relatlimab (BMS-986016)

P2, N=90, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Phase classification: P1 --> P2

P1/2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=33, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P2/3, N=135, Not yet recruiting, Linnaeus Therapeutics, Inc. | Phase classification: P3 --> P2/3

Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

P2, N=42, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

Currently, with the approval of relatlimab, a LAG-3 blocking antibody, a third player, has been used in the fight against cancer...However, the complex biology of LAG-3 may hinder its full development as a therapeutic alternative. In this review, we provide in-depth insight into the biology of LAG-3 and its current and future development in cancer treatment.

P2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P2, N=30, Not yet recruiting, University of California, San Diego

P3, N=135, Not yet recruiting, Linnaeus Therapeutics, Inc.

P2, N=42, Completed, John Kirkwood | Active, not recruiting --> Completed | Trial completion date: Jul 2027 --> Jul 2024 | Trial primary completion date: Jul 2027 --> Jul 2024

Our retrospective review at a tertiary cancer center of patients with stage 3 and 4 melanoma treated with NIVO-RELA revealed an overall response rate (ORR) of 39%, with notable improvements in median PFS and ORR, especially in first-line treated patients. Our study highlights the superior efficacy of NIVO-RELA over previous reports, demonstrating its significant potential in the treatment landscape of advanced melanoma.

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P1, N=32, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2025 --> Aug 2025 | Trial primary completion date: Sep 2024 --> Mar 2025

Several LAG-3 targeting inhibitors in clinical trials and the combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) have been approved for treating - unresectable or metastatic melanoma. Despite the encouraging clinical potential of LAG-3, the physiological function and mechanism of action in tumors are still not well understood. In this review, we systematically summarized the structure of LAG-3, ligands of LAG-3, cell-specific functions and signaling of LAG-3, and the current status of LAG-3 inhibitors under development.

The rapidly expanding class of therapies targeting immune checkpoints for the treatment of various cancers now includes 8 clinically approved agents: a lymphocyte-activation gene 3 (LAG-3) inhibitor (relatlimab), a cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitor (ipilimumab), three programmed cell death protein 1 (PD-1) inhibitors (nivolumab, pembrolizumab and cemiplimab), and three programmed cell death ligand-1 (PD-L1) inhibitors (atezolizumab, durvalumab, and avelumab). Previously, we reviewed the mechanisms of immune-related adverse events (irAEs), strategies for management of irAEs, and highlighted similarities as well as differences amongst clinical guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), and European Society for Medical Oncology (ESMO). Herein, we provide an update that includes discussion of changes to these clinical guidelines since our last review, the new LAG-3 targeted agents, emerging patterns of irAEs, and new directions for improved monitoring and treatment of irAEs that could incorporate interdisciplinary pharmacist-led teams, artificial intelligence, and pharmacogenomics.

P2, N=162, Recruiting, Breast Cancer Trials | Active, not recruiting --> Recruiting | N=108 --> 162

P1, N=1, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2026 --> Jun 2025 | Trial primary completion date: Dec 2025 --> Jun 2024

P1/2, N=255, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Apr 2024 --> Nov 2026

P3, N=560, Recruiting, Regeneron Pharmaceuticals | Not yet recruiting --> Recruiting

Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

P2, N=385, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024

P3, N=400, Recruiting, Replimune Inc. | Not yet recruiting --> Recruiting

For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab...CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia...This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

P1, N=11, Terminated, Bristol-Myers Squibb | Phase classification: P1/2 --> P1 | Completed --> Terminated; Business objectives have changed.

The neoadjuvant platform offers unique insights into the tumor microenvironment and dynamics of the immune response over time. Our analysis reveals consistencies with previously published biomarkers associated with response to immune checkpoint inhibitors (IFN- γ) and provides insights into new biomarkers associated with response to nivo + rela, specifically B7-H3. Taken together, this work expands our insights into who may benefit from nivo + rela and provides insights into potentially actionable strategies to personalize tx approaches.

P1/2, N=1499, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Oct 2024 --> May 2024

P1, N=1, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jan 2027 --> Dec 2025

P1, N=90, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | N=30 --> 90

P1/2, N=1499, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: May 2024 --> Oct 2024

P2, N=20, Not yet recruiting, Melanoma Institute Australia | Trial completion date: Apr 2036 --> Jul 2036 | Initiation date: Apr 2024 --> Jul 2024 | Trial primary completion date: Jun 2026 --> Sep 2026

P2, N=25, Active, not recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Sep 2023 --> Sep 2024

P2, N=468, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: May 2024 --> Jan 2024

Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC.

Three outperformers, M208, M226, and M234, showed stronger blocking activity than Relatlimab in the FGL1 binding...In addition, GPC3-targeted CAR-T cells secreting IL-21-M234 scFv fusion protein exhibited enhanced activity in inhibiting tumor growth and greatly increased the survival rate of mice. Taken together, M234 has potential in cancer immunotherapy and warrants further clinical trial.

P1/2, N=1499, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Sep 2024 --> Jan 2025 | Trial primary completion date: Sep 2024 --> May 2024

P2/3; Phase classification: P3 --> P2/3

P2, N=385, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Feb 2024 --> Jun 2024

P2, N=0, Withdrawn, National Cancer Institute (NCI)

P2, N=59, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: May 2024 --> Feb 2024

Patients on arm B (n=10) received nivolumab and relatlimab on a similar induction schedule, but concurrent IO and CRT resulted in immune related adverse events and a protocol amendment to CRT (NCT03044613)...Fecal metabolomic analysis demonstrated six significant metabolites: in non-pCR, ropinirole, valine, phenylalanine, and isoleucine were enriched; in pCR, C16cer and D-urobilinogen were enriched (p < 0.05)... Patients with complete responses to combined CRT and IO for operable esophageal cancer had distinct fecal microbiome profiles as well as metabolomic pathways. These results may be useful to further characterize and predict patients who have improved responses to neoadjuvant therapy and serve as a basis for therapeutic intervention.