-ring cell carcinomas were classified as undifferentiated. Unavailable or unevaluable cases were classified as unknown and excluded from both histological categories. Posttreatment immune-related adverse events (irAEs) and subsequent therapy were assessed separately from baseline variables; irAEs were limited to those events that led to treatment delay or discontinuation, and subsequent therapy was treated as a post-baseline factor.
Outcome definitions
The primary endpoint was overall survival (OS), defined as the time from initiation of nivolumab therapy to death from any cause or last follow-up. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and disease control rate. PFS was defined as the time from nivolumab initiation to radiological or clinical progression or death. Response and progression were assessed by the treating investigators according to the RECIST version 1.1 guidelines. When no radiological progression date was available, the last date of nivolumab administration was used for clinically judged progression; other discontinuations without progression were censored at the last disease assessment. The final data cutoff was April 7, 2025.
Definition and calculation of the CALLY index
The CALLY index was calculated using a single pretreatment blood sample obtained within 1 week before the initial administration of nivolumab according to the following formula:
| CALLY Index = (Serum Albumin [g/dL] × Total Lymphocyte Count [/μL])/(C-Reactive Protein [mg/dL] × 104) |
A cutoff of 1.08 was used for the primary dichotomous analysis, with patients categorized into the CALLY-high (≥1.08) and CALLY-low (<1.08) groups. Because lower CALLY index values indicate higher risk, receiver operating characteristic analysis for the 1-year OS was performed using the inverse of the CALLY index as the predictor. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and Youden index (Sensitivity + Specificity − 1) were calculated, and the operating characteristics of the 1.08 cutoff were compared with the maximum Youden threshold. The receiver operating characteristic results are presented in Supplementary Table 1 and Supplementary Fig. 1.
Calculation of nutritional and inflammatory indices
In the exploratory analyses, additional nutritional and inflammatory indices were calculated using pretreatment laboratory data obtained within 1 week before the initial administration of nivolumab. The PLR was calculated as the platelet count divided by the total lymphocyte count, and the NLR as the neutrophil count divided by the total lymphocyte count. The lymphocyte to C-reactive protein ratio (LCR) was calculated as the total lymphocyte count divided by the C-reactive protein level, and the CAR was calculated as the C-reactive protein level divided by the serum albumin level. The PNI was calculated as 10 × Serum Albumin (g/dL) + 0.005 × Total Lymphocyte Count (/μL). The Japanese Modified Glasgow Prognostic Score (mGPS) was assigned as follows: patients with both a C-reactive protein level of >0.5 mg/dL and a serum albumin level of <3.5 g/dL were assigned a score of 2; those with either a C-reactive protein level of >0.5 mg/dL or a serum albumin level of <3.5 g/dL were assigned a score of 1; and those with neither abnormality were assigned a score of 0. The cutoff values for the PLR, NLR, LCR, CAR, and PNI were determined using receiver operating characteristic curve analysis for 1-year OS. For the mGPS, a score of 2 was defined as mGPS-high; scores of 0 to 1 were defined as mGPS-low.
