tobemstomig (RG6139) / Roche - LARVOL DELTA

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=518 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Liver Cancer • Oncology • Solid Tumor • PD-L1

A Randomized, Nivolumab-controlled, Phase 2 and Biomarker Study of Lomvastomig and Tobemstomig in Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus. (PubMed, Clin Cancer Res) - "Neither lomvastomig nor tobemstomig improved survival compared to nivolumab in the overall patient population. However, in the PD-L1-high (CPS≥10) and PD-L1-high/LAG3-high subgroups, tobemstomig was associated with prolonged survival, supporting PD-L1-guided treatment selection for tobemstomig in ESCC."

Biomarker • Clinical • IO biomarker • Journal • P2 data • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • HAVCR2 • LAG3

A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=62 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; Study was closed early as the sponsor decided not to continue development of certain treatment combinations.

Trial termination • Hepatocellular Cancer • Oncology • Solid Tumor

A phase II trial of tobemstomig (tobe) + platinum-based chemotherapy (chemo) vs pembrolizumab (pembro) + chemo in patients (pts) with untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) (ELCC 2025) - P2 | "BO44178 (NCT05775289) is a randomised, double-blind, phase II study evaluating tobe + chemo vs pembro + chemo in pts with NSCLC who are ineligible for surgery or definitive chemoradiotherapy. Eligible pts with previously untreated, locally advanced unresectable or metastatic NSCLC were randomised 1:1 to receive either induction tobe + chemo (carboplatin + paclitaxel/pemetrexed) or pembro + chemo for four 21-day cycles, followed by maintenance tobe or pembro with/without pemetrexed every 3 weeks until disease progression, toxicity or loss of clinical benefit. At this interim analysis, no ORR or PFS benefit was observed in pts with untreated locally advanced or metastatic NSCLC receiving tobe + chemo over pembro + chemo. OS data remain immature."

Clinical • IO biomarker • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • LAG3 • PD-L1

A global, multicentre, open-label, randomised phase II trial of tobemstomig (tobe) with or without tiragolumab (tira) vs atezolizumab (atezo) in patients (pts) with untreated metastatic urothelial cancer (mUC) ineligible for platinum-based chemotherapy (chemo) (ESMO 2023) - P2 | "This study will evaluate the effect of tobe and tobe + tira on investigator-assessed confirmed ORR (primary endpoint) relative to atezo. Secondary endpoints include PFS, OS, DOR, DCR and safety."

Clinical • IO biomarker • Metastases • P2 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • LAG3 • TIGIT

A Study of Tobemstomig Plus Platinum-Based Chemotherapy vs Pembrolizumab Plus Platinum-Based Chemotherapy in Participants With Previously Untreated Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=182 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

IO biomarker • Trial completion • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

GO42216: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients with Advanced Liver Cancers (Morpheus-Liver) (clinicaltrialsregister.eu) - P1/2 | N=29 | Recruiting | Sponsor: F. Hoffmann-La Roche AG | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • PD-L1

Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial. (PubMed, Nat Med) - P1/2 | "The NADINA trial evaluating neoadjuvant nivolumab plus ipilimumab and the SWOG-1801 trial evaluating neoadjuvant pembrolizumab have demonstrated superior clinical outcomes with neoadjuvant versus adjuvant checkpoint inhibition...Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab showed a lower pRR versus nivolumab plus ipilimumab (60.0% (12/20) and 45.0% (9/20) versus 77.3% (17/22), respectively)...In conclusion, in the Morpheus-Melanoma study, tobemstomig demonstrated a similar pathological response and improved safety profile versus nivolumab plus ipilimumab in patients with resectable stage III melanoma. ClinicalTrials.gov identifier: NCT05116202 ."

Checkpoint inhibition • IO biomarker • Journal • P1/2 data • Tumor mutational burden • Melanoma • Oncology • Solid Tumor • CD8 • IFNG • LAG3 • TIGIT • TMB

Tobemstomig, a novel bispecific antibody, preferentially blocks PD-1 and LAG-3 on CD8 TILs to expand stem-like T-cells for sustained tumor control. (PubMed, Cancer Res Commun) - "To address this limitation, we developed tobemstomig, a novel bispecific antibody to preferentially and simultaneously block PD-1 and LAG-3 in cis on tumor-specific CD8 TILs, while sparing Tregs. It provided superior tumor growth inhibition in mouse models by replenishing stem-like cells and cytotoxic effector CD8 TILs, resulting in durable responses compared to monospecific antibodies targeting PD-1 and LAG-3 separately, which eroded the stem-like T cell pool over time."

