Nivolumab Combined with Chemotherapy in FGFR2 and PD-L1 Co- Expressing Metastatic Gastric Cancer: A Prospective Phase 2 NIVOFGFR2 Study

doi:10.21203/rs.3.rs-5023943/v1

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Nivolumab Combined with Chemotherapy in FGFR2 and PD-L1 Co- Expressing Metastatic Gastric Cancer: A Prospective Phase 2 NIVOFGFR2 Study

https://doi.org/10.21203/rs.3.rs-5023943/v1

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Background

Immunotherapy is increasingly significant in treating metastatic gastric cancer. This prospective phase 2 study investigates the efficacy and safety of combining nivolumab with chemotherapy in patients with metastatic gastric cancer co-expressing FGFR2 and PD-L1.

Methods

Eligible patients were aged 18 years or older, with previously untreated HER-2 negative, PD-L1 positive, and FGFR2 positive metastatic gastric adenocarcinoma. Patients received nivolumab (360 mg every 3 weeks) in combination with chemotherapy (CAPOX: capecitabine 1000 mg/m² twice daily on days 1–14 and oxaliplatin 130 mg/m² on day 1, every 3 weeks). Tumor assessments were conducted using RECIST v1.1 every 8 weeks for 48 weeks, then every 12 weeks. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), objective response rate (ORR), and grade ≥ 3 adverse events (AEs).

Results

From June 2022 to October 2023, 194 patients were assessed for eligibility, with 23 patients enrolled and treated. At a median follow-up of 17.3 months, the 1-year PFS rate was 30.4%, with a median PFS of 6.0 months (95% CI, 4.3–7.7). The median OS was 15.1 months (95% CI, 13.2–16.8). The ORR was 21.7%, with one complete response and four partial responses. Grade 3 or higher TRAEs were reported in 34.8% of patients, primarily associated with chemotherapy. No treatment-related deaths occurred.

Conclusions

While the primary endpoint of improved 1-year PFS rate was not met, the study offers valuable insights into the potential benefits of combining nivolumab with chemotherapy in FGFR2 and PD-L1 co-expressing metastatic gastric cancer. Future research should optimize patient selection, assess combined immunotherapy and targeted anti-FGFR2 therapy, and further investigate the role of subsequent treatments to maximize therapeutic benefits.

metastatic gastric cancer

nivolumab

chemotherapy

FGFR2 overexpression

PD-L1 expression

First-line nivolumab in combination with chemotherapy is the standard for the treatment of metastatic HER2–negative gastric adenocarcinoma expressing PD-L1 [1]. After 4 years of follow-up in the randomized phase 3 Checkmate 649 study, nivolumab combined with chemotherapy continued to demonstrate clinically significant improvements in overall survival (OS), with sustained separation of the Kaplan-Meier curves, higher objective response rates, and continued progression-free survival (PFS) benefits, particularly in patients with PD-L1 combined positive score (CPS) ≥ 5 [2]. The 4-year OS rate for these patients was twice as high in the immunochemotherapy group compared to the chemotherapy group, at 17% versus 8%, respectively. The median OS was 14.4 months in the immunochemotherapy group versus 11.1 months in the chemotherapy group (HR = 0.7). The 4-year PFS rate was also significantly better in the nivolumab group compared to chemotherapy alone (HR = 0.71), at 12% versus 7%, with median PFS of 8.3 months and 6.1 months. Additionally, the objective response rate was higher in the immunochemotherapy group, at 60% compared to 45%.

In instances where the disease progressed after first-line therapy, PFS2 still favored the nivolumab plus chemotherapy group over chemotherapy alone, with a median of 13.7 months compared to 9.8 months (HR = 0.67). The updated analysis of quality-adjusted time without symptoms and toxicity also demonstrated improved outcomes for the nivolumab and chemotherapy combination [3].