Statistical analysis
Continuous variables are expressed as medians with interquartile ranges, and categorical variables are summarized as frequencies and percentages. Clinicopathological factors were compared between the CALLY-high and CALLY-low groups using the Mann-Whitney U test for continuous variables and the χ2 test (with Yates’ continuity correction for 2×2 tables) for categorical variables; Fisher’s exact test was used when any expected cell count was less than 5. OS and PFS were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. To identify prognostic factors for OS and PFS, Cox proportional hazards models were fitted in univariable and multivariable analyses. Candidate variables for multivariable modeling were selected based on previous reports and clinical relevance. The candidate variables were sex, age, ECOG PS, tumor location at the esophagogastric junction, tumor size, histological type, HER2 status, CALLY index, baseline tumor marker (carcinoembryonic antigen and CA19-9) levels, presence of peritoneal metastasis, presence of distant lymph node metastasis, number of metastatic organs, and previous gastrectomy. Variables with a P-value of <0.10 in the univariable analysis were included in the multivariable model. Because irAEs occurred after initiation of nivolumab therapy and may have introduced immortal time bias, irAEs were not included in candidate screening or primary multivariable models. Their frequency is descriptively presented in a separate posttreatment section of Table 1 without a between-group hypothesis test. Sensitivity analyses were performed by forcing previous gastrectomy into the multivariable models. In the primary models, the HER2 status was analyzed as positive vs. negative among patients with a known HER2 status; patients with an unknown HER2 status were excluded using complete-case analysis for this covariate. In the additional sensitivity analyses, HER2 status was treated using the categories of positive, negative, and unknown or using categories of positive vs. nonpositive, with the latter group including negative and unknown cases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. As supplementary robustness analyses, the CALLY index was modeled as a log2-transformed continuous variable (HR per doubling) and as tertiles. Exploratory univariable Cox analyses and pairwise comparisons of 1-year time-dependent AUCs were used to evaluate the CALLY index alongside other nutritional and inflammatory indices; these analyses were not designed to establish marker superiority. Comprehensive formal discrimination comparisons, such as C-index analyses or likelihood-ratio tests, were not performed. The Fisher’s exact test was used to compare the ORR and disease control rate between the groups. A 2-sided P-value of <0.05 was considered statistically significant. All statistical analyses were performed using R software (version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria) [23] in the RStudio environment [24]. EZR (Easy R) version 1.68 (Jichi Medical University Saitama Medical Center, Saitama, Japan) [25], a graphical user interface for R, was also used to perform the statistical analyses.
Table 1. Patient characteristics according to pretreatment CALLY index grouping.
| Variables | Overall (n=126) | CALLY-high group (n=67) | CALLY-low group (n=59) | P | |
|---|---|---|---|---|---|
| Age (yr) | 72 (65–77) | 72 (64–77) | 72 (65–78) | 0.841 | |
| Sex | 0.945 | ||||
| Male | 89 (70.6) | 48 (71.6) | 41 (69.5) | ||
| Female | 37 (29.4) | 19 (28.4) | 18 (30.5) | ||
| Body mass index (kg/m2) | 19.7 (17.8–22.0) | 20.2 (18.0–21.9) | 19.6 (17.6–22.2) | 0.592 | |
| ECOG PS | 0.149 | ||||
| 0 | 63 (50.0) | 39 (58.2) | 24 (40.7) | ||
| 1 | 59 (46.8) | 26 (38.8) | 33 (55.9) | ||
| 2 | 4 (3.2) | 2 (3.0) | 2 (3.4) | ||
| Carcinoembryonic antigen (ng/mL) | 8.8 (4.6–26.1) | 8.0 (5.2–22.0) | 9.3 (4.3–33.4) | 0.776 | |
