sabatolimab (MBG453)

P1/2, N=24, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2024 --> Aug 2024

P1/2, N=12, Not yet recruiting, M.D. Anderson Cancer Center

P3, N=530, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P2, N=39, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.

P1/2, N=45, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P1, N=52, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business decision

P2, N=127, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types.

P1, N=241, Completed, Novartis Pharmaceuticals | Phase classification: P1b --> P1

P1/2, N=24, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2024 --> Dec 2024 | Trial primary completion date: Aug 2024 --> Dec 2024

P2, N=70, Recruiting, Novartis Pharmaceuticals | Trial primary completion date: Sep 2027 --> Feb 2028

P2, N=39, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2024 --> Oct 2024

P2, N=90, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2024 --> Oct 2024 | Trial primary completion date: Jul 2024 --> Oct 2024

P1/2, N=24, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=59 --> 24

P2, N=20, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; Study was stopped following a strategic decision from the Sponsor. It was not based on any safety findings or safety concerns with sabatolimab.

P1, N=33, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons

P2, N=39, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 39

P1/2, N=59, Recruiting, Novartis Pharmaceuticals | N=27 --> 59 | Trial completion date: Apr 2027 --> Aug 2024 | Trial primary completion date: Nov 2024 --> Jul 2024 | Active, not recruiting --> Recruiting

P2, N=70, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2028 --> Feb 2028

P2, N=90, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Jul 2024 | Trial primary completion date: Mar 2026 --> Jul 2024

P2, N=90, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Sep 2023

P1/2, N=0, Withdrawn, Novartis Pharmaceuticals | N=63 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=27, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=59 --> 27

P2, N=20, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting | Trial completion date: Dec 2022 --> Jan 2026 | Trial primary completion date: Jun 2022 --> Jun 2024

P3, N=530, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2027 --> Sep 2024 | Trial primary completion date: Jan 2027 --> Sep 2024

P1/2, N=45, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Jul 2024

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.

The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting.

Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.

Among 3 MDS with MECOM rearrangement, one patient received azacitidine with investigational drug (sabatolimab/placebo) and achieved complete hematologic response. Chemotherapy should be avoided in this subtype due to non-responsiveness, hypomethylating agent showed benefit and can be considered as a bridging treatment before stem cell transplantation. Novel therapy targeting MECOM gene should be further explored to improve outcomes in this AML subtype.

Conversely, we observed a down-regulation of metallothionein genes (MT1E, MT1G, MT2A) as well as a collection of transcription factors (NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors (NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR <0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis.

Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA.

In adult pts with AML who are in hematological CR with MRD+ after alloSCT, sabatolimab 400 mg and 800 mg monotherapies were well tolerated. Cytopenias occurred at low rates, were generally G1–2 and mostly related to imminent relapse. Importantly, there were no cases of GvHD reported or any immune-related AEs commonly seen with checkpoint inhibitors.

P1, N=33, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=90 --> 33 | Trial completion date: Sep 2024 --> May 2024 | Trial primary completion date: Sep 2024 --> May 2024

Galectin-9-induced effects on cytotoxicity can be abrogated using the clinical-grade anti-TIM-3 blocking antibody, MBG453...This may be due to higher intratumoral galectin-9 protein expression in HPV+ HNSCC lesions. Conclusions Our data stress the importance and complexity of TIM-3 in the context of NK cells and suggest that targeting the TIM-3/galectin-9 pathway may be a cogent immunotherapeutic strategy to reinvigorate NK cell effector function in HPV+ HNSCC patients.

P1, N=16, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2024 --> Sep 2025

P1/2, N=59, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2026 --> Mar 2027 | Trial primary completion date: Jun 2024 --> Oct 2024

P2, N=20, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P1b, N=241, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2023 --> Sep 2023 | Trial primary completion date: Apr 2023 --> Sep 2023

In addition, the model predicted membrane-bound TIM-3 occupancy in the bone marrow was above 95% in over 95% of patients. Therefore, these results support the selection of the 400-mg Q2W and 800-mg Q4W dosing regimens for the STIMULUS clinical trial program.