Imjudo (tremelimumab-actl)

P2, N=70, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

P2, N=40, Recruiting, Anwaar Saeed | Not yet recruiting --> Recruiting

P3, N=110, Recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Mar 2026 | Trial primary completion date: Jun 2025 --> Sep 2025

P2, N=32, Recruiting, The University of Texas Health Science Center at San Antonio | Not yet recruiting --> Recruiting

The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as pre-operative treatment in dMMR/MSI GAC/GEJAC and the first available feasibility results of a NOM strategy in this disease setting, worth of further validation in larger cohorts.

We reviewed cfDNA results from a local prospective solid tumour cohort (PREDiCT-l) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care in metastatic colorectal cancer) and CCTG PA.7 (gemcitabine and nab-paclitaxel +/- D+T in metastatic pancreatic adenocarcinoma). CHIP is common in patients with solid tumours. Although not appearing to impact rates of adverse events, CHIP may impact outcomes from immunotherapy or chemotherapy.

P2, N=32, Completed, Spanish Oncology Genito-Urinary Group | Active, not recruiting --> Completed

P2, N=29, Active, not recruiting, Sheba Medical Center | Recruiting --> Active, not recruiting

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P1, N=20, Not yet recruiting, University of California, San Diego

P2, N=40, Not yet recruiting, Anwaar Saeed

P2, N=40, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed

D+T is active in mCRPC but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.

These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

P2, N=0, Withdrawn, Georgetown University | N=28 --> 0 | Recruiting --> Withdrawn

P2, N=79, Terminated, Grupo Espanol de Tumores Neuroendocrinos | Trial completion date: Dec 2025 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2025 --> Nov 2024; In compliance with current legislation applicable to Clinical Trials, following the instructions of the Spanish Agency for Medicines and Health Products.

The treatment regimen comprised durvalumab, tremelimumab, carboplatin, and nab-paclitaxel. Clinicians should be aware that COVID-19 might be associated with the development of severe irAEs and unexpectedly enhanced antitumor effects. The findings also suggest new fields of study regarding the interaction between viral infection and tumor immune response, which may inform future therapeutic approaches.

P1, N=18, Terminated, The Netherlands Cancer Institute | N=34 --> 18 | Trial completion date: Jan 2021 --> Nov 2024 | Unknown status --> Terminated | Trial primary completion date: Jan 2021 --> Nov 2024; Based on initially defined safety rules not continued with expansion phase of study (too much toxicity with neo-adjuvant immunotherapy)

P2, N=69, Completed, Queen Mary University of London | Active, not recruiting --> Completed | N=181 --> 69 | Trial completion date: Mar 2023 --> Jul 2024 | Trial primary completion date: Mar 2023 --> Jul 2024

P1/2, N=22, Terminated, University of Maryland, Baltimore | Trial completion date: Jun 2037 --> Jun 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2032 --> Jun 2024; Limited Accrual

Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/β-catenin signaling and CD8+ TIL infiltration.

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.

Scenario analysis confirmed the study's primary findings, with the exception of a scenario where durvalumab was offered at no cost. The findings suggests that T + D + CT may not be a cost-effectiveness first-line treatment for EGFR/ALK wild-type mNSCLC in the US, given its high ICERs and limited cost-effectiveness in the majority of PD-L1 expression subgroups.

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Oct 2032 --> Mar 2031

P1, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Sep 2024 --> Jan 2025

P1/2, N=79, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Aug 2033 --> Oct 2032

P2, N=61, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Updated analyses from POSEIDON after median FU of >5 y showed durable long-term OS benefit with the approved regimen of T+D+CT (vs CT alone). These results support its use as a 1L treatment option for pts with mNSCLC, including harder-to-treat subgroups such as those with PD-L1 TC <1%.

Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

P2, N=79, Active, not recruiting, Grupo Espanol de Tumores Neuroendocrinos | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

The patient was treated with tremelimumab and durvalumab but passed away shortly afterward due to decompensation from her disease. In this instance, the high TMB would point toward a worse prognosis, but further study of high-TMB cases is necessary to support a correlation. Given the prevalence of HCC worldwide, any potential avenues that could help guide clinical decision-making should be explored.

The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy.

P3, N=1246, Active, not recruiting, AstraZeneca | Trial primary completion date: Aug 2024 --> Jun 2025

P1/2, N=43, Not yet recruiting, Case Comprehensive Cancer Center

The results of durvalumab plus tremelimumab were better in terms of costs and health outcomes in patients with HBV-related HCC and high alpha-fetoprotein levels. First-line durvalumab plus tremelimumab was estimated to be dominant for the treatment of unresectable HCC compared with sorafenib from a US payer's perspective.

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Mar 2031 --> Aug 2033

P2, N=12, Completed, Baki Topal | Active, not recruiting --> Completed

P2, N=21, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Completed | N=30 --> 21 | Trial completion date: Dec 2024 --> Aug 2024

P2, N=120, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Dec 2024 --> Sep 2025

After median follow-up of >5 years, T+D+CT showed durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

P2; Active, not recruiting --> Completed