Background

A high unmet need remains for predictive biomarkers for efficacy in patients (pts) treated with immunotherapy. Here we report primary results from Parts 1 and 2 of CheckMate 592 (NCT03001882), an open-label, phase 2 trial exploring the association of biomarkers with efficacy of 1L NIVO + IPI in pts with mNSCLC.

Methods

Pts with previously untreated mNSCLC were enrolled to either Part 1 (stratified by tumor PD-L1 ≥1% and <1%) or Part 2 and received NIVO (240 mg Q2W) + IPI (1 mg/kg Q6W) until disease progression, unacceptable toxicity, or for ≤ 2 y of treatment (tx). Primary endpoints (EPs): ORR (per investigator) by baseline (BL) and on-tx biomarkers including PD-L1 expression in Part 1; ORR by BL tumor mutational burden in tissue and blood (tTMB and bTMB) in both Parts 1 and 2. Other EPs included safety and exploratory biomarker analyses. Four-gene inflammatory gene signature (CD8A, CD274, STAT-1, LAG-3) was assessed in biopsy samples at BL and on-tx by RNA sequencing.

Results

BL characteristics were generally similar between Part 1 (n = 60) and Part 2 (n = 170), and across tTMB and bTMB subgroups. At 12.5-mo minimum follow up, ORR in Part 1 was 30% and 39% in PD-L1 ≥1% (n = 30) and <1% (n = 28) subgroups, respectively. ORR by TMB (Parts 1 and 2 combined) is shown in the table. Four-gene inflammatory gene signature score showed a trend of increase on-tx (n = 17) compared to BL (n = 40) and was numerically higher in responders (complete or partial response; n = 13) vs non-responders (stable or progressive disease; n = 27); supporting data and additional efficacy results will be presented. Grade 3/4 tx-related adverse events occurred in 33% of treated pts. Table: 2MO

ORR by TMB

Conclusions

In CheckMate 592, high tTMB and bTMB were associated with better responses to 1L NIVO + IPI in pts with mNSCLC. Exploratory analyses suggest that tumor inflammation, measured by 4-gene inflammatory gene signature score, may increase with NIVO + IPI treatment.

Clinical trial identification

NCT03001882.

Editorial acknowledgement

Medical writing and editorial assistance was provided by Meenakshi Subramanian at Evidence Scientific Solutions Inc.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