| CA19-9 (U/mL) | 32 (16–76) | 29 (12–63) | 35 (23–137) | 0.045 | |
| Tumor size (mm) | 50 (40–70) | 50 (40–72) | 50 (39–68) | 0.706 | |
| Tumor at EGJ | 0.045 | ||||
| Yes | 18 (14.3) | 14 (20.9) | 4 (6.8) | ||
| No | 108 (85.7) | 53 (79.1) | 55 (93.2) | ||
| Borrmann type | 0.415 | ||||
| Type 4 | 29 (23.0) | 13 (19.4) | 16 (27.1) | ||
| Others | 97 (77.0) | 54 (80.6) | 43 (72.9) | ||
| Histological type | 0.172 | ||||
| Differentiated | 57 (45.2) | 35 (52.2) | 22 (37.3) | ||
| Undifferentiated | 67 (53.2) | 31 (46.3) | 36 (61.0) | ||
| Unknown | 2 (1.6) | 1 (1.5) | 1 (1.7) | ||
| HER2 status | 0.086 | ||||
| Positive | 20 (15.9) | 14 (20.9) | 6 (10.2) | ||
| Negative | 93 (73.8) | 44 (65.7) | 49 (83.1) | ||
| Unknown | 13 (10.3) | 9 (13.4) | 4 (6.8) | ||
| No. of metastatic organs | 0.873 | ||||
| 1 | 81 (64.3) | 44 (65.7) | 37 (62.7) | ||
| ≥2 | 45 (35.7) | 23 (34.3) | 22 (37.3) | ||
| Peritoneal metastasis | 0.569 | ||||
| Yes | 66 (52.4) | 33 (49.3) | 33 (55.9) | ||
| No | 60 (47.6) | 34 (50.7) | 26 (44.1) | ||
| Lymph node metastasis | 0.402 | ||||
| Yes | 53 (42.1) | 31 (46.3) | 22 (37.3) | ||
| No | 73 (57.9) | 36 (53.7) | 37 (62.7) | ||
| No. of previous chemotherapy regimens | 0.513 | ||||
| 2 | 90 (71.4) | 46 (68.7) | 44 (74.6) | ||
| 3 | 29 (23.0) | 18 (26.9) | 11 (18.6) | ||
| 4 | 7 (5.6) | 3 (4.5) | 4 (6.8) | ||
| Previous gastrectomy | 0.006 | ||||
| Yes | 58 (46.0) | 39 (58.2) | 19 (32.2) | ||
| No | 68 (54.0) | 28 (41.8) | 40 (67.8) | ||
| Resection of recurrent lesions | 0.281 | ||||
| Yes | 8 (6.3) | 6 (9.0) | 2 (3.4) | ||
| No | 118 (93.7) | 61 (91.0) | 57 (96.6) | ||
| Posttreatment descriptive information | |||||
| irAEs leading to treatment delay or discontinuation | 21 (16.7) | 13 (19.4) | 8 (13.6) | ||
Values are shown as median (interquartile range) or number (%). CALLY-high and CALLY-low were defined as a CALLY index of ≥1.08 and one of <1.08, respectively. Posttreatment irAEs are reported descriptively; no between-group test was performed.
CALLY = C-reactive protein–albumin–lymphocyte; ECOG PS = Eastern Cooperative Oncology Group Performance Status; CA19-9 = carbohydrate antigen 19-9; EGJ = esophagogastric junction; HER2 = human epidermal growth factor receptor 2; irAE = immune-related adverse event.
RESULTS
Patient characteristics
A total of 126 patients were included in this study and were dichotomized into the CALLY-high (n=67) and CALLY-low (n=59) groups. The patient characteristics are summarized in Table 1. All patients had received at least 2 systemic chemotherapy regimens before nivolumab treatment was initiated; 90 patients (71.4%) had received 2 regimens, 29 (23.0%) had received 3, and 7 (5.6%) had received 4. The median age of the entire cohort was 72.0 years, and 89 patients (70.6%) were male. A history of gastrectomy was more frequent in the CALLY-high group than in the CALLY-low group (58.2% vs. 32.2%; P=0.006). Nominal between-group differences were observed for the CA19-9 levels and tumor location at the esophagogastric junction (both P=0.045); no other significant differences in baseline clinicopathological characteristics were observed. Consistent with the index definition, the CALLY-low group had a higher pretreatment C-reactive protein level (median, 1.13 vs. 0.11 mg/dL), lower serum albumin level (3.0 vs. 3.5 g/dL), and lower total lymphocyte count (1,341 vs. 1,602/μL) than the CALLY-high group (Supplementary Table 2). In the separate section of Table 1 in which posttreatment characteristics are presented, irAEs leading to treatment delay or discontinuation were documented in 21 patients (16.7%): 13 of 67 patients (19.4%) in the CALLY-high group and 8 of 59 patients (13.6%) in the CALLY-low group. Subsequent therapy after nivolumab treatment was treated as a post-baseline factor and was more frequently administered in the CALLY-high group than in the CALLY-low group (49.3% vs. 28.8%; unadjusted P=0.031).
