cibisatamab (RG7802) / Roche - LARVOL DELTA

A Model-Based Approach to Evaluate Anti-Drug Antibody Impact on Drug Exposure With Biologics: A Case Example With the CD3 T-Cell Bispecific Cibisatamab. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The administration of biologics can lead to immunogenic responses that trigger anti-drug antibody (ADA) formation. The investigated patient demographics, dose or dosing schedule, or atezolizumab coadministration were not identified as factors influencing exposure loss due to ADAs. The developed model can be used to differentiate patients with and without ADA-driven exposure loss, as well as for a precise PK characterization in patients even with ADA formation."

Journal • Oncology

In Vitro Evaluation of the Safety and Efficacy of Cibisatamab Using Adult Stem Cell-Derived Organoids and Colorectal Cancer Spheroids. (PubMed, Cancers (Basel)) - "This highlights our model's potential to predict clinical immunotherapy outcomes, capturing complex responses like immune activation, therapeutic selectivity, and potential resistance mechanisms. These findings underscore the utility of our model as a reliable, physiologically relevant tool for screening new immunotherapies and advancing our understanding of tumor-immune dynamics."

IO biomarker • Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • CEACAM5 • GZMB

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=675 ➔ 314

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

BP42675: Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=54 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | N=80 ➔ 54

Enrollment change • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • CEACAM5

A CB21-targeted T cell engager is a promising therapeutic for the treatment of colorectal cancer (SITC 2024) - "T cell engagers as a modality have gained attraction in solid tumors, but despite the early data that T cells can infiltrate cold CRC tumors with therapies such as Cibisatamab, treatment remains challenging due to poor target specificity and related on-target off-tumor toxicity. We have demonstrated efficacy and safety of Cartography's CB21 TCE in a preclinical setting. Data generated strongly supports clinical development of this CB21 TCE."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI

Enhanced pharmacodynamic effects upon combination of cibisatamab and FAP-4-1BBL in 3L+ mMSS CRC patients (ESMO 2024) - P1, P1/2, P1b, P1b/2a, P2 | "Clinical trial identification: BP42675 "an open-label, multicenter, phase Ib study to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RO7122290, a fibroblast activation protein-a (FAP) targeted 4-1BB ligand (CD137L), in combination with cibisatamab with obinutuzumab pre-treatment, in participants with previously treated, metastatic, microsatellite-stable colorectal adenocarcinoma". The enhanced clinical PD effects of the combination of cibisatamab and FAP-4-1BBL demonstrate the additive effects of costimulation to signal 1 only providers such as TCBs in a tumor considered largely insensitive to cancer immunotherapies. These encouraging results advocate for further studies exploring the combination of T cell engagers such as TCBs with FAP-4-1BBL, as this approach holds the potential to unlock new frontiers in cancer treatment."

Clinical • IO biomarker • PK/PD data • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • CD4 • CD8 • IFNG • IL2RA • IL6

A Phase Ib Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Participants With Previously Treated Metastatic Colorectal Adenocarcinoma (clinicaltrials.gov) - P1 | N=47 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; The Sponsor terminated the study because development of cibisatamab has been discontinued.

Combination therapy • Metastases • Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5 • MSI

Characterization of anti-drug antibody responses to the T-cell engaging bispecific antibody cibisatamab to understand the impact on exposure. (PubMed, Front Immunol) - P1 | "Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure."

Journal • P1 data

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=675 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Jun 2026 ➔ Sep 2025 | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2027 ➔ Nov 2026

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials. (PubMed, Nat Commun) - P1 | "Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC."

Journal • P1 data • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials (Nature, Nat Commun) - "Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713)....S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs)."

Retrospective data • Solid Tumor

CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials (Nature, Nat Commun) - "Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713)....S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs)."

Retrospective data • Solid Tumor

A Phase Ib Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Participants With Previously Treated Metastatic Colorectal Adenocarcinoma (clinicaltrials.gov) - P1 | N=47 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5 • MSI

Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jul 2025 ➔ Dec 2024 | Trial primary completion date: Jul 2025 ➔ Dec 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=675 | Recruiting | Sponsor: Hoffmann-La Roche | N=470 ➔ 675 | Trial completion date: Nov 2026 ➔ Sep 2027 | Trial primary completion date: Aug 2025 ➔ Jun 2026

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

Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. Depending on the dosing schedule and FAP-4-1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose-response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection."

