Phase 1b/2 study of BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients with advanced pancreatic or colorectal cancer

Abstract

Background

Cysteine–cysteine chemokine receptors 2 (CCR2) and 5 (CCR5) contribute to immune suppression in tumor microenvironments. CCR2 and CCR5 antagonists have demonstrated antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively. This phase 1b/2, open-label study evaluated BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC.

Methods

Part 1 included patients with metastatic untreated (first-line (1L)) PDAC, 1L CRC, or previously treated (second or third line (2/3L)) microsatellite stable (MSS) CRC. Patients received 2 weeks of BMS-813160 monotherapy (300 mg two times a day, 600 mg once daily, 300 mg once daily, or 150 mg once daily) and then BMS-813160+chemotherapy (gemcitabine+nab-paclitaxel (gem/nabP; 1L PDAC), 5-fluorouracil+leucovorin+irinotecan (FOLFIRI; 1L CRC)), or nivolumab (2/3L MSS CRC).

Part 2 included patients with metastatic 1L PDAC or 2L CRC. Patients received BMS-813160 300 mg two times a day+gem/nabP±nivolumab (1L PDAC), BMS-813160 300 mg two times a day or 150 mg once daily+FOLFIRI (2L CRC), or chemotherapy alone. Primary endpoints were safety and pharmacodynamics (Part 1) and efficacy (Part 2).

Results

In Part 1, 22 of 75 (29%) and 54 of 72 (72%) patients experienced a treatment-related adverse event during monotherapy lead-in and overall, respectively. Two dose-limiting toxicities (rash and pericardial effusion with pericarditis, both grade 3) occurred. In Part 2, patients with 1L PDAC who received BMS-813160 300 mg two times a day+gem/nabP+nivolumab achieved an overall response rate (ORR) of 37% (13/35); the median duration of response (DOR) was 45 weeks (95% CI 26.1 to not evaluable). ORRs with BMS-813160 300 mg two times a day+gem/nabP and gem/nabP alone were 26% (9/35) and 28% (9/32), respectively; median DORs were 121 and 31 weeks, respectively. Progression-free survival rates at 24 weeks were 56% (BMS-813160 300 mg two times a day+gem/nabP+nivolumab), 56% (BMS-813160 300 mg two times a day+gem/nabP), and 50% (gem/nabP). ORRs in 2L CRC were 19% (6/32; BMS-813160 300 mg two times a day+FOLFIRI), 13% (4/32; BMS-813160 150 mg once daily+FOLFIRI), and 27% (7/26; FOLFIRI).

Conclusions

In 1L PDAC, BMS-813160 300 two times a day+gem/nabP±nivolumab demonstrated durable antitumor response and was well tolerated. BMS-813160 combination regimens were tolerable in other cohorts, but clinical efficacy was not demonstrated.

Trial registration number

NCT03184870.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Cysteine–cysteine chemokine receptor (CCR)2 and CCR5 antagonists have shown antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively, although the clinical impact of BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC is unknown.

WHAT THIS STUDY ADDS

• In patients with untreated metastatic PDAC, BMS-813160+gemcitabine/nab-paclitaxel±nivolumab was well tolerated and demonstrated a more durable response. In other cohorts, combination therapy with BMS-813160 was well tolerated, but clinical efficacy was not demonstrated.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Results from this study suggest that CCR2/5 antagonists such as BMS-813160 might represent a new treatment approach for first-line PDAC.

Background

Immunotherapies have emerged as a significant advancement in the cancer treatment landscape.¹ Current approaches under investigation include blocking immunosuppressive mechanisms with antagonistic antibodies and stimulating immunity with agonistic antibodies.^{1 2} Unfortunately, many cancers, like pancreatic ductal adenocarcinoma (PDAC) and microsatellite stable (MSS) colorectal cancer (CRC), are not responsive to current clinically available immunotherapies,^{3 4} highlighting the need for new methods that target different immune cell types or pathways.

Chemokines are a diverse family of small, secreted proteins that stimulate cell migration and accumulation of immune cells, including myeloid and regulatory T cells (Tregs), into the tumor microenvironment (TME).^{5 6} Two chemokine receptors, cysteine–cysteine chemokine receptor 2 (CCR2) and 5 (CCR5), mediate migration and accumulation of specific myeloid cells with M2-polarized phenotype, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), into the TME.⁶ Data have demonstrated that a 12-chemokine (chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, and CCL21; C-X-C motif ligand 9 (CXCL9), CXCL10, CXCL11, and CXCL13) signature was strongly associated with inflammation-related and immune cell-related apoptosis pathways as well as with tumor-infiltrating immune cells in patients with CRC.⁷

CCL2 is secreted by tumors and recruits CCR2-positive inflammatory monocytes to the TME, where they differentiate into immunosuppressive TAMs and prevent antitumor immunity; inhibition of this axis has resulted in antitumor responses in preclinical models.^{8 9} Variations in genes that regulate TAM-related functions were significantly associated with improved clinical outcomes in patients with metastatic CRC treated with bevacizumab-containing chemotherapy.¹⁰

CCR5 is expressed on tumor cells, TAMs, and circulating Tregs and plays a role in immune processes that promote tumor growth.¹¹ Maraviroc, a CCR5 antagonist, reduces tumor-promoting cytokine levels, increases tumor death in explant models, and improves potential responses to chemotherapy.^{12 13} Therefore, blocking CCR2 and CCR5 may overcome immunosuppressive effects on the TME and promote antitumor activity.

In phase 1 clinical trials, CCR2 and CCR5 antagonists combined with chemotherapy have demonstrated clinical activity in PDAC¹⁴ and refractory CRC,¹³ respectively. When combined with folinic acid, fluorouracil, irinotecan, and oxaliplatin chemotherapy, PF-04136309, a small-molecule antagonist of CCR2, demonstrated a positive antitumor response in the treatment of borderline resectable or locally advanced, first-line (1L) pancreatic cancer; 97% of patients (n=32) achieved local tumor control, and 49% (n=16) had an objective tumor response.¹⁴ In a separate study, maraviroc reduced tumor cell proliferation and increased tumor cell death in patients with refractory CRC treated with two to seven lines of prior therapy.¹³

Given the antitumor activity of individual CCR2 and CCR5 antagonists in PDAC and CRC and the lack of overlapping toxicity profiles, targeting CCR2 and CCR5 in combination with chemotherapy may offer enhanced benefit compared with each therapy alone. Additionally, the immune effects observed when CCR2 and CCR5 pathways were targeted suggested that a combination with other immunotherapies such as nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, may enhance immune responses and improve antitumor activity.