S. Gettinger: Other, Personal and Institutional, Member, Member of safety committee for another BMS trial evaluating immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Thoracic Medical Oncology, Yale Comprehensive Cancer Center. M. Schenker: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Sanofi, Regeneron, GSK, BeiGene, Astellas, Amgen, Bayer, Clovis, Gilead, Ipsen, Novartis, Pfizer, PharmaMar, Eisai, Tesaro. J. De Langen: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Boehringer, AstraZeneca; Non-Financial Interests, Institutional, Other: Merck Serono, Roche. J.R. Fischer: Financial Interests, Institutional, Research Grant: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead; Financial Interests, Institutional, Advisory Role: Bristol Meyers Squibb, MSD, Roche, Novartis, AstraZeneca, Sanofi, Pfizer, GSK, BeiGene, Pharma Mar, Amgen, Bayer, Gilead. D. Morgensztern: Financial Interests, Personal, Advisory Role: AbbVie, G1 Therapeutics, Lilly, Arcus; Financial Interests, Institutional, Research Grant: Heat Biologics, Merck, Celgene, AstraZeneca, Baxter, Incyte, Bristol Myers-Squibb, Epicentrx, Pfizer, Roche, Lilly, Altum, Array, Surface, Boehringer Ingelheim, Y-mabs. T. Ciuleanu: Financial Interests, Personal and Institutional, Other, Fee for clinical trial activities: Astelas Pharma, Janssen, Merck Sharp & Dohme, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boerigher Ingelheim, Bristol Meyers Squibb; Financial Interests, Institutional, Research Grant, PN-II-P4-ID-PCE-2020-2: University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca. T. Beck: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb. J. De Castro Carpeno: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Jansen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Sanofi; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Pfizer, F. Hoffmann-la Roche, Takeda, Sanofi, Bayer. C. Schumann: Non-Financial Interests, Personal, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Other, Clinical trial: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board, Presentation and medical writing: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb. K. Deschepper: Financial Interests, Institutional, Advisory Board: Amgen Belgium, Bristol Myers Squibb, AstraZeneca, MSD Belgium. E. Nadal: Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck Serono, Roche; Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb, MSD, Merck Serono, AstraZeneca, Lilly, Sanofi, Boehringer Ingelheim, Amgen, Roche, Bayer; Financial Interests, Institutional, Advisory Board: Roche, Apollomica. K. Schalper: Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Navigate Biopharma, Tesaro/GSK, Moderna Inc., Takeda, Surface Oncology, Pierre-Fabre, Merck, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer Ingelheim, Akoya Biosciences; Financial Interests, Personal and Institutional, Advisory Role: Clinica Alemana Santiago, Shattuck Labs, EMD Serono, Torque/Repertoire Therapeutics, Agenus, Genmab, OnCusp, Parthenon Therapeutics, Molecular Templates, Genmab; Financial Interests, Institutional, Invited Speaker: PeerView, Roche, Genmab, BMS, Takeda, Merck; Financial Interests, Institutional, Advisory Board: Agenus, Shattuck Labs. T. Spires: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Full or part-time Employment, Stock or stock options: Bristol Myers Squibb. S. Karam: Financial Interests, Personal, Full or part-time Employment, Stock Options: Bristol Myers Squibb. D.R. Spigel: Financial Interests, Institutional, Research Grant: Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeutics, Ascendis Pharma, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, Bristol Meyers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Endeavor, Erasca, Faeth Therapeutics, FujiFilm Pharmaceuticals, G1 Therapeutics, Roche/Genentech, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo Oncology, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, SeaGen, Shenzhen Chipscreen Biosciences, Synthekine, Taiho, Tango Therapeutics, Tarveda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Zai Laboratory; Financial Interests, Institutional, Advisory Role: AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, GlaxoSmithKline, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Novocure, Pfizer, Pyxis Oncology, Regeneron Pharmaceuticals, Roche/Genentech, Sanofi-Aventis. All other authors have declared no conflicts of interest.

Background

Prediction of ICIs efficacy in combination with chemotherapy remains an unmet need in patients (pts) with advanced NSCLC. The PIONeeR trial aims to predict response/resistance to PD1/L1 ICIs through a comprehensive multiparametric BMs analysis.

Methods

We focused on the first 155 ECOG PS0-1 pts treated with pembrolizumab in combination with platinum-based chemotherapy as 1^st line therapy. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout 24 weeks. Immune contexture was characterized in tumor & blood through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC / digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma pharmacokinetics, leading to 298 assessed BMs. Multimodal data integration through supervised machine learning (SML) was performed with bootstrap LASSO on a train (N=116) and a test dataset (N=39) to establish a BMs signature able to predict progression-free-survival (PFS) at 1 year.

Results

Pts were mainly male (65%), smokers (96%) and <70yrs (82%). Tumors were mainly nonsquamous (87%) with PD-L1 TPS>1% in 38.4% of cases. With a median follow of 11.4 months, median PFS was 9.8 months and median overall survival was not reached. Using baseline data, SML identified a 15 BMs signature including classical (age, ECOG PS, PD-L1 TPS…) but also experimental parameters (CD45+ CD16+ cells density in tumor, CD45- CD73+ cells density in stroma, tissue factor and CD31+ CD41+ AnC+ microparticles blood concentrations…) with high predictive performance for PFS. On the train dataset, C-index was 0.79±0.13 and AUC was 0.81±0.28. These scores were confirmed on the test dataset, with C-index of 0.80 and AUC of 0.84.

Conclusions

The PIONeeR trial provides a novel comprehensive BMs analysis to establish predictive models of response/resistance to ICI in advanced NSCLC pts. Combination of BMs can individually predict outcomes of chemo-immunotherapy.

Clinical trial identification

NCT03493581.

Legal entity responsible for the study

Assistance Publique des Hôpitaux de Marseille.

Funding

French National Research Agency.

Disclosure

F. Monville, L. Ghezali, J. Fieschi-Meric: Financial Interests, Personal, Full or part-time Employment: Veracyte. All other authors have declared no conflicts of interest.