IO biomarker • Journal • Oncology • CD8 • LAG3

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=518 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2027 ➔ Sep 2027 | Trial primary completion date: Dec 2027 ➔ Jul 2027

Trial completion date • Trial primary completion date • Liver Cancer • Oncology • Solid Tumor • PD-L1

A first-in-human phase 1 clinical trial evaluating clinical activity and proof-of-mechanism of tobemstomig, a PD1-LAG3 bispecific antibody, in patients with CPI-experienced melanoma. (PubMed, Clin Cancer Res) - "Tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications. The encouraging antitumor activity associated with pharmacodynamic activity, and proof-of-mechanism in CPI-experienced melanoma patients, indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings."

First-in-human • Journal • P1 data • Esophageal Squamous Cell Carcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CD8 • LAG3 • PD-1

Tobemstomig, a novel bispecific checkpoint inhibitory antibody to preferentially block PD-1 and LAG-3 on CD8 TILs over Tregs (AACR 2024) - "LAG-3 is constitutively expressed by regulatory T cells (on Tregs) and it has been reported that its blockade increases Treg suppressive function which could potentially off-sets the benefit of blocking LAG-3 on tumor-reactive CD8 T cells.We therefore developed a 1+1 PD1-LAG3 bispecific antibody, Tobemstomig, with a unique PD-1 binder recognizing a glycoepitope and more than 20 fold higher affinity than the LAG-3 binder which recognizes a novel and differentiated binding epitope (E3). This difference in affinities allows for an avidity driven selectivity gain to PD-1 and LAG-3 double positive T cells over and the following advantages over monospecific and other bispecific aPD-1/-L1 and aLAG-3 antibodies:1.improved targeting to tumor-reactive T cells rather than Tregs due to the selectivity gain and different expression patterns of PD-1 and LAG-3 on these two T cell types, 2.reduced internalization, 3.resistance to drug-shaving by macrophages due to Fc -silencing via..."

Bispecific • Checkpoint inhibition • IO biomarker • Oncology • Solid Tumor • CD8 • LAG3

CO44194: A Study of Tobemstomig/RO7247669 Combined with Nab-Paclitaxel Compared with Pembrolizumab Combined with Nab-Paclitaxel in Participants with Previously Untreated, PD-L1-Positive, Locally-Advanced Unresectable or Metastatic Triple-Negative Breast Cancer (clinicaltrialsregister.eu) - P1/2 | N=71 | Completed | Sponsor: F. Hoffmann-La Roche AG | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=170 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

First-in-human • Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2 | N=199 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jul 2026 ➔ Oct 2026 | Trial primary completion date: Jul 2026 ➔ Oct 2026

Checkpoint inhibition • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Study Evaluating Different Immunotherapies (LAG-3 and PD-1 With or Without TIGIT, Compared to PD-L1 Alone) in Participants With Untreated Locally Advanced Metastatic Urothelial Cancer (clinicaltrials.gov) - P2 | N=204 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Mar 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=518 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Liver Cancer • Oncology • Solid Tumor • PD-L1

A Study of Multiple Doses of RO7247669 in Participants With Previously Untreated Unresectable or Metastatic Melanoma (clinicaltrials.gov) - P2 | N=93 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Phase classification: P1/2 ➔ P2

Phase classification • Trial completion • Melanoma • Oncology • Solid Tumor • BRAF • PD-L1

LAG-3 antagonists for cancer treatment: an updated patent review (2020-2025). (PubMed, Expert Opin Ther Pat) - "The trend shows that monospecific antibodies against LAG-3 continue to be the main antagonists, followed by multispecific t, treatment methods using known LAG-3 antagonists, LAG-3 binding peptides, and LAG-3 binding small molecules. The monospecific antibodies encelimab, miptenalimab, and the bispecific antibodies tobemstomig, IBI323, ABL501, fanastomig, and FS118 are added, during this period, to the potential drugs targeting LAG-3."

Journal • Review • Oncology • CD4 • CD8 • IFNG • LAG3

A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=62 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Sep 2028 ➔ Nov 2025

Trial completion • Trial completion date • Hepatocellular Cancer • Oncology • Solid Tumor

A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2 | N=199 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2025 ➔ Jul 2026 | Trial primary completion date: Oct 2025 ➔ Jul 2026

Checkpoint inhibition • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Study Evaluating Different Immunotherapies (LAG-3 and PD-1 With or Without TIGIT, Compared to PD-L1 Alone) in Participants With Untreated Locally Advanced Metastatic Urothelial Cancer (clinicaltrials.gov) - P2 | N=204 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2026 ➔ Mar 2026 | Trial primary completion date: Dec 2026 ➔ Mar 2026

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • PD-L1

A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma (clinicaltrials.gov) - P2 | N=199 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2026 ➔ Oct 2025 | Trial primary completion date: Oct 2026 ➔ Oct 2025

Checkpoint inhibition • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=170 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=62 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | N=150 ➔ 62

Enrollment change • Enrollment closed • Hepatocellular Cancer • Oncology • Solid Tumor