Survival analysis
Kaplan-Meier analysis demonstrated that the CALLY-high group had significantly longer OS than the CALLY-low group (log-rank test, P=0.004; Fig. 1). The median OS was 377 days (95% CI, 229–495) in the CALLY-high group, compared with 164 days (95% CI, 128–284) in the CALLY-low group; the 1-year OS rates were 53.7% and 23.7%, respectively. PFS was significantly longer in the CALLY-high group (log-rank test, P<0.001). The median PFS was 104 days (95% CI, 70–170) in the CALLY-high group and 56 days (95% CI, 39–81) in the CALLY-low group. The 1-year PFS rates were 23.9% in the CALLY-high group and 5.1% in the CALLY-low group.
Fig. 1. Kaplan–Meier curves for OS and PFS according to pretreatment CALLY index group. (A) OS. (B) PFS. The blue line indicates the CALLY-high group, and the orange line indicates the CALLY-low group. Shaded areas indicate 95% confidence intervals. P-values were calculated using the log-rank test. Numbers at risk are shown below each panel.
OS = overall survival; PFS = progression-free survival; CALLY = C-reactive protein–albumin–lymphocyte.
Receiver operating characteristic analysis for 1-year OS yielded an AUC of 0.660 (95% CI, 0.565–0.754). The maximum Youden operating point corresponded to a threshold of 1.05, with a sensitivity of 0.592, specificity of 0.720, and Youden index of 0.312. Because no patient had a CALLY index of between 1.05 and 1.08, the 2 thresholds produced identical patient classifications and operating characteristics; therefore, 1.08 was retained for the primary dichotomous analysis (Supplementary Table 1, Supplementary Fig. 1).
Treatment response
The CALLY-high group showed a numerically higher ORR than the CALLY-low group, although the difference did not reach statistical significance; the disease control rate also did not differ significantly between the groups (Table 2). The ORRs were 10.4% and 1.7% (P=0.066) and the disease control rates 28.4% and 20.3% (P=0.310) in the CALLY-high and CALLY-low groups, respectively; 45 patients (35.7%) were not evaluable for response.
Table 2. ORR and DCR according to the pretreatment CALLY index grouping.
| Variables | Overall (n=126) | CALLY-high group (n=67) | CALLY-low group (n=59) | P | |
|---|---|---|---|---|---|
| Best overall response | 0.214 | ||||
| CR | 3 (2.4) | 3 (4.5) | 0 (0.0) | ||
| PR | 5 (4.0) | 4 (6.0) | 1 (1.7) | ||
| SD | 23 (18.3) | 12 (17.9) | 11 (18.6) | ||
| PD | 50 (39.7) | 22 (32.8) | 28 (47.5) | ||
| NE | 45 (35.7) | 26 (38.8) | 19 (32.2) | ||
| ORR | 8 (6.3) | 7 (10.4) | 1 (1.7) | 0.066 | |
| DCR | 31 (24.6) | 19 (28.4) | 12 (20.3) | 0.310 | |
Values are presented as number (%). ORR was defined as CR + PR, and DCR as CR + PR + SD.
Rates were calculated using all patients in each group as the denominator.
CALLY = C-reactive protein–albumin–lymphocyte; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable; ORR = objective response rate; DCR = disease control rate.
Prognostic factors for OS
In the primary multivariable analysis from which irAEs were excluded, the CALLY index was identified as an independent prognostic factor for OS (Table 3). Patients in the CALLY-low group had a HR of 2.05 (95% CI, 1.31–3.21; P=0.002) compared with the CALLY-high group. The ECOG PS (HR, 2.55; 95% CI, 1.65–3.92; P<0.001) and CA19-9 levels (HR, 1.69; 95% CI, 1.11–2.58; P=0.015) were independently associated with poor survival. Peritoneal metastasis was not independently associated with OS (P=0.098).
