lirilumab (BMS-986015) / Innate, BMS, Ono Pharmaceutical - LARVOL DELTA

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy. (PubMed, Eur Urol Oncol) - P1, P3 | "Neoadjuvant nivolumab-based immunotherapy was safe, feasible, and well tolerated in cisplatin-ineligible patients with MIBC. Although ypT0N0 rates were lower than expected, 2-yr survival rates seem to be comparable with those of other neoadjuvant immunotherapy trials. Nivolumab is being evaluated in the CA-017-078 trial (NCT03661320)."

Journal • P1 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris

New P1/2 trial • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=397 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | N=285 ➔ 397 | Trial completion date: Dec 2020 ➔ Jan 2022 | Trial primary completion date: Dec 2020 ➔ Jan 2022

Enrollment change • Trial completion date • Trial primary completion date • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=460 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jan 2022 ➔ Aug 2027 | Trial primary completion date: Jan 2022 ➔ Aug 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

CD40L and IL-4 Lymph Node-Associated Signals Protect B Cells from Rituximab-Induced ADCC via KIR and NKG2A. (PubMed, Clin Exp Immunol) - "Overall, this study identifies a novel mechanism of resistance of B cells to NK cell cytotoxicity and indicates that blockade of the HLA-E:NKG2A and HLA:KIR checkpoint axes could be beneficial for improving B cell depletion in patients with autoimmune diseases."

Journal • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus • CD40LG • HLA-E • IL4 • KLRC1

Nivolumab and pembrolizumab in treatment of relapsed or refractory classical Hodgkin lymphoma: Systematic review and meta-analysis of clinical trials (ASH 2025) - "Managementinvolves platinum/gemcitabine-based chemotherapy, brentuximab vedotin (BV), autologous stem celltransplant (ASCT), or PD-1 inhibitors that have led to improved outcomes in the past decade...Nivolumab andpembrolizumab monotherapies were investigated in 5 and 3 trials, respectively; BV with nivolumab wasstudied in 2 trials, the rest of the studies evaluated different combinations of immune-chemotherapies(n=2) or different immunotherapies (n=4), such as ipilimumab (±BV) and lirilumab... This meta-analysis confirms that both pembrolizumab and nivolumab in the treatment ofr/r cHL similarly improve clinical outcomes with an acceptable safety profile. As the treatment landscapeof r/r cHL evolves and with the Introduction of PD-1 inhibitors in the frontline setting, the efficacy of theseagents in combination with other treatment modalities, including emerging immunotherapeutic agents,should be investigated. Patients with multiple comorbidities, prior..."

Retrospective data • Review • Classical Hodgkin Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Human Immunodeficiency Virus • Infectious Disease • Lymphoma

Neoadjuvant Immunotherapy in Bladder Cancer: Ushering in a New Era of Treatment-A Systematic Review of Current Evidence. (PubMed, Eur Urol Open Sci) - "Perioperative chemoimmunotherapy with durvalumab plus cisplatin/gemcitabine showed greater OS than chemotherapy alone in the NIAGARA trial. The NEMIO trial achieved the highest 12-mo OS rate of 97%, using durvalumab in combination with tremelimumab and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, followed by the AURA trial (95%) and the LCCC1520 trial (91%). At 24 mo, the NEBULA trial reported a 100% OS rate with three doses of atezolizumab, while PrECOG PrE0807 reached and OS rate of 89% with nivolumab and lirilumab. The highest rates of grade 3 and 4 irAEs were reported for nivolumab combined with ipilimumab (54%) and for durvalumab combined with tremelimumab (64%)...The results suggest that a combination of immunotherapy and chemotherapy may improve outcomes and reduce the risk of cancer returning. These findings could help shape future treatment options for patients with muscle-invasive bladder cancer."

IO biomarker • Journal • Review • Bladder Cancer • Dermatology • Genito-urinary Cancer • Oncology • Renal Disease • Solid Tumor

Rationale and feasibility of a rapid integral biomarker program that informs immune-oncology clinical trials: the ADVISE trial. (PubMed, J Immunother Cancer) - P1 | "Actualization of a patient-specific I-O combination treatment selection strategy is feasible, however, determination of de novo integral biomarker thresholds of novel I-O targets to facilitate effective treatment of PD-1-refractory cancer remains fraught. These data emphasize the difficulty of integral biomarker development for I-O in translating from immunotherapy treatment-naïve biospecimens to the selection of patients in the PD-1-refractory state."

