falbikitug (AZD0171) / Boehringer Ingelheim, AstraZeneca - LARVOL DELTA

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=126 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2025 ➔ Dec 2025

Trial completion date • Solid Tumor • CA 19-9

First-line (1L) AZD0171 + durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): Phase II study results (ESMO 2025) - P1b/2, P2 | "This phase 2 study (NCT04999969) evaluated 1L AZD0171 + D + standard-of-care gemcitabine (gem) and nab-paclitaxel (nab) in untreated mPDAC...Table: 2223P N=126 Any / AZD0171-related AE, n (%) 126 (100) / 99 (78.6) Grade ≥3 115 (91.3) / 46 (36.5) Serious 72 (57.1) / 14 (11.1) Immune-mediated 45 (35.7) / 28 (22.2) Leading to discontinuation of AZD0171 32 (25.4) / 11 (8.7) Leading to death 15 (11.9) / 3 (2.4)* OS Events, n (%) 76 (60.3) OS-12, % (80% CI) 53.8 (47.8–59.5) Median, mo (80% CI) 13.7 (11.6–15.6) PFS Events, n (%) 95 (75.4) Median, mo (80% CI) 7.3 (6.8–7.9) OR rate, % (80% CI) 34.9 (29.3–40.9) Disease control rate ≥16 weeks, % (80% CI) 65.9 (59.9–71.5) Median duration of response, mo (80% CI) 7.7 (6.4–9.5) Median tumoural CD8+ T cells, cells/mm 2 (range) Baseline (n=126) 271 (92–3847) Cycle 3 (n=23) 254 (23–1551) *Gastroenteritis, sepsis, septic shock; n=1 each Conclusions Safety of AZD0171 + D + gem + nab was consistent with prior studies of IO + CT...."

Clinical • IO biomarker • Metastases • P2 data • Hematological Malignancies • Leukemia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • LIF

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=126 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2024 ➔ Aug 2025

Trial completion date • Oncology • Solid Tumor

AstraZeneca CEO defends 'fantastic' Alexion buyout in face of $753M hit from dropped drug (FierceBiotech) - "Sabestomig, a PD-1xTIM3 bispecific antibody, was the other victim of AstraZeneca’s strategic portfolio prioritization. The company was testing the candidate in patients with lung and gastric cancers in a phase 1/2a trial but stopped enrollment well short of its target in December. Data did for the other two programs. AstraZeneca scrapped a phase 2 trial of anti-LIF antibody AZD0171 in pancreatic cancer because of efficacy data, although it still lists the asset as part of the multiregimen NeoCOAST-2 trial."

Enrollment status • Trial termination • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

AZD0171 (αLIF) in combination with chemotherapy and αPDL1 alters myeloid and cancer associated fibroblast (CAF) phenotype in the tumour microenvironment (TME) in preclinical models (SITC 2024) - P2 | "This was also observed with a combination of mAZD0171 with chemotherapy (docetaxel) and αPDL1.In the CAF rich D2A1-m2 orthotopic model, mAZD0171 in combination with αPDL1 resulted in significant transcriptomic changes that were not observed in the monotherapy arms; including alterations in CAF and myeloid populations and functional pathways...All animal protocols were approved by the institutional AWERB (Animal Welfare and Ethical Review Board) as well as by the UK Govt. Home Office under project licence number PP5259481."

Combination therapy • Preclinical • Tumor microenvironment • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • CSF1 • IL6 • LIFR

NeoCOAST-2: Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=490 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2029 ➔ May 2030 | Trial primary completion date: Dec 2029 ➔ May 2030

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

NeoCOAST-2: Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=490 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2028 ➔ Dec 2029 | Trial primary completion date: Dec 2028 ➔ Dec 2029

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W."

Journal • P2 data • PK/PD data • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Hepatology • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • IL6 • LIF • LIFR • STAT3

NeoCOAST-2: Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=490 | Recruiting | Sponsor: AstraZeneca | N=350 ➔ 490

Enrollment change • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

NeoCOAST-2: Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=350 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2026 ➔ Dec 2028 | Trial primary completion date: Mar 2026 ➔ Dec 2028

IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=126 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Gastrointestinal Cancer • Oncology • Solid Tumor • CA 19-9 • CD8

mAZD0171 mediated LIF blockade in combination with chemotherapy and PD-L1 inhibition repolarizes macrophages and increases T cell infiltration via CX3CR1-CX3CL1 axis (SITC 2023) - P2 | "In preclinical models we found that adding mAZD0171 to anti-PD-L1 enhanced chemotherapy efficacy and increased the frequency of immune-supportive macrophages and effector T-cells via a mechanism involving the CX3CR1/CX3CL1 axis. Together these preclinical data support the hypothesis that AZD0171 has the potential to sensitize solid tumors to chemotherapy/IO combinations, thereby supporting clinical assessment of this combination strategy (e. g. NCT04999969)."