BMS-813160 is a dual, equipotent, selective, reversible small-molecule antagonist of CCR2 and CCR5 that was previously well tolerated in healthy participants and in patients with diabetic kidney disease.^{15 16} This phase 1b/2 CV202-103 study was designed to evaluate the safety and preliminary efficacy of BMS-813160 plus chemotherapy with or without nivolumab in advanced PDAC and CRC.^{17 18}

Methods

Study design and patients

CV202-103 was an open-label, two-part, multicenter, phase 1b/2 clinical trial of BMS-813160 in combination with gemcitabine (gem)/nab-paclitaxel (nabP), nivolumab, gem/nabP plus nivolumab, or FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) compared with chemotherapy alone in patients with advanced PDAC or CRC (online supplemental figure S1A,B). Eligible patients had a histologically or cytologically confirmed diagnosis of metastatic PDAC or CRC measurable by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. In part 1 of the trial, patients were selected and grouped as follows: the 1L PDAC group comprised patients who had previously untreated metastatic PDAC (systemic recurrence after surgery or >6 months post adjuvant therapy was allowed); the 1L CRC group included patients who had previously untreated metastatic CRC (systemic recurrence after surgery or >6 months post adjuvant therapy was allowed); the previously treated metastatic PDAC group (second-line (2L) PDAC); and the 2L/third-line (2/3L) MSS CRC group, who were previously treated with systemic chemotherapy. Patients with 2/3L MSS CRC were required to have received an oxaliplatin-containing regimen and an irinotecan-containing regimen but received ≤2 lines of systemic chemotherapy for metastatic disease. In part 2, patients had either 1L PDAC, as defined above, or metastatic CRC previously treated with one line of oxaliplatin-based therapy (2L CRC).

Additional key inclusion criteria included Eastern Cooperative Oncology Group performance status of ≤1, willingness to provide mandatory pretreatment and on-treatment biopsies, and adequate bone marrow and other organ function. Select exclusion criteria included histology other than adenocarcinoma (neuroendocrine or acinar cell); suspected or known central nervous system metastases; prior treatment with CCR2/5 inhibitors or anti-PD-1, anti-programmed death-ligand 1, or cytotoxic T-lymphocyte-associated protein 4 antibodies; and any anticancer therapy within 4 weeks prior to the first dose of study treatment.

Good Clinical Practice

This study was conducted at 40 sites across six countries (Australia, Belgium, Canada, Germany, Spain, and the USA). The protocol was reviewed and approved by the institutional review board/independent ethics committee at each study location, per applicable local regulations, prior to study initiation. This study was conducted in accordance with Good Clinical Practice as defined by the International Conference on Harmonization and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the US Code of Federal Regulations, Title 21, Part 50 (21CFR50). Informed consent was obtained prior to any study-related procedures in adherence to the ethical principles described in the Declaration of Helsinki.

Treatment regimens

Part 1 consisted of a 2-week BMS-813160 monotherapy lead-in followed by combination treatment (online supplemental figure S1A). During the monotherapy lead-in, all patients received oral BMS-813160 300 mg two times a day, 600 mg once daily, 150 mg once daily (2/3L MSS CRC), or 300 mg once daily (2/3L MSS CRC) for 2 weeks. Following monotherapy lead-in, patients in the 1L PDAC cohort received oral BMS-813160 300 mg two times a day or 600 mg once daily in combination with gem 1,000 mg/m² intravenous and nabP 125 mg/m² intravenous on days 1, 8, and 15 of a 28-day cycle. Patients in the 1L CRC cohort received oral BMS-813160 300 mg two times a day or 600 mg once daily in combination with FOLFIRI (irinotecan 180 mg/m²; leucovorin 400 mg/m²; 5-fluorouracil 400 mg/m² followed by 2,400 mg/m²) on days 1 and 15 of a 28-day cycle. Those with 2/3L MSS CRC or 2L PDAC received oral BMS-813160 300 mg two times a day, 600 mg once daily, 300 mg once daily (CRC only), or 150 mg once daily (CRC only) in combination with nivolumab 480 mg intravenous every 4 weeks.

In part 2, patients in the 1L PDAC cohort were randomly assigned to receive BMS-813160 300 mg two times a day in combination with gem/nabP, BMS-813160 300 mg two times a day in combination with gem/nabP and nivolumab, or gem/nabP alone (online supplemental figure S1B). Those in the 2L CRC cohort were randomly assigned to receive BMS-813160 300 mg two times a day, BMS-813160 150 mg once daily in combination with FOLFIRI, or FOLFIRI alone. Patients continued treatment until disease progression, intolerance to treatment, or withdrawal of consent.

Endpoints and assessments

Detailed information on endpoints is shown in online supplemental materials and methods. The primary endpoints in part 1 were safety and tolerability and pharmacodynamic (PD) parameters in tumor samples. BMS-813160 pharmacokinetics (PK) was a secondary endpoint.

In part 2, the primary endpoints were overall response rate (ORR) as assessed by blinded independent central review (BICR) per RECIST V.1.1, median duration of response (DOR), and progression-free survival (PFS) rate by BICR per RECIST V.1.1 at 24 weeks. Secondary endpoints included safety and tumor PD parameters (Tregs, TAMs, and tumor-infiltrating lymphocytes). Exploratory endpoints were overall survival (OS) rate and biomarker analyses.

Imaging via CT and/or MRI was performed at baseline and every 8 weeks until disease progression, treatment discontinuation, or withdrawal from the study. Images were assessed per BICR. Adverse events (AEs) were recorded throughout the study and for ≥30 days (±7 days) after the last dose of study treatment.

PD, immunohistochemistry, PK, and biomarker assessments

Plasma PK values of BMS-813160 and its metabolite were collected at selected time points and derived from plasma concentration versus time data. Individual participant PK parameter values were derived by non-compartmental methods using a validated PK analysis program.

