LBA TBC (ID 783)
2MO - First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in metastatic non-small cell lung cancer (mNSCLC): clinical outcomes and biomarker analyses from CheckMate 592 (ID 347)
- S. Gettinger (New Haven, CT, United States of America)
- S. Gettinger (New Haven, CT, United States of America)
- M. Schenker (Craiova, Dolj, Romania)
- J. De Langen (Amsterdam, Netherlands)
- J. Fischer (Weinsberg, Germany)
- D. Morgensztern (St. Louis, United States of America)
- T. Ciuleanu (Cluj-Napoca, Romania)
- T. Beck (Rogers, United States of America)
- J. De Castro Carpeno (Madrid, Spain)
- C. Schumann (Kempten, Germany)
- X. Yang (Midlothian, United States of America)
- B. Telivala (Jacksonville, United States of America)
- K. Deschepper (Sint-Niklaas, Belgium)
- E. Nadal (L'Hospitalet de Llobregat, Barcelona, Spain)
- K. Schalper (New Haven, United States of America)
- T. Spires (Lawrenceville, United States of America)
- D. Balli (Princeton, United States of America)
- A. Nassar (Uxbridge, United Kingdom)
- S. Karam (Cambridge, United States of America)
- A. Bhingare (Cambridge, United States of America)
- D. Spigel (Nashville, TN, United States of America)
Abstract
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.
| Parts 1 and 2 combined | |||||
|---|---|---|---|---|---|
| All treated pts n = 230 | tTMBa | bTMBa | |||
| ≥10 mut/Mb n = 49 | <10 mut/Mb n = 87 | ≥21 mut/Mb n = 57 | <21 mut/Mb n = 110 | ||
| ORR, % (95% CI) | 31.7 (25.8-38.2) | 51.0 (36.3-65.6) | 21.8 (13.7-32.0) | 47.4 (34.0-61.0) | 24.5 (16.8-33.7) |
| Odds ratio (95% CI) | - | 3.73 (1.75-7.94) | 2.77 (1.41-5.45) | ||
| atTMB was measured by the Illumina TruSight Oncology 500 assay or the FoundationOne CDx assay; bTMB by Guardant OMNI. TMB cutoffs were determined by the Youden Index, which enables the selection of an optimal threshold value for the diagnostic marker. | |||||
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.
3MO - Comprehensive biomarkers (BMs) analysis to predict efficacy of PD1/L1 immune checkpoint inhibitors (ICIs) in combination with chemotherapy: a subgroup analysis of the Precision Immuno-Oncology for advanced Non-Small CEll Lung CancER (PIONeeR) trial (ID 583)
- F. Barlesi (Villejuif, CEDEX 20, France)
- L. Greillier (Marseille, France)
- F. Monville (Marseille, Cedex 9, France)
- C. Audigier Valette (Toulon, CEDEX, France)
- S. Martinez (Aix-en-Provence, France)
- N. Cloarec (Avignon, France)
- S. Van Hulst (Nimes, Cedex 9, CEDEX 9, France)
- L. Odier (Gleize, France)
- F. Vely (Marseille, France)
- L. Juquel (Marseille, France)
- L. Arnaud (Marseille, France)
- S. Bokobza (Abingdon-on-Thames, United Kingdom)
- M. Hamimed (Marseille, France)
- M. Karlsen (Marseille, France)
- P. Dufosse (Marseille, France)
- A. Pouchin (Marseille, France)
- L. Ghezali (Marseille, Cedex 9, France)
- M. Le Ray (Marseille, Cedex 07, France)
- J. Fieschi-Meric (Marseille, Cedex 9, France)
- F. Barlesi (Villejuif, CEDEX 20, France)
- S. Benzekry (Le Chesnay, France)
Abstract
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 1st 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
Invited Discussant TBC (ID 784)
LBA TBC (ID 785)
62MO - Naxitamab Pivotal Clinical Trial Planned Interim Analysis of PFS and OS in Patients with Relapsed or Refractory High-risk Neuroblastoma (ID 611)
- J. Mora (Esplugues de Llobregat, Spain)
- J. Mora (Esplugues de Llobregat, Spain)
- G. Chan (Hong Kong, Hong Kong PRC)
- D. Morgenstern (Toronto, Canada)
- L. Amoroso (Genoa, Italy)
- K. Nysom (Copenhagen, Denmark)
- J. Faber (Mainz, Germany)
- A. Wingerter (Mainz, Germany)
- M. Bear (Indianapolis, United States of America)
- A. Rubio San Simon (Madrid, Spain)
- K. Tornøe (Hoersholm, Denmark)
- P. Sørensen (Hoersholm, Denmark)
- B. Kushner (New York, United States of America)
Abstract
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.
| KM estimates | PFS (N=52) | OS (N=52) |
| Median wks [95% CI] | 30.3 [18.4 – NE] | NE* [140 – NE] |
| At 26 wks [95%CI] | 59.8% [43.8 – 72.7] | 95.7% [84, 98.9] |
| At 52 wks [95% CI] | 34.9% [17.3 – 53.2] | 93.2 [80.3, 97.8] |
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
Invited Discussant TBC (ID 786)
LBA TBC (ID 787)
200MO - Anti–IL-8 BMS-986253 + nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with advanced cancer: update of initial phase 1 results (ID 442)
- M. Simonelli (Milan, Italy)
- E. Calvo (Madrid, Spain)
- D. Davar (Pittsburgh, United States of America)
- D. Richards (Tyler, TX, United States of America)
- M. Gutierrez (Hackensack, United States of America)
- V. Moreno Garcia (Madrid, Spain)
- T. Marron (New York, United States of America)
- S. Rottey (Gent, Belgium)
- A. Orcurto (Lausanne, Switzerland)
- D. Renouf (Vancouver, Canada)
- M. Joerger (St. Gallen, Switzerland)
- S. Barriga Falcon (Sevilla, Spain)
- J. Fan (Cambridge, United States of America)
- E. Gibson (Cambridge, United States of America)
- D. Chakraborty (Cambridge, United States of America)
- V. Arora (Cambridge, United States of America)
- I. Melero (Pamplona, Spain)
- M. Simonelli (Milan, Italy)
Abstract
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