The instability of the fibroblast growth factor receptor 2 (FGFR2) signaling pathway, caused by the accumulation of genetic and molecular alterations, is linked to the development and progression of gastric cancer [4]. FGFR2 is overexpressed in 30% of gastric cancer patients. It is known to mediate various processes such as angiogenesis, cell proliferation, survival, and differentiation by activating downstream signaling pathways like RAS, RAF, and MAPK [5]. Moreover, FGFR2 plays a crucial role in shaping the tumor microenvironment, which affects resistance to checkpoint inhibitors [6]. Therefore, FGFR2 presents a promising alternative target for therapy. Recently, monoclonal antibodies and allosteric extracellular inhibitors have been developed to neutralize FGFR2 [7, 8].

The efficacy of first-line immunotherapy in patients with FGFR2 expression has not been previously studied. The NIVOFGFR2 study aimed to evaluate the preliminary efficacy of first-line nivolumab in combination with chemotherapy in metastatic gastric cancer co-expressing PD-L1 and FGFR2.

Study design and participants

This is a single-arm, multicenter, phase 2 study. Eligible patients were adults aged 18 years or older with newly diagnosed, HER-2 negative, PD-L1 positive, and FGFR2 positive metastatic gastric adenocarcinoma. Additional inclusion criteria included an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2, measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), sufficient organ function, and the ability to provide a fresh or archival formalin-fixed paraffin-embedded tissue sample for PD-L1 and FGFR2 expression analysis. Patients who had received prior adjuvant or neoadjuvant chemotherapy, radiotherapy, or chemoradiotherapy at least six months before randomization were eligible. However, those with a known HER2-positive status, untreated CNS metastases, bone fractures, grade 2 or higher peripheral neuropathy, autoimmune diseases, or a history of adjuvant clinical trials (i.e. immunotherapy or FGFR2 inhibitors) were excluded.

The trial adhered to Good Clinical Practice guidelines established by the International Council for Harmonisation and was conducted in compliance with the trial protocol. The protocol received approval from the institutional review boards at each participating site. All patients provided written informed consent in accordance with the principles of the Declaration of Helsinki. The study is registered on ClinicalTrials.gov under the identifier NCT05859477.

Procedures

Patients received nivolumab (360 mg every three weeks) in combination with chemotherapy (CAPOX regimen: capecitabine 1000 mg/m² twice daily on days 1–14 and oxaliplatin 130 mg/m² on day 1, every three weeks). All treatments were administered intravenously, except for capecitabine, which was taken orally. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Nivolumab was administered for a maximum of two years, while chemotherapy followed local standards. Patients were allowed to continue treatment beyond initial disease progression at the investigator's discretion.

Tumors were assessed using computed tomography (CT) scans according to RECIST version 1.1, every 8 weeks from the start of cycle 1 for the first 48 weeks, and then every 12 weeks until disease progression.

PD-L1 immunohistochemistry was performed at a central laboratory using the Dako PD-L1 IHC 28 − 8 pharmDx assay (Dako, Santa Clara, CA, USA) following the manufacturer’s instructions with the Dako Autostainer Link-48 system. Tumor cell PD-L1 expression was defined as the percentage of viable tumor cells with partial or complete membrane staining, assessed in a sample of at least 100 viable tumor cells. CPS was calculated by re-scoring PD-L1 stained slides using the CPS algorithm, which is defined as the number of PD-L1-positive tumor cells (showing partial or complete membrane staining), lymphocytes, and macrophages (showing membrane or intracellular staining, or both) divided by the total number of viable tumor cells, multiplied by 100.

FGFR2 immunohistochemistry was done at central laboratory using the Abсam FGFR2 immunohistochemistry EPR24075-418 assay (Abcam, Cambridge MA, USA) according to the previously described protocols [9]. Tumor cell FGFR2 expression was defined as the presence of partial or complete membrane staining in at least 1% of viable tumor cells, assessed in a sample of at least 100 viable tumor cells. Expression levels were categorized as moderate (2+) or strong (3+).

Treatment-related adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Outcomes and statistical analysis

The primary endpoint was the 1-year PFS rate. Secondary endpoints included median PFS and OS, objective response rate (ORR) and Grade ≥ 3 treatment-related adverse events (TRAEs) rate.