Monocytic MDSCs (CD3⁻CD19⁻CD56⁻HLA-DR^negCD11^loCD33⁺CD14⁺CD15⁻) were measured by flow cytometry using fresh whole blood at multiple time points by Q2 Solutions (Atlanta, Georgia, USA). Serum levels of CCL4 (macrophage inflammatory protein-1β), CCL2 (monocyte chemoattractant protein), CCL5 (regulated on activation, normal T-cell expressed and presumably secreted (RANTES)), CXCL8 (interleukin 8 (IL-8)), and other cytokines were measured prior to treatment over multiple cycles of treatment with a multiplex immunoassay (R&D Systems; Minneapolis, Minnesota, USA). Batched frozen serum aliquots were analyzed to interrogate PD changes and identify biomarkers predictive of efficacy. Change (or % change) from baseline in various biomarker levels in the tumor (Tregs, TAMs, and tumor-infiltrating lymphocytes) and peripheral blood (CCL2, CCL4, and MDSCs) was summarized by study day and dose.

Tumor core biopsy samples were collected from pretreatment and post-treatment lesions, fixed in 10% neutral buffered formalin, and embedded into tissue blocks (online supplemental materials and methods). For CCR2, CD163, forkhead box P3 (FOXP3), and CD8 immunohistochemistry (IHC), Mosaic Laboratories (Lake Forest, California, USA) performed IHC staining and analysis from fresh cut slides. Tumor gene expression was interrogated by the EdgeSeq Precision immuno-oncology panel V2 (HTG Molecular; Tucson, Arizona, USA), which analyzes over 1,300 genes from a single sample.

Statistical analyses

Efficacy and safety analyses were performed on the treated population, defined as all patients who received ≥1 dose of study treatment. The BICR response–evaluable population was defined as all treated patients with measurable disease at baseline and ≥1 post-baseline assessment, clinical progression, or death. PD analyses were performed in all treated patients who also had PD data collected. Biomarker analyses were performed using data from all treated patients with available biomarker data.

ORRs and corresponding two-sided exact 95% CIs were calculated using the Clopper-Pearson method by treatment for each tumor type. Median DOR was estimated using the Kaplan-Meier method, and the corresponding two-sided 95% CIs were calculated using Brookmeyer-Crowley methodology by treatment for each tumor type. PFS and OS were estimated using the Kaplan-Meier method, and corresponding 95% CIs were derived based on the Greenwood formula. The database cut-off was December 20, 2021. Additional information on statistical analyses for safety and biomarkers is shown in online supplemental materials and methods.

Results

Part 1

Patients

In total, 75 patients with 1L PDAC, 2L PDAC, 1L CRC, or 2/3L MSS CRC were treated in part 1 of the study. Patients with 2L PDAC (n=3) were only included in the monotherapy lead-in safety analysis.

In the 1L PDAC cohort, 21 patients were treated (BMS-813160 300 mg two times a day+gem/nabP, n=10; BMS-813160 600 mg once daily+gem/nabP, n=11). Median (range) ages were 63 (54–80) and 62 (51–80) years in those receiving BMS-813160 300 mg two times a day and 600 mg once daily, respectively. All patients were white, and 43% were male (online supplemental table S1). Of 81% who completed the monotherapy lead-in, all entered the combination phase. During the combination phase, the most common reason for treatment discontinuation was progressive disease (online supplemental figure S2).

In the 1L CRC cohort, 18 patients were treated (BMS-813160 300 mg two times a day+FOLFIRI, n=10; BMS-813160 600 mg once daily+FOLFIRI, n=8). Median (range) ages were 66 (54–83) and 56 (28–66) years in those treated with BMS-813160 300 mg two times a day+FOLFIRI and BMS-813160 600 mg once daily+FOLFIRI, respectively (online supplemental table S1). Most patients were white (67%) and male (72%). 94% of patients completed the monotherapy lead-in.

In the 2/3L CRC cohort, 33 patients were treated (BMS-813160 300 mg two times a day+nivolumab, n=8; BMS-813160 600 mg once daily+nivolumab, n=7; BMS-813160 300 mg once daily+nivolumab, n=7; BMS-813160 150 mg once daily+nivolumab, n=11). Median age ranged from 43 to 63 years, and most patients were white (82%) men (67%). Almost all patients with 2/3L CRC completed the monotherapy lead-in (97%).

Safety and tolerability

BMS-813160 was well tolerated during the monotherapy lead-in phase. Treatment-emergent AEs (TEAEs) occurred in 59 patients (79%). Grade 3/4 treatment-emergent serious AEs (SAEs) occurred in 7 patients (9%), with most occurring in those treated with BMS-813160 300 mg two times a day (n=6, table 1). Overall, 29% of patients (22/75) experienced a treatment-related AE (TRAE). TRAEs reported in ≥2 patients across doses during monotherapy were nausea (n=8), vomiting (n=4), anemia (n=5), fatigue (n=4), dysgeusia (n=2), and dermatitis acneiform (n=2). In most patients (73%), TRAEs were mild (grade 1) in severity. A single grade 3/4 TRAE occurred (lymphocyte count decreased, BMS-813160 300 mg two times a day).

Table 1. Safety from part 1 monotherapy lead-in^*.

	BMS-813160 300 mg two times a day n=29	BMS-813160 600 mg once daily n=28	BMS-813160 300 mg once daily n=7	BMS-813160 150 mg once daily n=11
TEAE, any grade, n (%)	25 (86.2)	23 (82.1)	6 (85.7)	5 (45.5)
TEAE, grade 3/4	7 (24.1)	2 (7.1)	1 (14.3)	1 (9.1)
TRAE, any grade	10 (34.5)	8 (28.6)	4 (57.1)	0
TRAE, grade 3/4	1 (3.4)	0	0	0
Treatment-emergent SAE, any grade	6 (20.7)	3 (10.7)	1 (14.3)	0
Treatment-emergent SAE, grade 3/4	6 (20.7)	1 (3.6)	0	0
Treatment-related SAE, any grade	0	0	0	0
TEAE leading to discontinuation, any grade	1 (3.4)	1 (3.6)	0	0
TEAE leading to discontinuation, grade 3/4	1 (3.4)	1 (3.6)	0	0
TRAE leading to discontinuation, any grade	0	0	0	0

^*Three patients with 2L PDAC were treated during part 1 of the study (BMS-813160 300 mg two times a day, n=1; BMS-813160 600 mg once daily, n=2); data from these patients are included in the monotherapy lead-in safety assessment only.