Background

Up to 10% of patients (pts) with NB develop CNS/LM metastases, with recently reported 1-year overall survival rate of ∼25% (+/-6%). OMB is a murine monoclonal antibody that binds B7H3, a transmembrane glycoprotein highly expressed in NB and other solid tumors. Iodine-131-labeled OMB is administered into the CSF via indwelling intraventricular Ommaya reservoir to achieve a high cerebrospinal fluid (CSF):blood absorbed dose ratio. We report an updated analysis of Trial 101: ¹³¹I-OMB in pts with NB CNS/LM metastases.

Methods

Trial 101 (NCT03275402) is a phase-2/3, single-arm, global trial in pts 0-18 years old with radiographically and/or histologically confirmed CNS/LM NB. As of 31 March 2022, 50 pts were included in the efficacy and safety analysis. Treatment consisted of 2 doses of up to 50 mCi ¹³¹I-OMB (age-based) administered at least 4-weeks apart. A dosimetry dose of 2 mCi ¹³¹I-OMB was administered to 26 out of the 50 patients 1 week before the first treatment dose. The primary endpoint was CNS/LM progression-free survival (PFS) at 6 months (mo). Secondary endpoints were overall survival (OS) at 12 mo (from first treatment dose) and independently assessed objective response rate (ORR) at 6 mo. CSF:blood absorbed dose ratio and absorbed doses to normal organs were assessed. Long-term follow-up is ongoing.

Results

The estimated CNS/LM PFS at 6 mo was 75% (95% CI 61-85); 12-mo OS was 79% (95% CI 64-89). ORR was 35% (7 / 20 pts with measurable disease at baseline) with complete response (CR) of 25%. Disease control rate (CR+PR+SD) was 70%. Most frequent grade 3-4 adverse events were myelosuppression. Four pts had intracranial hemorrhage; 2 had chemical meningitis (prior to implementing high-dose corticosteroid pre-medication). The CSF:blood absorbed dose mean ratio was 1.219 Gy:0.016 Gy, or ∼76 times higher in the CSF compared to the blood, following the dosimetry dose. Liver, brain, bladder showed highest organ absorbed doses.

Conclusions

These results suggest that ¹³¹I-OMB has an acceptable dosimetry, manageable safety profile, and may provide survival and clinical benefit (OS, CNS/LM PFS, ORR) for pts with NB CNS/LM metastases.

Clinical trial identification

NCT03275402.

Legal entity responsible for the study

Y-mAbs Therapeutics.

Funding

Y-mAbs Therapeutics.

Disclosure

J. Mora, M. Bear: Financial Interests, Personal, Advisory Role: Y-mabs Therapeutics. K. Streby: Financial Interests, Personal, Advisory Role: Y-mabs Therapeutics, Illumina Radiopharmaceuticals, LLC. H. Sano: Financial Interests, Personal, Other, Honoraria: Sanofi, Chugai, Bayer, Kyowa Kirin, JCR Pharma. A. Marachelian: Financial Interests, Personal, Other, Honoraria: Y-mabs Therapeutics; Financial Interests, Personal, Advisory Board: Y-mabs Thereapeutics; Financial Interests, Personal and Institutional, Research Grant: Y-mabs Therapeutics, United Therapeutics, Pfizer, Jubilant Therapeutics. K. Nysom: Financial Interests, Personal, Other, Honoraria: Y-mabs Therapeutics; Financial Interests, Personal, Advisory Role: Y-mabs Thereapeutics, Bayer, EUSA Pharma, Lilly; Financial Interests, Personal, Other, Teaching: Y-mabs Therapeutics, Bayer. N. Pandit-Taskar: Financial Interests, Personal, Advisory Role: Actinium Pharmaceuticals Inc., Illumina, ImaginAb, Medimmune Llc/AstraZeneca, Progenics Pharmaceuticals; Financial Interests, Personal and Institutional, Research Grant: Bayer, Bristol Myers Squibb, Clarity Pharma Ltd, ImaginAb, Janssen Pharmaceuticals, Regeneron Pharmaceuticals, Y-mAbs Therapeutics. P. Zanzonico: Financial Interests, Personal, Advisory Role: Radionetics Oncology; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Invited Speaker, Intellectual property license: Y-mabs Thereapeutics. S. Fabricius: Financial Interests, Personal, Stocks/Shares: Y-mabs Therapeutics; Financial Interests, Personal, Full or part-time Employment: Y-mabs Thereapeutics. M. During: Financial Interests, Personal, Full or part-time Employment: Y-mabs Therapeutics; Financial Interests, Personal, Stocks/Shares: Y-mabs Thereapeutics. J.R. Nielsen: Financial Interests, Personal, Full or part-time Employment: Y-mabs Therapeutics; Financial Interests, Personal, Stocks/Shares: Y-mabs Thereapeutics. K. Kramer: Financial Interests, Personal, Other, Intellectual Property Rights: Y-mabs; Financial Interests, Personal, Stocks/Shares: Y-mabs; Financial Interests, Personal, Other, Provision of services: Y-mabs. All other authors have declared no conflicts of interest.