The sample size of 23 patients was calculated based on the following assumptions. The null hypothesis was that the 12-month progression-free survival (PFS) rate would be 20%, as observed in patients treated with chemotherapy in the CheckMate 649 trial [10]. The alternative hypothesis assumed that the 12-month PFS rate would increase to 45% in patients with PD-L1 and FGFR2 expression treated with nivolumab and chemotherapy. The calculation was conducted with a type I error rate of 0.05 and a power of 0.8. The final efficacy and safety analysis included patients who received at least one dose of the nivolumab.

Descriptive statistics (means, medians, and proportions) were used to describe baseline patient characteristics. Quantitative data are expressed as mean ± standard deviation. The Mann–Whitney U-test was used as a nonparametric test to analyze variables that were not normally distributed. Survival time was calculated from the start of systemic therapy to the day of disease progression or death from any cause (PFS) or to the day of death (OS). The one-year PFS rate was defined as the proportion of patients in the study who had not experienced disease progression at 12 months from the start of treatment. Survival curves were evaluated using the Kaplan-Meier method. Associations between outcomes, and clinical and demographic factors were assessed using Kaplan-Meier analyses and log-rank comparisons. All P-values were two-sided, and values of < 0.05 were considered statistically significant. Tests assumed a 95% confidence interval (CI). All statistical analyses were performed using IBM SPSS Statistics Base v22.0 software (SPSS, Inc., Chicago, Illinois, USA).

Patient characteristics

From June 2022 to October 2023, 194 patients were assessed for eligibility. Among these, 74 patients (38%) were PD-L1 positive, and 23 of the 74 patients (31%) were FGFR2 positive. A total of 23 patients were assigned to receive nivolumab in combination with CAPOX, and all patients received one or more doses of the prescribed treatment.

The baseline characteristics of the patients are outlined in Table 1. The median age was 61 years (range, 44–79), with 30% of patients aged over 65 years. The majority of patients were male (N = 17; 74%) and had an ECOG PS of 1 (N = 16; 69%). All patients had confirmed adenocarcinoma localized in the stomach as the primary tumor site, with a predominance of the intestinal type (N = 13; 57%) according to the Lauren classification. PD-L1 CPS ≥ 20 was found in 11 patients (47.8%), and 11 patients (48%) had strong (3+) FGFR2 expression. Fourteen patients (61%) had undergone previous surgery, while 11 patients (48%) had a time to metastatic disease of less than one year, with 18 patients (78%) having metastases in two or more sites. The median neutrophil-to-lymphocyte ratio (NLR) was 2.1 (range, 0.71–4.45). Almost all patients (N = 20; 87%) had chronic or concomitant diseases.

Table 1

Patient characteristics
All patients, N	23
Age, years, median (range)	61 (44–79)
Sex, N (%) Male Female	17 (74) 6 (26)
Race, N (%) Caucasian Other	21 (91) 2 (9)
ECOG performance status, N (%) 0 1 2	5 (22) 16 (69) 2 (9)
Lauren classification, N (%) Intestinal type Diffuse type Unknown	13 (57) 6 (26) 4 (17)
Organs with metastases, N (%) 1 ≥ 2	5 (22) 18 (78)
Previous adjuvant/ neoadjuvant therapy, N (%)	4 (17)
Previous surgery, N (%)	14 (61)
Time to metastatic disease, N (%) < 1 year ≥ 1 year	11 (48) 12 (52)
PD-L1 status (CPS), N (%) 5–20 ≥ 10	12 (52) 11 (48)
FGFR2 IHC expression status, N (%) Moderate (2+) Strong (3+)	12 (52) 11 (48)