2L PDAC, second-line pancreatic ductal adenocarcinoma; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

BMS-813160 demonstrated an acceptable safety profile across all doses and combination regimens tested. When safety data across treatment cohorts were pooled, 75% of patients (54/72) experienced a TRAE of any grade, and 28% (20/72) experienced a grade 3/4 TRAE during either monotherapy or combination treatment (table 2). Two dose-limiting toxicities were reported in patients with 1L PDAC during the combination treatment phase. One patient receiving BMS-813160 300 mg two times a day+gem/nabP experienced grade 3 rash; another patient receiving BMS-813160 600 mg once daily+gem/nabP had a grade 3 pericardial effusion with pericarditis. Both patients continued treatment with one dose reduction for both BMS-813160 (300 mg two times a day to 150 mg two times a day and 600 mg once daily to 300 mg once daily) and chemotherapy (gem 1,000 mg/m² to 800 mg/m² and nabP 125 mg/m² to 100 mg/m²). No grade 5 TRAEs were reported.

Table 2. Overall^* safety in patients with PDAC or CRC from part 1 of the study.

n (%)		Exposure duration, median (range), weeks	TEAE, any grade; grade 3/4	TRAE, any grade; grade 3/4	Treatment-emergent SAE, any grade; grade 3/4	TEAE leading to discontinuation, any grade; grade 3/4	TRAE leading to discontinuation, any grade; grade 3/4
1L PDAC	BMS-813160 300 mg two times a day+gem/nabP n=10	20 (0.6–67)	10 (100); 8 (80)	9 (90); 5 (50)	5 (50); 5 (50)	1 (10); 0	1 (10); 0
	BMS-813160 600 mg once daily+gem/nabP n=11	10 (0.1–43)	11 (100); 10 (91)	10 (91); 8 (73)	7 (64)†; 7 (64)	5 (46); 6 (55)	6 (55); 5 (46)
1L CRC	BMS-813160 300 mg two times a day+FOLFIRI n=10	28 (2–163)	10 (100); 8 (80)	9 (90); 2 (20)	5 (50)‡; 5 (50)	2 (20); 2 (20)	1 (10); 1 (10)
	BMS-813160 600 mg once daily+FOLFIRI n=8	18 (4–35)	8 (100); 4 (50)	8 (100); 1 (13)	5 (63); 4 (50)	0; 0	0; 0
2/3L CRC	BMS-813160 300 mg two times a day+nivolumab n=8	10 (2–26)	8 (100); 4 (50)	6 (75); 1 (13)	5 (63); 3 (38)	0; 0	0; 0
	BMS-813160 600 mg once daily+nivolumab n=7	7 (3–18)	7 (100); 3 (43)	2 (29); 1 (14)	6 (86); 2 (29)	1 (14); 1 (14)	0; 0
	BMS-813160 300 mg once daily+nivolumab n=7	7 (4–16)	7 (100); 1 (14)	5 (71); 1 (14)	6 (86); 1 (14)	0; 0	0; 0
	BMS-813160 150 mg once daily+nivolumab n=11	8 (0.1–26)	11 (100); 3 (27)	5 (46); 1 (9)	6 (55); 3 (27)	1 (9); 1 (9)	0; 0

^*Includes data from both the monotherapy lead-in and combination therapy phases.

^†Five patients (46%) had a treatment-related, any-grade SAE.

^‡One patient (10%) had a treatment-related, any-grade SAE.

CRC, colorectal cancer; FOLFIRI, 5-fluorouracil+leucovorin+irinotecan; gem, gemcitabine; 1L, first line; 2L, second line; nabP, nab-paclitaxel; PDAC, pancreatic ductal adenocarcinoma; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.

PD biomarkers

Peripheral target engagement and proximal PD effects were detected at all doses. Across all cohorts, increases in peripheral serum CCL4 (average change from baseline: 1L CRC, 200% (300 and 600 mg); 1L PDAC, 300% (300 and 600 mg); 2/3L CRC, 400% (300 mg) and 500% (600 mg)) and CCL2 (average change from baseline: 1L CRC, 1,000% (300 mg) and 2,000% (600 mg); 1L PDAC, 1,000% (300 and 600 mg); 2/3L CRC, 1,000% (300 and 600 mg)) were observed with BMS-813160 treatment (online supplemental figure S3A,B). On initiation of BMS-813160, transient depletion of peripheral mononuclear MDSCs occurred (0.5-fold reduction across 1L CRC, 1L PDAC, and 2/3L CRC); however, these changes were confounded when peripheral mononuclear MDSC levels increased at the start of chemotherapy (online supplemental figure S3C).

In the 1L PDAC and 1L CRC cohorts, densities of CD163⁺ TAMs and FOXP3⁺ cells in tumor tissue remained relatively unchanged from baseline through the end of BMS-813160 monotherapy lead-in (C0D14). In the 2/3L CRC cohort, modest decreases in FOXP3⁺ cell counts were observed in tumor tissue following BMS-813160 monotherapy lead-in treatment (online supplemental figure S3D,E). Decreases in CD8⁺ T-cell densities were observed during BMS-813160 monotherapy lead-in treatment across all three cohorts (online supplemental figure S3F).

Pharmacokinetics

There was no consistent difference in BMS-813160 PK parameters at steady state (end of monotherapy lead-in; C0D14) among tumor type and dose. Within treatment groups, BMS-813160 600 mg once daily elicited a higher C_max and AUC_(0-24) than BMS-813160 300 mg two times a day (online supplemental table S2). Generally, BMS-813160 exposure exhibited a greater than dose-proportional increase. Based on available safety, PK, and PD data from Part 1, BMS 300 mg two times a day was selected as the recommended dose for Part 2.

Part 2

Patients

In the 1L PDAC cohort, 115 patients were randomized, 102 (89%) were treated, and 93 (81%) were evaluable by BICR (online supplemental figure S4). The most common reasons for discontinuation across treatment groups were progressive disease and AEs unrelated to the study drug. Median age was 66 years (table 3). Most patients were white (91%) and male (56%). The most common prior systemic therapy was adjuvant therapy (14%). The proportion of patients with liver metastases was higher in the BMS-813160 300 mg two times a day+gem/nabP+nivolumab group (63%) than in the BMS-813160 300 mg two times a day+gem/nabP (51%) or gem/nabP (44%) groups.

Table 3. Baseline demographics and clinical characteristics of patients with 1L PDAC in part 2.