Table 3. Univariable and multivariable analyses of risk factors for overall survival.
| Variables | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Sex (male vs. female) | 0.77 (0.51–1.14) | 0.190 | - | - |
| Age (>72 vs. ≤72 yr)* | 1.05 (0.73–1.52) | 0.787 | - | - |
| ECOG PS (1–2 vs. 0) | 1.96 (1.35–2.84) | <0.001 | 2.55 (1.65–3.92) | <0.001 |
| Tumor at EGJ (yes vs. no) | 0.58 (0.34–0.99) | 0.048 | 0.77 (0.42–1.41) | 0.398 |
| Tumor size (>50 mm vs. ≤50 mm)* | 0.97 (0.67–1.41) | 0.887 | - | - |
| Histological type (undifferentiated vs. differentiated) | 1.30 (0.90–1.87) | 0.169 | - | - |
| HER2 status (positive vs. negative) | 0.63 (0.38–1.04) | 0.071 | 0.57 (0.32–1.02) | 0.056 |
| CALLY index (CALLY-low vs. CALLY-high) | 1.72 (1.19–2.48) | 0.004 | 2.05 (1.31–3.21) | 0.002 |
| Carcinoembryonic antigen level (>5 ng/mL vs. ≤5 ng/mL) | 1.03 (0.68–1.54) | 0.901 | - | - |
| CA19-9 level (>37 U/mL vs. ≤37 U/mL) | 1.57 (1.08–2.28) | 0.019 | 1.69 (1.11–2.58) | 0.015 |
| Peritoneal metastasis (yes vs. no) | 1.46 (1.02–2.11) | 0.041 | 1.48 (0.93–2.34) | 0.098 |
| Lymph node metastasis (yes vs. no) | 0.60 (0.41–0.88) | 0.008 | 0.75 (0.47–1.19) | 0.221 |
| No. of metastatic organs (1 vs. ≥2) | 0.87 (0.59–1.28) | 0.483 | - | - |
| Previous gastrectomy (yes vs. no) | 0.78 (0.54–1.13) | 0.194 | - | - |
Variables with P<0.10 in univariable analysis were entered into the multivariable model. The model included 109 patients and 100 deaths; HER2-unknown cases were excluded using complete-case analysis.
HR = hazard ratio; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGJ = esophagogastric junction; HER2 = human epidermal growth factor receptor 2; CALLY = C-reactive protein–albumin–lymphocyte; CA19-9 = carbohydrate antigen 19-9.
*Age and tumor size were dichotomized at the median of the cohort.
Prognostic factors for PFS
Consistent with the OS results, the CALLY index also demonstrated independent prognostic value for PFS in the primary multivariable analysis from which irAEs were excluded (Table 4). The CALLY-low group was significantly associated with a higher risk of progression (HR, 2.00; 95% CI, 1.33–3.02; P<0.001). Along with the CALLY index, the ECOG PS was also identified as an independent prognostic factor (HR, 1.60; 95% CI, 1.07–2.38; P=0.021), whereas peritoneal metastasis did not retain statistical significance (P=0.158).
Table 4. Univariable and multivariable analyses of risk factors for progression-free survival.