Background

Naxitamab (NAX) is a humanized GD2-binding monoclonal antibody approved in the US with granulocyte-macrophage colony-stimulating factor (GM-CSF) under accelerated approval based in part on ad hoc analysis of data from the registrational phase II 201 trial (NCT03363373). We report progression free (PFS) and overall survival (OS) results of prespecified interim analyses.

Methods

This ongoing trial is evaluating NAX+GM-CSF in patients (pts) with relapsed/refractory high-risk neuroblastoma with residual disease in bone/bone marrow (BM). Pts with progressive or residual soft tissue disease were excluded. NAX was given intravenously on days 1/3/5 at 3mg/kg/day with GM-CSF subcutaneously on days -4 to 5; cycles repeated every 4 weeks (wks). Efficacy was evaluated centrally by independent pathology and radiology review per International Neuroblastoma Response Criteria (Park et al 2017). Kaplan-Meier (KM) analysis estimated duration of response (DoR), OS and PFS.

Results

At data cutoff (Dec 31, 2021), 52 pts with evaluable disease at baseline were eligible for efficacy assessment. Analyses showed 50% overall response rate (ORR; [95% CI 36-64%], 30% complete response (CR) rate [95% CI 25-53%] and 12 partial response (PR) rate [95% CI 4-23%]. Median number of cycles to onset of response in pts with CR or PR (n=26) was 2 (range 2-4), the same for pts with CR only (n=20) (range 2-8). Median number of wks to CR or PR was 6.7 (range 5.4-30.7). Median DoR was not estimable (NE; [95% CI, 24.9-NE]), i.e., 20 of 26 responders had ongoing response. See table for OS and PFS results. Frequent CTCAE grade 3 adverse events (AEs; safety population n=74) included hypotension (58%) and pain (54%); 6.8% of pts discontinued NAX due to AEs. Table: 62MO

Conclusions

NAX+GM-CSF provided durable and clinically significant ORR and CR, and promising OS and PFS. With a manageable safety profile and an option for outpatient administration NAX treatment addresses a significant unmet medical need.

Clinical trial identification

NCT03363373.

Legal entity responsible for the study

Y-mabs Therapeutics.

Funding

Y-mabs Therapeutics.

Disclosure

J. Mora: Financial Interests, Personal, Advisory Role: Y-mabs. D.A. Morgenstern: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Clarity Pharmaceuticals, EUSA Pharma, Roche, Y-mabs Therapeutics, Oncoheroes Biosciences. K. Nysom: Financial Interests, Personal, Advisory Role: Y-mAbs, EUSA Pharma, Bayer; Financial Interests, Personal, Invited Speaker: Y-mAbs, Bayer; Financial Interests, Personal, Other, Data Monitoring Committee: Lilly. J. Faber: Financial Interests, Institutional, Invited Speaker: Y-mAbs Therapeutics Inc.; Non-Financial Interests, Personal, Principal Investigator: Y-mAbs Therapeutics Inc.; Non-Financial Interests, Institutional, Other, Participation in compassionate use program: Y-mAbs Therapeutics Inc. M. Bear: Financial Interests, Personal, Advisory Role: Y-mAbs. K. Tornøe: Financial Interests, Personal, Full or part-time Employment: Y-mAbs; Financial Interests, Personal, Stocks/Shares: Y-mAbs. P.S. Sørensen: Financial Interests, Personal, Full or part-time Employment: Y-mAbs; Financial Interests, Personal, Stocks/Shares: Y-mAbs. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICIs) have clinical efficacy in the neoadjuvant setting in multiple solid cancer types. However, suitable tissue-agnostic complementary diagnostics to help guide and tailor treatment recommendations are still lacking. Ki67, a routinely used proliferation marker predicts efficacy of chemotherapeutics but not ICIs. Forkhead Box C1 (FOXC1), a transcriptional driver of cell plasticity/partial EMT/metastasis was recently demonstrated to have potential value in predicting therapeutic efficacy of chemotherapy+immunotherapy in TNBC. PDL1, a marker of immune evasion, is a proven companion diagnostic for ICI therapy in some but not all situations. We sought to evaluate a Ki67+FOXC1+PDL1-expression based response predictor as a possible complementary diagnostic for ICI therapy in the neoadjuvant setting across different cancer types.