	BMS-813160 300 mg two times a day+gem/nabP+nivolumab n=35	BMS-813160 300 mg two times a day+gem/nabP n=35	gem/nabP n=32
Age, median (range), years	66 (43–85)	66 (46–76)	66 (49–84)
Age ≥65 years, n (%)	19 (54)	22 (63)	17 (53)
Male, n (%)	20 (57)	20 (57)	17 (53)
White, n (%)	34 (97)	32 (91)	27 (84)
Baseline BMI, median (range), kg/m2	25 (17–38)	26 (19–41)	25 (16–35)
ECOG PS, n (%)
0	18 (51)	15 (43)	11 (34)
1	17 (49)	20 (57)	21 (66)
Prior systemic therapy, n (%)
Adjuvant	5 (14)	2 (6)	7 (22)
Neoadjuvant	2 (6)	5 (14)	1 (3)
Radiotherapy	0	0	0
Prior pancreas surgery (pancreatectomy or Whipple), n (%)	8 (23)	9 (26)	7 (22)
Liver metastases, n (%)	22 (63)	18 (51)	14 (44)
Lung metastases, n (%)	2 (6)	5 (14)	4 (13)
Neutrophil:lymphocyte ratio, median (range)	4 (1–24)	4 (1–9)	3 (1–14)

BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; gem, gemcitabine; 1L PDAC, first-line pancreatic ductal adenocarcinoma; nabP, nab-paclitaxel.

In the 2L CRC cohort, 100 patients were randomized, 90 (90%) were treated, and 80 (80%) were evaluable by BICR (online supplemental figure S4). The most common reason for treatment discontinuation was progressive disease. Median age was 53 years (online supplemental table S3). Most patients were white (84%) and male (63%).

In both the 1L PDAC and 2L CRC cohorts, a disproportionate number of patients randomized to the chemotherapy-only treatment group (1L PDAC, n=41; 2L CRC, n=33) were not treated (1L PDAC, n=9 (22%); 2L CRC, n=7 (21%)).

Efficacy: 1L PDAC cohort

Among patients with 1L PDAC, those receiving BMS-813160 300 mg two times a day+gem/nabP+nivolumab had an ORR of 37%, including 1 patient who achieved a complete response (CR) and 12 patients who achieved partial responses (PRs) (table 4). The ORR was 26% (3 CRs and 6 PRs) in patients receiving BMS-813160 300 mg two times a day+gem/nabP and 28% (0 CRs and 9 PRs) in those receiving gem/nabP. The median DOR among responders treated with BMS-813160+gem/nabP+nivolumab was 45 weeks (95% CI 26.1 to not evaluable) compared with 121 weeks in the BMS-813160+gem/nabP group and 31 weeks for gem/nabP only. In addition, 91% and 88% of responses lasted ≥24 weeks in the BMS-813160+gem/nabP+nivolumab and BMS-813160+gem/nabP cohorts versus 57% in the gem/nabP cohort.

Table 4. Best overall response and duration of response per RECIST V.1.1 by BICR in patients with 1L PDAC in part 2.

BOR, n (%)	BMS-813160 300 mg two times a day+gem/nabP+nivolumab n=35	BMS-813160 300 mg two times a day+gem/nabP n=35	gem/nabP n=32
ORR	13 (37.1)	9 (25.7)	9 (28.1)
95% CI	21.5 to 55.1	12.5 to 43.3	13.7 to 46.7
CR	1 (2.9)	3 (8.6)	0
PR	12 (34.3)	6 (17.1)	9 (28.1)
SD	10 (28.6)	16 (45.7)	11 (34.3)
PD	2 (5.7)	2 (5.7)	6 (18.8)
NE*	10 (28.6)	8 (22.9)	6 (18.8)
Time to response, median (range), weeks	8.4 (6.1–23.1)	7.9 (6.9–16)	9.0 (7.1–20.4)
DOR, median (95% CI), weeks	44.6 (26.1 to NE)	121.0 (16.3 to NE)	31.0 (13.1 to NE)
DOR ≥24 weeks, %	91	88	57

^*Includes those that were missing imaging (baseline and/or on treatment) or did not have measurable disease at baseline.

BICR, blinded independent central review; BOR, best overall response; CR, complete response; DOR, duration of response; gem, gemcitabine; 1L PDAC, first-line pancreatic ductal adenocarcinoma; nabP, nab-paclitaxel; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

The 24-week PFS rate was 56% in the BMS-813160 300 mg two times a day+gem/nabP+nivolumab group, 56% in the BMS-813160 300 mg two times a day+gem/nabP group, and 50% in the gem/nabP group (figure 1A). The 52-week OS rate was 37% with BMS-813160 300 mg two times a day+gem/nabP+nivolumab, 51% with BMS-813160 300 mg two times a day+gem/nabP, and 29% with gem/nabP alone (figure 1B).

Figure 1. (A) PFS per RECIST V.1.1 by BICR and (B) OS in patients with 1L PDAC in part 2. Red lines indicate PFS and OS rates at 24 and 52 weeks. BICR, blinded independent central review; gem, gemcitabine; mOS, median overall survival; mPFS, median progression-free survival; nabP, nab-paclitaxel; nivo, nivolumab; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; 1L PDAC, first-line pancreatic ductal adenocarcinoma.

Safety: 1L PDAC cohort

Median (range) duration of BMS-813160 exposure was 12 weeks (0.7–139) with BMS-813160 300 mg two times a day+gem/nabP+nivolumab and 19 weeks (0.4–130) with BMS-813160 300 mg two times a day+gem/nabP. Median (range) duration of gem/nabP exposure was 18 weeks (1–137) in the BMS-813160 300 mg two times a day+gem/nabP+nivolumab group, 24 weeks (1–128) in the BMS-813160 300 mg two times a day+gem/nabP group, and 15 weeks (1–47) with gem/nabP.

The proportions of patients experiencing any-grade TEAEs were similar across treatment groups (100% with BMS-813160 300 mg two times a day+gem/nabP+nivolumab, 100% with BMS-813160 300 mg two times a day+gem/nabP, and 97% with gem/nabP; table 5). Any-grade rash was more common with BMS-813160 300 mg two times a day+gem/nabP+nivolumab (n=12 (34%)) and BMS-813160 300 mg two times a day+gem/nabP (n=7 (20%)) than with gem/nabP alone (n=3 (9%)). The occurrence of any-grade TRAEs was also similar across treatment groups (94% with BMS-813160 300 mg two times a day+gem/nabP+nivolumab, 100% with BMS-813160 300 mg two times a day+gem/nabP, and 97% with gem/nabP); nausea, fatigue, diarrhea, and anemia were the most common TRAEs. Grade 3/4 TRAEs were reported in 60%, 86%, and 69% of patients treated with BMS-813160 300 mg two times a day+gem/nabP+nivolumab, BMS-813160 300 mg two times a day+gem/nabP, and gem/nabP, respectively.

