danvatirsen (AZD9150) / AstraZeneca, Ionis, Flamingo Therapeutics - LARVOL DELTA

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2026 ➔ Nov 2026

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CDKN2A • HRD • MYCL • MYCN • RB1

Platform study of neoadjuvant durvalumab (D) alone or combined with novel agents in patients (pts) with resectable, early-stage non-small cell lung cancer (NSCLC): Pharmacodynamic correlates and circulating tumor DNA (ctDNA) dynamics in the NeoCOAST study (ESMO 2022) - P2 | "NeoCOAST (NCT03794544) is a phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) D alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Association of tumor mutational burden and additional biomarkers with clinical outcomes will be reported. Conclusions Single cycle of D+O and D+M resulted in greater intra-tumoral immunomodulation than D alone."

Circulating tumor DNA • Clinical • IO biomarker • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CD8 • EGFR • KLRC1 • KRAS • STAT3 • STK11 • TMB

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase 2 NeoCOAST Platform Trial. (PubMed, Cancer Discov) - "Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). Safety profiles for the combinations were similar to that of durvalumab alone. Multiplatform immune profiling suggested improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune-cell activation."

Immuno-oncology • IO biomarker • Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1 • STAT3

NeoCOAST: open-label, randomized, phase 2, multidrug platform study of neoadjuvant durvalumab alone or combined with novel agents in patients (pts) with resectable, early-stage non-small-cell lung cancer (NSCLC) (AACR 2022) - P2 | "NeoCOAST (NCT03794544) is a global, randomized phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) durvalumab (D) alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Pts with previously untreated, cytologically/histologically documented, resectable, Stage I [>2 cm]-IIIA NSCLC and ECOG PS 0-1 were randomized 1:1:1:1 (stratified by lymph node involvement) to receive D 1500 mg IV alone Q4W or combined with O 3000 mg IV Q2W, M 750 mg IV Q2W, or Da 200 mg IV QW, for one 28-day cycle, followed by surgery. One cycle of D + O, M or Da improved MPR and pCR rates vs D alone, with no new safety signals. Responses were associated with baseline tumor PD-L1 and CD73 expression levels. Pts with MPR receiving D+O or D+M had peripheral transcriptomic signatures related to immune cell function."

Clinical • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLRC1 • NT5E • STAT3

HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed Phase 2 Study in NSCLC Patients Who Progressed on Anti-PD-(L)1 Therapy (IASLC-WCLC 2022) - P2 | "Here we present mature efficacy and safety results for the initial combinations - durvalumab plus: olaparib (PARP inhibitor; Module 1), danvatirsen (STAT3 inhibitor; Module 2), ceralasertib (ATR inhibitor; Module 3), and oleclumab (anti-CD73 antibody; Module 5). Durvalumab plus ceralasertib demonstrated a promising efficacy signal, with a tolerable safety profile, in patients with advanced/metastatic NSCLC following failure of anti-PD-1/PD-L1-containing immunotherapy and ≥1 platinum-doublet regimen."

Biomarker • Clinical • IO biomarker • P2 data • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Danvatirsen plus pembrolizumab versus pembrolizumab for recurrent and/or metastatic head and neck squamous cell carcinoma (PEMDA-HN): a randomized, phase 2 trial. (PubMed, Clin Cancer Res) - P2 | "Combination danvatirsen + pembrolizumab did not improve ORR compared to pembrolizumab alone in first-line treatment of R/M-HNSCC. Further exploration of STAT3-targeted approaches is needed within the context of immunotherapy."

IO biomarker • Journal • P2 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1 • STAT3

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=175 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2026 ➔ Jul 2026

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

ASO-mediated STAT3 knockdown relieves immunosuppression sensitizing tumors to immunotherapies (AACR 2025) - P2 | "Our study aims to dissect the immune-modulatory effects of danvatirsen, an antisense oligonucleotide (ASO) targeting the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) currently being studied in combination with pembrolizumab in the PEMDA-HN trial, a randomized Phase 2 trial in recurrent/metastatic head and neck squamous cell carcinoma (NCT05814666). Similar results were obtained in the EMT6 model. In conclusion, these data showed that ASO-mediated STAT3 KD relieves immunosuppression thereby sensitizing tumors to immunotherapies."

Breast Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STAT3

Danvatirsen plus pembrolizumab versus pembrolizumab as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (PEMDA-HN): final results of a randomized phase 2 trial (MHNCS 2026) - P2 | "Purpose/Objective(s): Danvatirsen, a STAT3 targeting anti-sense oligonucleotide, demonstrated activity in combination with the anti-PD-L1 durvalumab in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in single arm studies. D+P did not improve outcomes compared to P. The combination was generally well tolerated, with TEAEs similar to that reported in other danvatirsen trials. These negative results highlight the importance of randomized studies in drug development."

Clinical • IO biomarker • Metastases • P2 data • Head and Neck Cancer • Hematological Disorders • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STAT3

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=175 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: May 2023 ➔ Mar 2026

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

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=531 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2024 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=320 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2021 ➔ Sep 2022 | Trial primary completion date: Jul 2021 ➔ Sep 2022

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=175 | Active, not recruiting | Sponsor: AstraZeneca | N=258 ➔ 175 | Trial completion date: Mar 2026 ➔ May 2023 | Trial primary completion date: Mar 2026 ➔ May 2023

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

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: AstraZeneca

Biomarker • IO biomarker • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=420 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Oct 2023 ➔ Aug 2024 | Trial primary completion date: Oct 2023 ➔ Aug 2024

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=570 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2026 ➔ Feb 2025 | Trial primary completion date: Jan 2026 ➔ Feb 2025

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=420 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2023 ➔ Oct 2023 | Trial primary completion date: Jun 2023 ➔ Oct 2023

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting | Trial primary completion date: Jul 2020 ➔ Nov 2020

Biomarker • Enrollment open • IO biomarker • Trial primary completion date • Non Small Cell Lung Cancer

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=570 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Feb 2025 ➔ Sep 2024 | Trial primary completion date: Feb 2025 ➔ Sep 2024

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=530 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2024 ➔ Jan 2026 | Trial primary completion date: Aug 2024 ➔ Jan 2026

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=531 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=260 | Recruiting | Sponsor: AstraZeneca | N=200 ➔ 260 | Trial completion date: Nov 2020 ➔ Jul 2021 | Trial primary completion date: Nov 2020 ➔ Jul 2021

Biomarker • Enrollment change • IO biomarker • Trial completion date • Trial primary completion date • Non Small Cell Lung Cancer

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=212 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

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

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=257 | Recruiting | Sponsor: AstraZeneca | Active, not recruiting ➔ Recruiting

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

MAGELLAN: A Study of Novel Anti-cancer Agents in Patients With Previously Untreated NSCLC (clinicaltrials.gov) - P1 | N=212 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2024 ➔ Mar 2026 | Trial primary completion date: Jan 2024 ➔ Mar 2026

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