Immuno-oncology • IO biomarker • Journal • Preclinical • Oncology • FAP

A Phase Ib Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Participants With Previously Treated Metastatic Colorectal Adenocarcinoma (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2023 ➔ Mar 2024 | Trial primary completion date: Oct 2023 ➔ Mar 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5 • MSI

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=470 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Aug 2025 ➔ Nov 2026 | Trial primary completion date: Apr 2024 ➔ Aug 2025

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

Using quantitative systems pharmacology modeling to optimize combination therapy of anti-PD-L1 checkpoint inhibitor and T cell engager. (PubMed, Front Pharmacol) - "We generated a virtual patient cohort with the model to conduct in silico virtual clinical trials for combination therapy of a PD-L1 checkpoint inhibitor (atezolizumab) and a bispecific T cell engager (cibisatamab). Using the model calibrated against the clinical trials, we conducted several virtual clinical trials to compare various doses and schedules of administration for two drugs with the goal of therapy optimization. Moreover, we quantified the score of drug synergy for these two drugs to further study the role of the combination therapy."

Checkpoint inhibition • Combination therapy • IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Oncology • Solid Tumor

Partners-in-Crime: Co-Stimulation via 4-1BB or CD28 to Boost the Efficacy of T Cell Bispecifics (PEGS 2023) - "The presentation will cover an overview and update on preclinical properties of solid and heme tumor co-stimulators including FAP-4-1BBL, CD19-4-1BBL, and CD19-CD28 in active clinical development in combination with cibisatamab and glofitamab, respectively."

Clinical • Oncology

Phase I studies of the novel carcinoembryonic antigen T-cell bispecific (CEA-CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients (pts) with metastatic colorectal cancer (mCRC) (ESMO 2017) - P1; "...CEA-CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells...Evidence of antitumor activity in advanced CRC and other CEA-expressing tumors was observed during dose escalation with CEA-CD3 TCB monotherapy. Enhanced activity and a manageable safety profile was seen in combination with atezolizumab."

Combination therapy • P1 data • Colorectal Cancer • Hepatocellular Cancer

Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). (ASCO 2017) - P1; "Evidence of antitumor activity was observed with RO6958688 monotherapy in ongoing dose escalation. Activity appeared to be enhanced with doses in combination with atezolizumab, with a manageable safety profile. Updated data will be presented."

Combination therapy • P1 data • Biosimilar • Colorectal Cancer • Immunology

Enhancement of the anti-tumor activity of CEA TCB via combination with checkpoint blockade by PD-L1 and interleukin-2 variant immunocytokine (AACR 2017) - P1; "CEA TCB (RG7802, RO6958688) is a novel T cell bispecific antibody targeting carcinoembryonic antigen (CEA) on tumor cells and CD3 on T cells, currently being investigated as single agent and in combination with atezolizumab in Phase 1/1b studies in patients with advanced and/or metastatic CEA-expressing tumors (NCT02324257; NCT02650713). This is accompanied by up-regulation of PD-1/PD-L1 suppressive pathway, which can be overcome by combination therapy with a PD-L1 inhibitor. In vivo efficacy of CEA TCB is further potentiated when administered in combination with immunotherapies that increase the pool of available tumor-infiltrating effector cells."

Checkpoint inhibition • Combination therapy • Biosimilar • Oncology

Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA-CD3 TCB) for the treatment of CEA-positive solid tumors (ESMO 2017) - P1; "...CEA-CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3e on T cells...On-treatment increases in intratumoral CD8 T cells consistent with the mechanism of action and support that CEA-CD3 TCB is the first tumor-targeted T cell bispecific showing biological activity. The activation level of intratumoral T cells at BSL could be a predictive biomarker of response. In preclinical models, tumor targeting has been demonstrated."

Colorectal Cancer