Table 5. Safety in patients with 1L PDAC in part 2.

n (%)	BMS-813160 300 mg two times a day+gem/nabP+nivolumab n=35		BMS-813160 300 mg two times a day+gem/nabP n=35		Gem/nabP n=32
	Any Grade	Grade 3–5	Any Grade	Grade 3–5	Any Grade	Grade 3–5
TEAE	35 (100)	30 (85.7)*	35 (100)	32 (91.4)	31 (96.9)	25 (78.1)†
TRAE	33 (94.3)	21 (60.0)	35 (100)	30 (85.7)	31 (96.9)	22 (68.8)
Treatment-emergent SAE	22 (62.9)	16 (45.7)*	24 (68.6)	18 (51.4)	15 (46.9)	13 (40.6)†
Treatment-related SAE	12 (34.3)	7 (20.0)	9 (25.7)	7 (20.0)	3 (9.4)	2 (6.3)
TEAE leading to discontinuation	8 (22.9)	5 (14.3)	11 (31.4)	8 (22.9)	3 (9.4)	1 (3.1)
TRAE leading to discontinuation	5 (14.3)	2 (5.7)	8 (22.9)	7 (20.0)	2 (6.3)	0
Most common TRAEs (occurring in ≥20% of patients in any treatment group)
Nausea	18 (51.4)	1 (2.9)	21 (60.0)	0	14 (43.8)	2 (6.3)
Fatigue	20 (57.1)	3 (8.6)	18 (51.4)	3 (8.6)	15 (46.9)	2 (6.3)
Peripheral sensory neuropathy	10 (28.6)	0	17 (48.6)	7 (20.0)	8 (25.0)	0
Anemia	15 (42.9)	15 (14.3)	17 (48.6)	9 (25.7)	18 (56.3)	7 (21.9)
Alopecia	11 (31.4)	0	13 (37.1)	0	12 (37.5)	0
Rash	12 (34.3)	0	7 (20.0)	1 (2.9)	3 (9.4)	0
Diarrhea	11 (31.4)	2 (5.7)	11 (31.4)	2 (5.7)	7 (21.9)	1 (3.1)
Decreased appetite	11 (31.4)	1 (2.9)	11 (31.4)	1 (2.9)	8 (25.0)	0
Fever	11 (31.4)	0	9 (25.7)	0	9 (28.1)	0
Decreased WBC count	7 (20.2)	1 (2.9)	8 (22.9)	5 (14.3)	6 (18.8)	3 (9.4)
Peripheral edema	5 (14.3)	0	8 (22.9)	0	7 (21.9)	0
Decreased neutrophil count	10 (28.6)	7 (20.0)	7 (20.0)	5 (14.3)	14 (43.8)	12 (37.5)
Neutropenia	4 (11.4)	2 (5.7)	7 (20.0)	4 (11.4)	4 (12.5)	2 (6.3)
Decreased platelet count	7 (20.2)	2 (5.7)	7 (20.0)	2 (5.7)	8 (25.0)	2 (6.3)
Dizziness	0	0	7 (20.0)	0	1 (3.1)	0

^*Grade 5 TEAEs were cerebrovascular accident (n=1) and sepsis (n=1).

^†Grade 5 TEAE was malignant neoplasm progression (n=1).

gem, gemcitabine; 1L PDAC, first-line pancreatic ductal adenocarcinoma; nabP, nab-paclitaxel; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; WBC, white blood cell.

TRAEs led to treatment discontinuation in 14% (n=5; BMS-813160 300 mg two times a day+gem/nabP+nivolumab), 23% (n=8; BMS-813160 300 mg two times a day+gem/nabP), and 6% (n=2; gem/nabP alone) of patients (table 5). Peripheral sensory neuropathy was the most common AE leading to discontinuation of BMS-813160 300 mg two times a day+gem/nabP+nivolumab (n=2) and BMS-813160 300 mg two times a day+gem/nabP (n=4; 3 were grade 3/4). The only treatment-related SAEs reported in >1 patient per cohort were febrile neutropenia (BMS-813160 300 mg two times a day+gem/nabP+nivolumab, n=2; BMS-813160 300 mg two times a day+gem/nabP, n=2; and gem/nabP, n=1) and fever (BMS-813160 300 mg two times a day+gem/nabP+nivolumab, n=3; BMS-813160 300 mg two times a day+gem/nabP, n=3; and gem/nabP, n=1). Three grade 5 TEAEs occurred (cerebrovascular accident (n=1) and sepsis (n=1), each in a patient receiving BMS-813160 300 mg two times a day+gem/nabP+nivolumab, and malignant neoplasm progression (n=1) in a patient receiving gem/nabP); none were considered treatment related by the treating investigator.

Efficacy: 2L CRC cohort

Among patients with 2L CRC, ORRs were 19% (3 CRs and 3 PRs) with BMS-813160 300 mg two times a day+FOLFIRI, 13% (1 CR and 3 PRs) with BMS-813160 150 mg once daily+FOLFIRI, and 27% (2 CRs and 5 PRs) with FOLFIRI alone (online supplemental table S4); median DORs among responders were 32 weeks, 42 weeks, and not reached, respectively. The 24-week PFS rate was highest (72%) with FOLFIRI, followed by BMS-813160 300 mg once daily+FOLFIRI (42%) and BMS-813160 150 mg once daily+FOLFIRI (40%; online supplemental figure S5A). The 52-week OS rate was also highest with FOLFIRI (72%) compared with patients receiving BMS-813160 300 mg once daily+FOLFIRI (61%) and BMS-813160 150 mg once daily+FOLFIRI (71%) (online supplemental figure S5B).

Safety: 2L CRC cohort

Median (range) duration of BMS-813160 exposure was similar across treatment groups (17 weeks (0.1–103) with BMS-813160 300 mg two times a day+FOLFIRI; 20 weeks (3–99) with BMS-813160 150 mg once daily+FOLFIRI). Median (range) duration of FOLFIRI exposure was also similar (19 weeks (2–95) with BMS-813160 300 mg two times a day+FOLFIRI; 22 weeks (2–99) with BMS-813160 150 mg once daily+FOLFIRI; and 16 weeks (2–111) with FOLFIRI).