Methods

Pre-treatment tumor biopsy MKI67, FOXC1 and PDL1 mRNA expression values were retrospectively obtained from patients who had been enrolled and treated in independent clinical trial cohorts (1. I-SPY2 TNBC: AC+taxane+pembrolizumab; 2. I-SPY2 TNBC: AC+olaparib+paclitaxel+durvalumab; 3. HNSCC: Nivolumab/Pembrolizumab). Optimized biomarker cut-off values based on model area-under-curve were leave-one-out cross validated in the first dataset for Predicted Responder (PR) and Predicted Non-responder (NR) prediction. The unmodified strategy was then validated in the other datasets.

Results

Observed response rates were 66% (n=29), 43% (n=21) and 11% (n=102) in the different regimens in datasets 1-3. In the biomarker-defined PR groups (n=22, n=12 and n=38) response rates were 82%, 75% and 21% in datasets 1-3. In the biomarker-defined NR groups (n=7, n=9 and n=64) response rates were 14%, 0% and 4% in datasets 1-3 (OR=27, 2.5-291.2 95%CI, p=0.003; OR=52, 2.3-1141.0 95%CI, p=0.01; OR=5, 1.3-21.9, 95%CI, p=0.008 respectively). Multiple logistic regression models may further improve predictive accuracy.

Conclusions

Complementary diagnostic role of pre-treatment MKI67+FOXC1+PDL1 expression merits prospective clinical trial evaluation in multiple cancer types treated with neoadjuvant ICIs alone or in combination with chemotherapeutics.

Legal entity responsible for the study

Onconostic Technologies, Inc.

Funding

Has not received any funding.

Disclosure

P.S. Ray: Non-Financial Interests, Institutional, Advisory Role: Onconostic Technologies: Practicing surgical oncologist and clinical investigator, identified as the presenting author on the submitted abstract. PSR is not an employee of the company (Onconostic Tehcnologies), but is founder and Chairman of the Scientific Advisory Board of the company which is an unpaid position. T. Ray: Financial Interests, Institutional, Project Lead: Onconostic Technologies. R. Hussa: Financial Interests, Institutional, Leadership Role: Onconostic Technologies.

Background

IL-8 is a CXC chemokine that exerts protumorigenic effects by promoting immunosuppression through neutrophil and myeloid-derived suppressor cell recruitment into the tumor microenvironment. Elevated serum IL-8 (sIL-8) is a negative prognostic factor in multiple cancer types. BMS-986253, a fully human IgG1κ anti–IL-8 mAb, binds IL-8 and prevents signaling through CXCR1/CXCR2. We present updated results from part 1 of the phase 1/2 trial of BMS-986253 + NIVO ± IPI in pts with advanced cancer (NCT03400332).

Methods

Pts with metastatic solid tumors and sIL-8 > 10 pg/mL at screening received IV BMS-986253 Q2W (1200, 2400, or 3600 mg) or Q4W (600, 1200, or 2400 mg) + NIVO 480 mg Q4W; pts with any sIL-8 at screening received BMS-986253 3600 mg Q2W + 4 doses of NIVO 1 mg/kg + IPI 3 mg/kg Q3W followed by BMS-986253 3600 mg Q2W + NIVO 480 mg Q4W.