Biomarker • IO biomarker • Journal • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • CD8 • CSF1R • FOXP3 • IDO1 • LAG3 • PD-L1 • TNFA

POTENTIATION OF PD-L1- AND PD-1-INDUCED PNEUMONITIS (CHEST 2024) - "CASE PRESENTATION: 65-year -old male with metastatic non-small lung cancer NSCLC (T4N1M0, stage IIIA) completed neoadjuvant chemo immunotherapy with carboplatin/paclitaxel/nivolumab between January and March...He was initially treated with solumedrol, meropenem, levaquin, bactrim but intubated on hospital day 4 for worsening hypoxia...Additionally, this incidence rises to over 11.8% when combination therapy includes nivolumab and other immune checkpoint inhibitors i.e lirilumab or Ipilimumab[1]... Although pneumonitis following immunotherapy has been well described in the literature, most cases respond to steroids. There has been no large-scale study that evaluates the possibility of an "additive" effect on the risk of developing high grade, fatal pneumonitis when Durvalumab is used after Nivolumab. As clinical guidelines recommend increasing use of Durvulumab, the possibility of potentiated toxicity resulting from the interaction from these two immunotherapy..."

IO biomarker • Cardiovascular • CNS Disorders • Cough • Fatigue • Infectious Disease • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Embolism • Solid Tumor • PD-1 • PD-L1

CheckMate 039: An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=316 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Jul 2024

Trial completion • Trial completion date • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

[PREPRINT] Randomized Phase 2 Trial of Lirilumab as maintenance Treatment in Acute Myeloid Leukemia: Results of the EFFIKIR Trial (medRxiv) - P2 | N=152 | EFFIKIR (NCT01687387) | Sponsor: Innate Pharma | "The median follow-up was 36.6 months. Lirilumab was well tolerated, with no significant hematological toxicity. The median LFS were 17.6, 6.7 and 13.9 months in the 0.1mg/kg arm, 1mg/kg arm and placebo arm, respectively. An excess in early relapse led to early termination of treatment in the 1mg/kg arm. Extensive analysis of immune cell fate following KIR blockade evidenced a decrease of KIR+ NK cell absolute counts following KIR blockade, associated with a decrease of Bcl-2. Lirilumab also bound antigen-experienced CD8+ T cells, and induced a transient decrease of CD69 expression. Besides, lirilumab bound vδ2+ γδT cells with a high cytotoxic potential, and induced a decrease of DNAM-1 and Bcl-2, the latter being associated with a decrease of KIR+ γδT cell, and with a drastic reduction of time to relapse."

P2 data • Preprint • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets. (PubMed, J Immunother Cancer) - "Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets."

Journal • Tumor cell • Melanoma • Oncology • Solid Tumor • B2M • HLA-E • IFNG • IL2 • KIR3DL1 • KLRC1

Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab. (PubMed, Sci Rep) - "Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells."

Checkpoint inhibition • Journal • Oncology • KIR2DL3

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy (Eur Urol Oncol, ScienceDirect) - P1b | N=43 | PrE0807 (NCT03532451) | "Among 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0–21%) of patients in cohort 1 and 7% (90% CI 1–20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, < ypT2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively."

P1 data • Bladder Cancer

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy (Eur Urol Oncol, ScienceDirect) - P1b | N=43 | PrE0807 (NCT03532451) | "Among 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0–21%) of patients in cohort 1 and 7% (90% CI 1–20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, < ypT2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively."

P1 data • Bladder Cancer

This is a product of teamwork for many years: investigator-initiated trial of nivolumab +/- lirilumab as neoadjuvant Tx in cisplatin-ineligible pts with MIBC! @koshkin85 was a fellow when we started! @SuzanneColeMD @MattGalsky @OncoAlert @Uromigos @eaonc

CheckMate 039: An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=316 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Nov 2022 ➔ Dec 2023

IO biomarker • Monotherapy • Trial completion date • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • PD-L1

Phase IB/II Study of Lirilumab with Azacytidine (AZA) in Relapsed AML (ASH 2017) - P2; "Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML with poor risk disease features. The efficacy data are preliminary and the study is ongoing. AZA with lirilimumab is also undergoing investigation in frontline and salvage settings in myelodysplastic syndrome (NCT02599649)."