| Variables | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Sex (male vs. female) | 0.79 (0.53–1.18) | 0.249 | - | - |
| Age (>72 vs. ≤72 yr)* | 0.92 (0.64–1.32) | 0.646 | - | - |
| ECOG PS (1–2 vs. 0) | 1.68 (1.17–2.42) | 0.005 | 1.60 (1.07–2.38) | 0.021 |
| Tumor at EGJ (yes vs. no) | 0.75 (0.45–1.26) | 0.277 | - | - |
| Tumor size (>50 mm vs. ≤50 mm)* | 0.95 (0.66–1.37) | 0.787 | - | - |
| Histological type (undifferentiated vs. differentiated) | 1.16 (0.81–1.68) | 0.415 | - | - |
| HER2 status (positive vs. negative) | 0.66 (0.40–1.07) | 0.091 | 0.69 (0.42–1.14) | 0.146 |
| CALLY index (CALLY-low vs. CALLY-high) | 1.92 (1.33–2.77) | <0.001 | 2.00 (1.33–3.02) | <0.001 |
| Carcinoembryonic antigen level (>5 ng/mL vs. ≤5 ng/mL) | 0.96 (0.64–1.44) | 0.830 | - | - |
| CA19-9 level (>37 U/mL vs. ≤37 U/mL) | 1.36 (0.94–1.96) | 0.101 | - | - |
| Peritoneal metastasis (yes vs. no) | 1.41 (0.98–2.02) | 0.061 | 1.37 (0.89–2.11) | 0.158 |
| Lymph node metastasis (yes vs. no) | 0.71 (0.49–1.02) | 0.065 | 0.90 (0.58–1.40) | 0.645 |
| No. of metastatic organs (1 vs. ≥2) | 1.09 (0.74–1.58) | 0.670 | - | - |
| Previous gastrectomy (yes vs. no) | 0.75 (0.52–1.07) | 0.116 | - | - |
Variables with P<0.10 in univariable analysis were entered into the multivariable model. The model included 113 patients and 107 progression-free survival events; HER2-unknown cases were excluded using complete-case analysis.
HR = hazard ratio; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGJ = esophagogastric junction; HER2 = human epidermal growth factor receptor 2; CALLY = C-reactive protein–albumin–lymphocyte; CA19-9 = carbohydrate antigen 19-9.
*Age and tumor size were dichotomized at the median of the cohort.
When previous gastrectomy was forced into the multivariable models, the CALLY-low group remained significantly associated with a shorter OS (HR, 1.94; 95% CI, 1.23–3.07; P=0.005) and PFS (HR, 1.87; 95% CI, 1.22–2.89; P=0.004). In the sensitivity analyses addressing HER2-unknown cases, the association of CALLY-low status with poorer outcomes remained significant when the HER2 status was modeled using the categories of positive, negative, and unknown (OS: HR, 1.59; 95% CI, 1.04–2.42; P=0.031 and PFS: HR, 1.64; 95% CI, 1.09–2.47; P=0.017) and when HER2-negative and HER2-unknown cases were grouped as nonpositive (OS: HR, 1.59; 95% CI, 1.05–2.43; P=0.030 and PFS: HR, 1.65; 95% CI, 1.09–2.47; P=0.017). These sensitivity analyses are detailed in Supplementary Table 3.
Additional analyses of the CALLY index
In the supplementary univariable analyses, a higher continuous CALLY index was associated with lower hazards of death (HR, 0.88 per doubling; 95% CI, 0.81–0.96; P=0.003) and progression (HR, 0.87 per doubling; 95% CI, 0.81–0.95; P<0.001). Compared with the highest tertile, the lowest tertile was associated with a shorter OS (HR, 1.85; 95% CI, 1.18–2.90; P=0.007) and PFS (HR, 1.70; 95% CI, 1.09–2.66; P=0.019), whereas the middle tertile did not differ significantly from the highest. Thus, the association was not solely dependent on the cutoff of 1.08, although the tertile separation was concentrated in the lowest group (Supplementary Table 4).
Exploratory comparative analyses of nutritional and inflammatory indices
Exploratory univariable analyses showed that the CALLY index was associated with both OS (HR, 1.72; 95% CI, 1.19–2.48; P=0.004) and PFS (HR, 1.92; 95% CI, 1.33–2.77; P<0.001). The PLR, NLR, LCR, and CAR were also associated with both outcomes, whereas the mGPS was only associated with PFS and the PNI was only associated with OS (Supplementary Table 5). Pairwise comparisons of 1-year time-dependent AUCs showed no statistically significant differences between the CALLY index and LCR, PLR, NLR, mGPS, or PNI. A nominal unadjusted difference was observed for the CAR (P=0.039), but this exploratory comparison was not interpreted as evidence of superiority (Supplementary Table 6).