Results

As of August 4, 2022, 159 pts (median age, 63 yr [range, 32–87]) received BMS-986253 with NIVO (n = 144) or BMS-986253 with NIVO + IPI (n = 15). Both regimens were well tolerated. Any-grade/grade ≥ 3 TRAEs were reported in 46.5%/7.6% of pts treated with BMS-986253 + NIVO and in 66.7%/33.3% of pts treated with BMS-986253 + NIVO + IPI. BMS-986253 exposure increased dose-proportionally. BMS-986253 resulted in dose-dependent reductions in free sIL-8, with tumor IL-8 suppression detected in most pts evaluated. Partial responses were observed in 6 of 46 (13%) pts with melanoma treated with BMS-986253 + NIVO; all pts with a response were previously treated with anti–PD-1 therapy, and 5 were previously treated with anti–CTLA-4 therapy. Complete response was achieved in 1 of 6 pts with melanoma treated with BMS-986253 + NIVO + IPI. Clinical activity with BMS-986253 + NIVO ± IPI was observed in pts with other tumor types.

Conclusions

BMS-986253 in combination with NIVO ± IPI demonstrated a tolerable safety profile with dose-proportional pharmacokinetics and robust free sIL-8 suppression. Preliminary and durable antitumor activity was observed across a range of doses/regimens. These findings support further evaluation of BMS-986253 in pts with melanoma following anti–PD-(L)1 therapy in the phase 2 part of this study.

Clinical trial identification

NCT03400332.

Editorial acknowledgement

Editorial assistance was provided by Matthew Weddig of Spark Medica Inc (USA), funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Chugai, Elevation Oncology, Ellipses Pharmacy, Genmab, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, SyneosHealth, T-knife, TargImmune; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Member of the Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Ownership Interest: Oncoart Associated, START; Financial Interests, Personal, Member, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi; Financial Interests, Personal, Member, Steering Committee Member: Novartis; Non-Financial Interests, Personal, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Personal, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) Foundation; Non-Financial Interests, Personal, Advisory Role: PsiOxus; Non-Financial Interests, Personal, Member: ASCO, EORTC, ESMO, SEOM. D. Davar: Financial Interests, Institutional, Research Grant: Arcus, Checkmate Pharmaceuticals, CellSight Technologies, Immunocore, Merck, Tesaro/GSK; Financial Interests, Personal, Other, Consultant: Checkmate Pharmaceuticals, Clinical Care Options (CCO), Finch Therapeutics, Gerson Lehrman Group (GLG), Medical Learning Group (MLG), Xilio Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Castle Biosciences; Financial Interests, Personal, Other, Intellectual Property: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020, US Patent 63/208,719, “Compositions and Methods For Determining Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Invited Speaker: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Sereno, Fate Therapeutics, GlaxoSmithKline, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta. V. Moreno Garcia: Financial Interests, Personal, Other, Consulting fees: Roche, BMS, Janssen, Basilea, Bayer; Financial Interests, Institutional, Principal Investigator, Institutional Funding: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BioInvent International AB, BMS, Boehringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. T. Marron: Financial Interests, Institutional, Research Grant: BMS, Boehringer Ingelheim; Financial Interests, Personal and Institutional, Research Grant: Regeneron; Financial Interests, Personal and Institutional, Advisory Board: Regeneron. D.J. Renouf: Financial Interests, Personal and Institutional, Other, Travel funds and research funding: Roche; Financial Interests, Personal, Advisory Board: Bayer, Elevation. M. Joerger: Financial Interests, Institutional, Advisory Role: Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi; Financial Interests, Personal, Research Grant: Swiss Cancer Research; Financial Interests, Personal, Other, Travel grants: Roche, Sanofi, Takeda. S. Barriga Falcon: Financial Interests, Institutional, Full or part-time Employment: BMS; Financial Interests, Institutional, Stocks/Shares: BMS. J. Fan: Financial Interests, Personal, Full or part-time Employment: BMS. E. Gibson: Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Stocks/Shares: Bristol Myers Squibb. D. Chakraborty: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. V. Arora: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. I. Melero: Financial Interests, Personal, Other, Grants and personal fees pertaining to the conduct of the study: Bristol Myers Squibb; Financial Interests, Personal, Other, Grants and personal fees: Genmab, Roche, AstraZeneca, PharmaMar; Financial Interests, Personal, Other, Personal consulting fees: F-Star, Numab, Gossamer, Pieris, Hotspot, Biolinerx, Bioncotech, Dompe, Boston Therapeutics, Alligator. All other authors have declared no conflicts of interest.