Efficacy and safety

At a median follow-up of 17.3 months, the 1-year PFS rate was 30.4%, with a median PFS of 6.0 months (95% CI, 4.3 to 7.7). The primary endpoint was not met. In the univariate analysis, there was no significant difference in median PFS between the cohorts of patients with moderate (2+) FGFR2 expression and those with strong (3+) FGFR2 expression (6.3 vs. 5.2 months, p = 0.083; Fig. 1A). In the cohort of patients with PD-L1 CPS ≥ 20, the median PFS was numerically better (6.3 vs. 4.7 months); however, these differences did not reach statistical significance (p = 0.358; Fig. 2A). The analysis did not reveal significant differences in PFS according to various patient and treatment characteristics, including age (< 65 vs. ≥65, p = 0.9), gender (male vs. female, p = 0.08), ECOG PS (0 vs. 1, p = 0.13), history of surgery (yes vs. no, p = 0.49), number of organs with metastases (1 vs. ≥2, p = 0.4), lactate dehydrogenase level (< upper limit vs. ≥ upper limit, p = 0.85), hemoglobin level (< 100 vs. ≥100 g/L, p = 0.4), NLR (below vs. above the median, p = 0.33), and number of cycles of first-line chemotherapy (4 vs. ≥5, p = 0.17). There was a significant trend suggesting that patients with aggressive disease (time to metastatic disease < 1 year) had worse PFS outcomes, with a median PFS of 5.1 months compared to 9.1 months for those with a longer time (≥ 1 year) to advanced disease (p = 0.005).

The median OS was 15.1 months (95% CI, 13.2 to 16.8), with 7 patients (30.4%) still alive. Patients who did not experience disease progression at the time of the last follow-up (in any line of treatment) demonstrated significantly longer OS compared to those with disease progression (p < 0.01). There were no significant differences in median OS between the cohorts of patients with moderate (2+) and strong (3+) FGFR2 expression (16.5 vs. 13.9 months, p = 0.065; Fig. 2A) or between the subgroups with PD-L1 CPS < 20 and ≥ 20 (14.7 vs. 15.12 months, p = 0.586; Fig. 2B).

The objective response rate was 21.7% (95% CI, 18 to 23.5). Among these, 1 patient (4.3%) achieved a complete response, 4 patients (17.4%) achieved partial responses, 14 patients (60.9%) had stable disease, and 4 patients (17.4%) experienced progressive disease. Over the additional 9 months of follow-up, no increase in the response rate was observed. Objective responses were associated with better PFS outcomes. The median PFS was 11.0 months (95% CI, 9.5 to 12.5) in responders and 5.1 months (95% CI, 4.1 to 6.1) in non-responders (p = 0.001). At the data cutoff, 2 (8.7%) patients were still receiving trial treatment. Among patients who discontinued study therapy due to progressive disease, 19 (82.6%) received second-line treatment with ramucirumab and paclitaxel, and 10 (43.5%) received subsequent late-line therapies. The median PFS2 was 5.9 months (95% CI, 4.5 to 7.3).

In all treated patients, any-grade TRAEs occurred in 17 (73.9%) cases, including grade ≥ 3 TRAEs in 8 (34.8%). The most serious adverse events were associated with chemotherapy and comprised neutropenia (N = 1) and thrombocytopenia (N = 1).

Immunotherapy is becoming increasingly important in the treatment of metastatic HER2-negative and HER2-positive gastric cancer [11]. To our knowledge, this NIVOFGFR2 study is the first to include patients with metastatic gastric cancer co-expressing FGFR2 and PD-L1 who received first-line nivolumab in combination with chemotherapy. Notably, about 50% of participants exhibited strong expression of both FGFR2 (3+) and PD-L1 (CPS ≥ 20). FGFR2 expression and amplification are associated with worse outcomes in patients with gastric cancer. This has been observed in various studies where higher levels of FGFR2 correlate with more aggressive disease and poorer prognosis [12–14]. Understanding the impact of FGFR2 on treatment outcomes is crucial, as it may influence treatment decisions and the development of targeted therapies.

Regarding prognostic factors in our study, patient characteristics were similar to those observed in real-world populations as well as in other studies [15, 16]. The majority of patients had an ECOG PS of 1, a primary tumor site in the stomach, metastases in two or more organs, and no history of surgical treatment, mirroring the patient demographics of the CheckMate 649 and ATTRACTION-4 studies [10, 17]. This similarity in patient characteristics underscores the relevance of our preliminary findings to broader clinical practice. The alignment with real-world and randomized study populations ensures that our results are applicable and can be interpreted. This is important for validating the generalizability of our outcomes and for understanding how our findings fit into the broader landscape of metastatic gastric cancer treatment.