Biomarker • Clinical • Next-generation sequencing • P1/2 data • Acute Myelogenous Leukemia • Biosimilar • Dermatology • Graft versus Host Disease • Myelodysplastic Syndrome

Randomized Phase 2 Trial of Lirilumab (anti-KIR monoclonal antibody, mAb) As Maintenance Treatment in Elderly Patients (pts) with Acute Myeloid Leukemia (AML): Results of the Effikir Trial (ASH 2017) - P2; "...Lirilumab is a 2nd generation anti-KIR mAb currently evaluated in multiple indications and combinations with encouraging preliminary results in combination with nivolumab in pts with squamous cell carcinoma of the head and neck (Leidner, SITC 2016)...Consolidation chemotherapy consisted of intermediate-dose single agent cytarabine (IDAC) in 53%, and 5+1 in 47% of the pts, according to the recommendations of the ALFA and FILO cooperative groups, respectively...Single agent lirilumab administered for up to 24 cycles was well tolerated. Lirilumab did not result in a statistically significant improvement of LFS in the challenging setting of maintenance in AML in elderly pts. Immune-pharmacological studies will be presented."

Clinical • P2 data • Acute Myelogenous Leukemia • Biosimilar • Dermatology • Head and Neck Cancer

Phase IB/II study of lirilumab with azacytidine (AZA) in relapsed AML. (ASCO 2017) - P2; "Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML. The efficacy data are still preliminary and the study is ongoing."

Biomarker • Clinical • Acute Myelogenous Leukemia • Biosimilar • Graft versus Host Disease • Pain

A randomized phase II study of chemoradiation (CRT) +/- nivolumab (Nivo) with sequential safety evaluations of Nivo +/- lirilumab (Liri) or ipilumumab (Ipi) concomitant with (C) RT in intermediate (IR) and high-risk (HR) head and neck squamous cell carcinoma (HNSCC) (RTOG 3504, NCT02764593). (ASCO 2017) - P3; "Parallel with Phase IIR are sequential safety evaluations (see Table) in platinum eligible and ineligible ( > 70 years; ≥3 grade neuropathy; ≥2 hearing loss; or CrCl 78% when the true toxicity rate is > 45% and treatment assessed tolerable is > 80% if the true toxicity rate is < 20%."

Biomarker • Clinical • HEOR • P2 data • Biosimilar • Gene Therapies • Head and Neck Cancer • Pain

PrE0807: Phase Ib Feasibility Trial of Neoadjuvant Nivolumab/Lirilumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=43 | Completed | Sponsor: PrECOG, LLC. | Active, not recruiting ➔ Completed

Trial completion • Bladder Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia. (ASCO 2022) - "gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm...studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose...noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine...reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm...administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70)...reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%)... Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.AE: adverse events; GI:..."

Review • Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Malignancies • Inflammation • Leukemia • Oncology • CD123

[VIRTUAL] PrE0807: A phase Ib feasibility trial of neoadjuvant nivolumab (N) without or with lirilumab (L) in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC). (ASCO 2021) - P1, P3 | "Clinical Trial Registry Number: NCT03532451 Funding: Bristol Myers Squibb Background: Neoadjuvant cisplatin-based chemotherapy (CT) prior to radical cystectomy (RC) improves overall survival (OS) in MIBC, but about half of pts are cisplatin-unfit or refuse it . Neoadjuvant N alone and N+L combination prior to RC were safe, feasible and well tolerated in cisplatin-ineligible pts with MIBC, but ypT0N0 rates were unexpectedly low, especially with N alone . Two phase 3 trials (NCT03661320; NCT04209114) are evaluating the peri-operative role of N + chemotherapy +/- Linrodostat in cisplatin-fit and N +/- Bempeg in cisplatin unfit patients and are also assessing biomarkers."

Clinical • IO biomarker • P1 data • Bladder Cancer • Cervical Cancer • Genito-urinary Cancer • Gout • Immune Modulation • Inflammation • Inflammatory Arthritis • Musculoskeletal Pain • Oncology • Otorhinolaryngology • Pain • Rheumatology • Solid Tumor • Urothelial Cancer • CD8