DISCUSSION
Our findings extend previous evidence on the CALLY index from surgical cohorts and ICI-treated cancer cohorts to patients receiving third- or later-line nivolumab monotherapy for unresectable or recurrent gastric cancer [20,21,22,26,27,28]. A low pretreatment CALLY index was independently associated with shorter OS and PFS, whereas the numerically higher ORR in the CALLY-high group did not reach statistical significance. First-line treatment options have also diversified, with zolbetuximab-based regimens being used for CLDN18.2-positive, HER2-negative disease [29,30], underscoring that this later-line cohort should be interpreted within an evolving treatment landscape. Because this was a single-arm cohort without a non-nivolumab comparator, the study findings cannot be used to determine whether the CALLY index predicts nivolumab-specific treatment benefit. The index should therefore be interpreted as a prognostic host-status marker for patients receiving nivolumab and as a complement to, rather than a replacement for, tumor-based predictive biomarkers.
Biologically, the CALLY index integrates systemic inflammation reflected by C-reactive protein levels, nutritional status reflected by albumin levels, and immune competence reflected by the peripheral lymphocyte count. These host domains may influence outcomes during PD-1 blockade through effects on antitumor immunity and cancer cachexia [15,31]. In a recent study, the baseline inflammatory burden was associated with primary resistance to first-line ICI plus chemotherapy; however, that predictive, combination-therapy context differs from the single-arm later-line nivolumab cohort of the present study [17]. The continuous analysis and excess risk observed in the lowest CALLY tertile support the robustness of the prognostic association, although the absence of a clear difference between the middle and highest tertiles does not establish a clear graded dose–response relationship.
Several other inflammatory and nutritional indices were also associated with outcomes, indicating that host status is broadly prognostic in this setting. The CALLY index offers the practical advantage of combining inflammation, nutrition, and lymphocyte-related immune status in a single readily available measure. Because these indices share overlapping components (C-reactive protein level, albumin level, and lymphocyte, platelet, or neutrophil counts), they were evaluated in separate exploratory univariable analyses rather than entered jointly into the same multivariable model. The exploratory AUC comparisons did not establish superiority over the NLR, PLR, LCR, CAR, mGPS, or PNI [32,33]. The CALLY index should therefore be viewed as an integrated option for risk stratification rather than as a uniquely superior blood-based marker.
Previous gastrectomy was substantially more frequent in the CALLY-high group. An unresected primary tumor may contribute to bleeding, stenosis, inflammation, and impaired oral intake, potentially lowering the CALLY index. However, previous gastrectomy may also correlate with disease biology, recurrence pattern, treatment sequencing, and fitness for subsequent therapy. Importantly, forcing previous gastrectomy into the multivariable models did not eliminate the association between a low CALLY status and shorter OS or PFS. Subsequent therapy was also more frequent in the CALLY-high group and may have contributed to the difference observed in OS; because subsequent therapy is a post-baseline consequence of clinical course and treatment eligibility, it was not included as a baseline covariate in the primary models. Nevertheless, the association observed between the CALLY index and PFS, which is determined before post-progression therapy, suggests that the imbalance in subsequent therapy does not fully account for the observed associations. Residual confounding from these factors is unavoidable.
From a clinical perspective, using the CALLY index may help identify patients with a vulnerable immuno-nutritional profile who warrant closer monitoring and early nutritional or supportive assessment before and during nivolumab therapy. This use reflects risk stratification, not treatment selection: a low CALLY index alone should not be used to withhold nivolumab therapy. Whether interventions directed at nutrition or systemic inflammation can improve outcomes requires prospective evaluation.