Despite the promising rationale for combining nivolumab with chemotherapy in this particular subgroup of gastric cancer patients with FGFR2 and PD-L1 expression, the results of our study were not as anticipated, and the primary endpoint of 1-year PFS rate was not met. Only a third of patients remained progression-free at 12 months, with a median PFS of 6.0 months. These outcomes are inferior to those reported for the nivolumab plus chemotherapy group in the randomized CheckMate 649 trial, where better PFS was observed [10]. The median PFS data in our study are more comparable to the chemotherapy alone group from CheckMate 649, which also had a median PFS of 6.0 months.

However, OS results in NIVOFGFR2 study were very similar to the figures demonstrated in the nivolumab group with CPS ≥ 5 in the CheckMate 649. In our cohort, the median OS was 15.1 months with a 95% CI of 13.2 to 16.8 months. This is comparable to the phase 3 study, where the median OS was 14.4 months with a 95% CI of 13.1 to 16.2 months.

On the one hand, these findings suggest that despite the lack of improvement in PFS, nivolumab combined with chemotherapy may still confer a survival benefit for patients with PD-L1 CPS ≥ 5. The impact of nivolumab on OS, even after disease progression or discontinuation, has been repeatedly described in other studies across various tumor types [18–21]. Thus, the alignment in OS outcomes highlights the potential role of nivolumab in extending survival in gastric cancer as well, even if the immediate control of disease progression, as measured by PFS, is not markedly improved.

On the other hand, the role of subsequent treatment cannot be excluded. In our study, all patients who experienced disease progression on the first-line therapy received ramucirumab in combination with paclitaxel as a second-line, and 40% received third- and subsequent lines of therapies. These additional treatments may have mitigated the shortcomings of the first-line and positively influenced the OS outcome [22, 23]. The potential influence of subsequent therapies underscores the complexity of assessing the true impact of the first-line treatment regimen. It is possible that the observed OS benefit may be partially attributable to the efficacy of second-line and later treatments. This highlights the need for a holistic approach to treatment planning that considers the entire continuum of care for patients with metastatic gastric cancer.

As for the response rate in the NIVOFGFR2 study, it was almost three times lower than in the CheckMate 649 and ATTRACTION-4 studies [2, 17], while the disease control rate was nearly the same across all studies. Despite the lower response rate, the development of a response to nivolumab in combination with chemotherapy was statistically significantly correlated with an increase in median PFS, which was twice as high in responders compared to non-responders. This finding highlights the importance of achieving a response to treatment in improving PFS outcomes. The comparable disease control rates to other studies indicate that even though fewer patients achieved a complete or partial response in NIVOFGFR2, many still maintained stable disease, contributing to overall disease management and clinical benefits.

Finally, the safety profile of the treatment was satisfactory. Despite a high rate of all TRAEs, grade ≥ 3 adverse events were reported in only a third of patients and were primarily associated with chemotherapy rather than nivolumab. Importantly, no patients discontinued treatment due to TRAEs, and no treatment-related deaths occurred.

In conclusion, while the primary endpoint of improved 1-year PFS rate was not met, our study provides valuable insights into the potential benefits of combining nivolumab with chemotherapy in patients with metastatic gastric cancer co-expressing FGFR2 and PD-L1. The OS results were comparable to other significant studies, and the safety profile was manageable. Future research should focus on optimizing patient selection, assessing the potential of combined immunotherapy and targeted anti-FGFR2 therapy, and further investigating the role of subsequent treatments to maximize the therapeutic benefits.

Author Contribution

I.T. designed the study and wrote the main manuscript text . All authors were involved in the organization of the study and reviewed the manuscript.

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No competing interests reported.

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You are reading this latest preprint version

Nivolumab Combined with Chemotherapy in FGFR2 and PD-L1 Co- Expressing Metastatic Gastric Cancer: A Prospective Phase 2 NIVOFGFR2 Study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Study design and participants

Procedures

Outcomes and statistical analysis

Results

Patient characteristics

Efficacy and safety

Discussion

Declarations

Author Contribution

References

Additional Declarations

Status:

Version 1