Almost all patients experienced a TEAE of any grade (100% with BMS-813160 300 mg two times a day+FOLFIRI; 100% with BMS-813160 150 mg once daily+FOLFIRI; and 96% with FOLFIRI). Any-grade TRAEs occurred in 97%, 88%, and 89% of patients treated with BMS-813160 300 mg two times a day+FOLFIRI, BMS-813160 150 mg once daily+FOLFIRI, and FOLFIRI, respectively (online supplemental figure S5). Nausea was the most common TRAE, reported in 31%, 28%, and 38% of patients treated with BMS-813160 300 mg two times a day+FOLFIRI, BMS-813160 150 mg once daily+FOLFIRI, and FOLFIRI, respectively. Grade 3/4 TRAEs were reported in 44%, 41%, and 50% of patients treated with BMS-813160 300 mg two times a day+FOLFIRI, BMS-813160 150 mg once daily+FOLFIRI, and FOLFIRI, respectively. Treatment-emergent SAEs occurred in 38% of patients treated with BMS-813160 300 mg two times a day+FOLFIRI, 38% of patients treated with BMS-813160 150 mg once daily+FOLFIRI, and 23% of those receiving FOLFIRI. Five patients (16%) in the BMS-813160 300 mg two times a day+FOLFIRI group, three (9%) in the BMS-813160 150 mg once daily+FOLFIRI group, and two (8%) in the FOLFIRI group discontinued due to a TRAE. No grade 5 TEAEs occurred in the 2L CRC cohort.

Pharmacokinetics and pharmacodynamics

In patients with 1L PDAC, serum concentrations of BMS-813160 or gem/nabP were unchanged by administration as a combination therapy. A trend of greater reduction in tumor size was observed with increasing BMS-813160 exposure, and the addition of BMS-813160 to gem/nabP appeared to lead to greater reductions in tumor size than gem/nabP alone (R²=0.022, p value=0.227; online supplemental figure S6A). In patients with 2L CRC, there was no association between BMS-813160 exposure and reduction in tumor size (R²=0.001, p value=0.816; online supplemental figure S6B).

In both the 1L PDAC (online supplemental figure S7A–C) and 2L CRC cohorts (online supplemental figure S7D–F), tumor PD effects were confounded by the addition of chemotherapy. In the 1L PDAC cohort, 50% and 42% of patients treated with BMS-813160 300 mg two times a day+gem/nabP and BMS-813160 300 mg two times a day+gem/nabP+nivolumab, respectively, showed a decrease in CCR2-positive cell density (online supplemental table S6). An increase in CD163⁺ TAM density was observed in 76% of patients treated with BMS-813160 compared with 46% treated with gem/nabP alone. A decrease in CD8⁺ T-cell density occurred in 64% of patients treated with BMS-813160 300 mg two times a day+gem/nabP versus an increase in 77% of patients treated with BMS-813160 300 mg two times a day+gem/nabP+nivolumab.

Treatment-specific tumor PD changes indicated that all treatment regimens demonstrated an upregulation of genes associated with macrophages (CD68, macrophage receptor with collagenous structure, and mannose receptor C1; figure 2A). BMS-813160 300 mg+gem/nabP treatment resulted in an upregulation of type I interferon response-related genes (figure 2B), whereas treatment with BMS 813160 300 mg+gem/nabP+nivolumab resulted in an upregulation of CD8 T-cell and interferon-γ pathway-associated genes (figure 2C). Furthermore, CCL18 was significantly upregulated with each treatment regimen (figure 2D). The CCR2/5 ligand, CCL13, was significantly upregulated in groups treated with BMS-813160 (figure 2E). Lastly, the BMS IO 4-gene (LAG3, CD274, STAT1, and CD8) signature¹⁹ score was significantly upregulated in only the BMS-813160 150 mg+gem/nabP+nivolumab treatment group (figure 2F).

Figure 2. Treatment-specific tumor pharmacodynamic changes at C1D28. Differentially expressed genes pretreatment versus on-treatment in patients treated with (A) gem/nabP, (B) BMS-813160 300 mg+gem/nabP, and (C) BMS-813160 300 mg+gem/nabP+nivolumab. CCL18, CCL13 mRNA expression and BMS T-cell inflammation gene expression signature scores²⁷ in pretreatment versus on-treatment gene by treatment groups (test used for significance (D–F)). ANOVA, analysis of variance; CCL, chemokine ligand; CR, complete response; gem, gemcitabine; mRNA, messenger RNA; NA, not applicable; nabP, nab-paclitaxel; nivo, nivolumab; PD, progressive disease.

Increases in peripheral serum CCL2 and CCL4 levels were generally greater with BMS-813160+chemotherapy±nivolumab than chemotherapy alone in the 1L PDAC and 2L CRC cohorts. The maximum average fold change increases from baseline in CCL2 and CCL4 levels were ≈11-fold and ≈3.5-fold with BMS-813160+gem/nabP+nivolumab and ≈8-fold and ≈4-fold with BMS-813160+gem/nabP, respectively, in patients with 1L PDAC. Similarly, in patients with 2L CRC, the maximum average increases from baseline in CCL2 and CCL4 levels were ≈10-fold and ≈5-fold with BMS-813160 300 mg two times a day+FOLFIRI and ≈7-fold and ≈2-fold with BMS-813160 150 mg once daily+FOLFIRI, respectively (online supplemental figure S8A–D).

Biomarkers

An exploratory biomarker analysis was conducted to identify potential markers for patient enrichment of response to BMS-813160 in the 1L PDAC group (online supplemental tables 6 and 7). Patients with low baseline serum concentrations of CCL5 (RANTES) demonstrated a higher ORR (36% vs 15%) and 24-week PFS rate (46% vs 8%) when treated with BMS-813160 (pooled analysis of both experimental arms) versus gem/nabP alone (figure 3A,B). The differential benefit observed with BMS-813160 versus gem/nabP alone was not seen in the subset of patients with high baseline serum RANTES levels (figure 3C,D).

Figure 3. PFS and OS stratified by low (A, B) and high (C, D) baseline serum RANTES levels, respectively. BID, two times a day; CRC, colorectal cancer; FOLFIRI, folinic acid, 5-fluorouracil, and irinotecan; gem, gemcitabine; nabP, nab-paclitaxel; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival; RANTES, regulated on activation, normal T-cell expressed and presumably secreted; 1L, first line; 2L, second line.