The HER2 status may influence later-line prognosis through access to HER2-directed treatments [5,34,35]. HER2 positivity was not significantly associated with outcomes in the primary complete-case analyses. In sensitivity analyses accounting for the 13 HER2-unknown cases, the association between a low CALLY status and poor outcomes was attenuated, but remained statistically significant whether unknown status was modeled as a separate category or grouped with HER2-negative cases as a nonpositive category. The combined positive score for PD-L1 is also relevant to ICI treatment selection, but testing was not routinely required during the early period of later-line nivolumab use in Japan; combined positive score data were therefore unavailable for most patients and could not be included in the prognostic analyses.
Because irAEs are posttreatment, time-dependent events, they were excluded from candidate screening and the primary Cox models to avoid immortal time bias; therefore, they are only reported descriptively. Their association with prognosis cannot be evaluated reliably using a conventional baseline-covariate model and should be examined in future studies using landmark or time-varying analyses [36].
Several limitations should be acknowledged. This retrospective study had a modest sample size and the findings may have been affected by selection bias and residual confounding. The combined positive score for PD-L1 and other clinically relevant variables—including the MMR/MSI status, Epstein–Barr virus status, presence of malignant ascites, and trastuzumab deruxtecan use in HER2-positive disease—were not consistently available. Although patients treated with first-line nivolumab or nivolumab-based combination therapy were excluded, previous exposure to other ICIs was not systematically recorded; therefore, complete ICI-naive status before nivolumab initiation could not be confirmed, and residual misclassification cannot be fully excluded. The cutoff of 1.08 was evaluated in the same cohort in which outcomes were analyzed and may therefore be optimistic. Although continuous and tertile analyses reduced dependence on a single dichotomy, spline-based modeling, formal internal validation (e.g., bootstrap optimism correction), and external validation were not performed and remain necessary. Comprehensive model-level discrimination comparisons, such as C-index or likelihood-ratio analyses, were also not performed. Finally, post-baseline treatment, treatment sequencing, inter-institutional laboratory variation, and transient non-tumor-related inflammation may have influenced the observed associations.
In conclusion, the pretreatment CALLY index was an independent prognostic biomarker for OS and PFS in patients with unresectable or recurrent gastric cancer receiving third- or later-line nivolumab monotherapy. By integrating the C-reactive protein level, albumin level, and lymphocyte count, the CALLY index provides an objective summary of immuno-nutritional status and may serve as a practical tool for pretreatment risk stratification in this setting.
Footnotes
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: 1F.M.
- Formal analysis: T.K.
- Investigation: T.K.
- Methodology: T.K.
- Resources: T.K., S.M., S.K., 1F.M., 2F.M., F.N., I.Y., T.Y.
- Supervision: 1F.M.
- Validation: T.K.
- Writing - original draft: T.K.
- Writing - review & editing: T.K., Y.F., E.K.
1F.M., Muneharu Fujisaki; 2F.M., Mizuki Fukuda.
SUPPLEMENTARY MATERIALS
ROC analysis for 1-year overall survival
Baseline CALLY component values by CALLY group
Cox sensitivity analyses
CALLY continuous and tertile analyses
Exploratory univariable marker analyses
Exploratory comparison of 1-year time-dependent AUCs
ROC curve for 1-year overall survival. The inverse C-reactive protein–albumin–lymphocyte index was used because lower values indicate higher risk.
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Associated Data
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Supplementary Materials
ROC analysis for 1-year overall survival
Baseline CALLY component values by CALLY group
Cox sensitivity analyses
CALLY continuous and tertile analyses
Exploratory univariable marker analyses
Exploratory comparison of 1-year time-dependent AUCs
ROC curve for 1-year overall survival. The inverse C-reactive protein–albumin–lymphocyte index was used because lower values indicate higher risk.