Combination therapy • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • CX3CL1 • CX3CR1 • GZMB • IL6 • LIF

Study to Evaluate Safety, PK, PD, Immunogenicity & Antitumor Activity of MSC-1 in Patients With Adv Solid Tumors (clinicaltrials.gov) - P1 | N=41 | Completed | Sponsor: AstraZeneca | Terminated ➔ Completed

Metastases • Trial completion • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=115 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2023 ➔ Nov 2024 | Trial primary completion date: Oct 2023 ➔ Nov 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Solid Tumor • CA 19-9 • CD8

NeoCOAST-2: Neoadjuvant and Adjuvant Treatment in Resectable Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=350 | Recruiting | Sponsor: AstraZeneca | N=210 ➔ 350

Enrollment change • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • PD-L1

AZD0171 (anti-LIF) combines productively with chemotherapy and anti-PD-L1 in mouse models of cancer (AACR 2022) - P2 | "In a non-small cell lung carcinoma patient derived xenograft model, AZD0171 improved the tumor growth inhibitory effect of Carboplatin + Paclitaxel...mAZD0171 addition to oxaliplatin (OHP) or Docetaxel (DTX) chemotherapy plus anti-PD-L1 significantly elevated CD8 abundance and granzyme B expression in MC38 colon tumors...Together these data support the hypothesis that AZD0171 has the potential to sensitize solid tumors to chemotherapy/IO combinations. The safety and activity of AZD0171 is currently being assessed in a Ph2 clinical trial in combination with durvalumab (anti-PD-L1) and chemotherapy in metastatic pancreatic cancer (NCT04999969)."

IO biomarker • Preclinical • Breast Cancer • Colon Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD44 • CD8 • CXCL12 • CXCL9 • GZMB • IL6 • LIFR • MRC1

Therapeutic targeting of LIF overcomes macrophage mediated immunosuppression of the local tumor microenvironment. (PubMed, Clin Cancer Res) - "Overall, our findings highlight LIF as a therapeutic target for cancer immunotherapy."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • LIFR

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=115 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2024 ➔ Oct 2023 | Trial primary completion date: Mar 2024 ➔ Oct 2023

Combination therapy • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Solid Tumor • CA 19-9 • CD8

A phase 2 trial of first-line AZD0171 + durvalumab and chemotherapy (CT) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and CD8+ T cell infiltration (AACR 2022) - P1, P2 | "AZD0171 (formerly MSC-1), a first-in-class, humanized, IgG1 monoclonal antibody, binds specifically and potently to LIF, preventing downstream signaling. Secondary endpoints include objective response rate, disease control rate (confirmed response or SD ≥16 weeks), duration of response, median progression-free survival (PFS), PFS rate at 4 months, median OS, pharmacokinetics, pharmacodynamics (changes in serum CA19-9 level and tumor CD8+ T cell infiltration) and immunogenicity. The trial is currently recruiting."

Clinical • IO biomarker • P2 data • Hematological Malignancies • Leukemia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9 • CD8

Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors. (PubMed, ESMO Open) - "MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors."

Journal • P1 data • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • Solid Tumor • CD8

AstraZeneca aims to transform the oncology treatment landscape with diverse early pipeline and novel combinations at AACR (AstraZeneca Press Release) - "AstraZeneca will present new data underscoring the breadth of the Company’s early oncology portfolio at the American Association for Cancer Research (AACR) Annual Meeting in New Orleans, 8 to 13 April 2022. Data from 60 presentations, including 5 oral and 3 mini-oral presentations, will feature the Company’s next wave of potential cancer medicines spanning its immuno-oncology (IO), DNA Damage Response (DDR) and Antibody Drug Conjugate (ADC) scientific platforms. This includes key data shared from three potential new medicines that illustrate the Company’s innovative approach to designing molecules that address key challenges in treating cancer, including the ability to target different, complementary mechanisms."

Clinical data • Preclinical • Lung Cancer • Oncology • Solid Tumor

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2; N=115; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Gastrointestinal Cancer • Oncology • Solid Tumor • Cancer antigen 19-9 • CD8

[VIRTUAL] Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors (AACR-I 2020) - "The most common considered drug-related AEs were fatigue (N=8, 20%) and gastrointestinal disorder (N=8, 20%), and there was 1 considered drug-related SAE (Gr 2 osteonecrosis of jaw in a head and neck cancer patient who previously received radiation to the area and denosumab). Analysis of paired biopsies collected from matched metastatic lesions supported MSC-1 mediated STAT3 signaling inhibition, stimulatory (M1) to suppressive (M2) macrophage skewing in the majority of paired biopsies evaluated and increased CD8 T-cell infiltration in a subset of samples.Single agent MSC-1 was well tolerated in doses ranged from 75 mg to 1500 mg IV OD in patients with advanced solid tumors, showed promising activity as an anti-cancer therapy, and is Phase 1b/2 ready for combination with other agents. The updated final safety, efficacy, PK, LIF stabilization analyses, and tumor biopsy data will be presented."

Clinical • P1 data • Head and Neck Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD8

Phase I dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients (pts) with advanced solid tumours: Updated results (ESMO 2019) - P1; "MSC-1 holds promise as an anti-cancer therapy and should be readily combinable with other agents. Updated safety, efficacy, PK, LIF stabilization analyses, and paired tumor biopsy data will be presented. Clinical trial identification: NCT03490669."

Clinical • P1 data • Hematological Malignancies • Leukemia • Oncology

Safety, Pharmacokinetics and Clinical Activity of AZD0171 in Combination With Durvalumab and Chemotherapy in Locally Advanced or Metastatic Solid Tumours (clinicaltrials.gov) - P2; N=115; Not yet recruiting; Sponsor: AstraZeneca

New P2 trial • Gastrointestinal Cancer • Oncology • Solid Tumor • Cancer antigen 19-9 • CD8