Patients with low baseline serum IL-8 levels also had a higher ORR (41% vs 20%) and 24-week PFS rate (41% vs 30%) when treated with BMS-813160 (pooled analysis) versus gem/nabP alone (figure 4A,B). The differential benefit observed with BMS-813160 versus gem/nabP alone was not seen in the subset of patients with high baseline serum IL-8 levels (figure 4C,D).

Figure 4. PFS and OS stratified by low (A, B) and high (C, D) baseline serum IL-8 levels, respectively. BID, two times a day; CRC, colorectal cancer; FOLFIRI, folinic acid, 5-fluorouracil, and irinotecan; gem, gemcitabine; IL, interleukin; nabP, nab-paclitaxel; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival; 1L, first line; 2L, second line.

Random forest modeling was conducted to analyze the correlation structure between RANTES, IL-8, and other known prognostic clinical markers in PDAC to determine if there was an imbalance in the 1L PDAC data that should have been corrected during exploratory analysis. Serum RANTES and IL-8 levels were not found to be highly correlated with each other or other levels of prognostic markers, and an imbalance in arms was not observed (online supplemental figure S9).

Discussion

In this phase 1b/2 study of BMS-813160 plus chemotherapy and/or nivolumab in patients with PDAC or CRC, durable antitumor activity and trends towards improved PFS and OS were observed in the 1L PDAC cohort. Patients with 1L PDAC who received BMS-813160+gem/nabP+nivolumab had an ORR of 37% and a median DOR of 45 weeks (95% CI 26.1 to NA). ORRs in 2L CRC were 19% (6/32; BMS-813160 300 mg two times a day+FOLFIRI), 13% (4/32; BMS-813160 150 mg once daily+FOLFIRI), and 27% (7/26; FOLFIRI).

In the 1L PDAC group, treatment with BMS-813160 300 mg two times a day+gem/nabP with or without nivolumab was generally well tolerated. TRAEs were mainly attributed to chemotherapy, and rates were comparable to previous findings.²⁰ While BMS-813160 combination regimens were tolerable in the 2L CRC cohort, significant clinical efficacy was not demonstrated. These findings are consistent with a previous phase 1b trial evaluating the CCR2 inhibitor, PF-0413609, in combination with gem/nabP in the 1L treatment of metastatic PDAC.²¹

PK results support that BMS-813160 contributed to the efficacy seen in the study. The PK profile of BMS-813160 observed in this study is consistent with previous results in healthy participants. Additionally, results demonstrated evidence of target engagement and PD effects in the periphery. However, intratumoral macrophage densities appeared to increase rather than decrease on treatment with BMS-813160. In the PDAC cohort of this study, the addition of nivolumab resulted in increased tumor T-cell infiltration and activation, but these changes did not enhance clinical efficacy. These results suggest that the observed effects of BMS-813160 did not translate to the TME. A similar conclusion was made in a clinical trial evaluating the effect of anti-IL1β, anti-PD-1, and chemotherapy as a triplet regimen for advanced pancreatic cancer; changes in monocytes reduced systemic myeloid suppression but did not result in clinically efficacious alterations in the TME.²² Furthermore, the increase in CD163⁺ TAMs may be attributable to CCR2/5-insensitive embryonically derived macrophages, which appear to be prevalent in PDAC and are capable of proliferating in situ, exhibiting a pro-fibrotic phenotype and contributing to PDAC progression. These results may also be used to explain the upregulation of CD163, as this type of pancreatic macrophage marker increases in PDAC tissue. The emerging data suggest that a substantial fraction of TAMs in PDAC are embryonically rather than bone marrow derived. Embryonically derived macrophages are not dependent on CCR2/5 signaling but are capable of proliferating in situ, which may explain why CD163⁺ TAM numbers increase rather than decrease on treatment with CCR2/5 antagonist.²³ Additionally, a treatment-related decrease in CD8⁺ T cells may also be explained by the fact that a subset of activated CD8⁺ T cells express CCR2 and could have been impacted by CCR2/5 blockade.²⁴

Two biomarkers potentially predictive of clinical efficacy of BMS-813160 were identified. Exploratory preliminary biomarker analysis conducted during the study revealed that patients with low baseline serum RANTES gene expression had better outcomes if they received BMS-813160+gem/nabP versus gem/nabP alone. This finding may suggest that low baseline RANTES levels followed by temporally rising RANTES concentrations may be required for chemokine gradient and directional migration of immune cells; high chemokine concentrations may desensitize target cells through receptor downregulation, thereby blocking immune cell migration. Furthermore, the hypothesis that variations in the expression of genes involved in the immune response are associated with varying outcomes to treatment is consistent with a study confirming that clinical outcomes were influenced by immune response and unique single-nucleotide polymorphisms within genes for immune checkpoints in patients with colorectal liver metastases pretreated with bevacizumab.²⁵ Alternatively, patients with high baseline serum RANTES expression may not benefit from CCR2/5 blockade since biological effects of RANTES can also be mediated by CCR1, CCR3, and CCR4. Patients with low serum baseline IL8 levels also had better outcomes if they received BMS-813160+gem/nabP versus gem/nabP alone. The low IL8 levels could reflect a TME with low neutrophil content, which suggests a potential resistance mechanism in patients treated with CCR2/5 antagonists. Conversely, high serum IL8 expression could indicate increased tumor neutrophil recruitment, which could potentially impede clinical efficacy of BMS-813160 therapy, a hypothesis consistent with published findings that elevated baseline serum IL8 levels are associated with poor outcomes.²⁶ Results from random forest modeling indicated that serum RANTES and IL-8 levels were not found to be highly correlated with other prognostic markers or each other. It should be recognized that these results should only be interpreted as hypothesis generating and should not be used to guide treatment decisions without validation.

We acknowledge that the relatively small number of patients in this phase 1b/2 trial (eg, the 2L CRC cohort and 1L PDAC cohort) could limit the analyses and interpretation of these data. Furthermore, patient dropout or discontinuation once randomized or assigned to standard of care is common in CRC and PDAC trials, as observed in this present study. This leads to a potential selection bias in the standard-of-care cohort, which may have limited statistical power for analyses, unbalanced cohorts, and skewed results. It should also be noted that the duration of treatment exposure was different between treatment arms, which is an important caveat to consider when evaluating BMS-813160 dosage effects.

Conclusion

This study demonstrated the tolerability of BMS-813160 and that the combination of BMS-813160 and chemotherapy with or without nivolumab elicited durable antitumor activity and trends towards improved PFS and OS in patients with 1L PDAC.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.