anetumab ravtansine (BAY 94-9343)

P1/2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P1/2, N=74, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1 --> P1/2

P1/2, N=46, Active, not recruiting, National Cancer Institute (NCI) | N=110 --> 46 | Trial completion date: Mar 2023 --> Jul 2024 | Trial primary completion date: Mar 2023 --> Jul 2023

Accrual was closed prior to meeting accrual goals following approval of frontline ipilimumab and nivolumab. The addition of anetumab ravtansine to pembrolizumab did not result in significant dose limiting toxicities. There were no differences in confirmed response rates between patients treated with the combination of anetumab ravtansine and pembrolizumab, or pembrolizumab alone. The confirmed response rates were lower than reported previously reported for pembrolizumab in pleural mesothelioma.

P1, N=74, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1/2 --> P1

P1/2, N=74, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2022 --> Oct 2023 | Trial primary completion date: Oct 2022 --> Oct 2023

Anetumab ravtansine (AR) is a fully human anti-MSLN immunoglobulin G1 antibody conjugated to the anti-tubulin maytansinoid DM4...AR was combined with nivolumab (ARM1), nivolumab/ipilimumab (ARM 2), or nivolumab plus gemcitabine (Gem) (ARM3), using an integrated biomarker analysis... Based on the observed disease control rate and acceptable toleratbility, ARM3 (both DL1 and DL2) will be tested in the expansion part. A further 20 patients will be recruited for dose confirmation and comprehensive biomarker evaluation. Pharmacokinetic/pharmacodynamic analysis is under way.

P1/2, N=74, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2022 --> Jan 2024 | Trial primary completion date: Apr 2022 --> Jan 2024

Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

P1/2, N=110, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2022 --> Feb 2023 | Trial primary completion date: Feb 2022 --> Feb 2023

P1/2, N=110, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.

P2, N=96, Recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2021 --> Oct 2022 | Trial primary completion date: Oct 2021 --> Oct 2022

P1b, N=173, Completed, Bayer | Active, not recruiting --> Completed

In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN-DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation.

P1/2, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2021 --> Apr 2022 | Trial primary completion date: Apr 2021 --> Apr 2022

P2, N=96, Recruiting, National Cancer Institute (NCI) | Phase classification: P1/2 --> P2

TC-210 expansion and serum cytokine levels were serially measured. Seven patients (6 MPM, 1 ovarian) received a single gavo-cel intravenous infusion at the initial dose of 5x107/m2 either alone (dose level [DL] 0, n=1) or following lymphodepletion (LD) (DL1, n=6) with fludarabine (30mg/m2/day x4) and cyclophosphamide (600mg/m2/day x3)...Four patients had received ≥4 lines of therapy, including immune checkpoint inhibitors (n=5), the anti-mesothelin ADC anetumab ravtansine (n=1), and anti-mesothelin mRNA CAR-T (n=1)...CRS and pneumonitis events resolved with tocilizumab and corticosteroids... Intravenous systemic administration of gavo-cel was generally safe and resulted in three of seven patients having objective partial response. Dose escalation is ongoing at 1x108/m2. Updated clinical and translational data will be presented.

The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology.

"ARv/PLD combination was safe and tolerated. No DLT was observed. MTD of ARv was 6.5 mg/kg Q3W."

P2; N=96; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Jun 2020 --> Jun 2021; Trial primary completion date: Jun 2020 --> Jun 2021

P1b; N=173; Active, not recruiting; Sponsor: Bayer; Recruiting --> Active, not recruiting; N=348 --> 173

In a current clinical trial, the highly potent anti-mesothelin antibody anetumab ravtansine is used in patients with mesothelin-positive tumors...New therapeutic targets are urgently required to improve the outcome of patients with locally advanced or metastasized esophageal carcinoma. The inhibition of mesothelin can be a new attractive target.

P1b, N=348, Recruiting, Bayer | Trial completion date: Oct 2021 --> Jul 2021

"Combining ARav at a dose of 7.5 mg/kg with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumor growth.MSLN is expressed in thymoma and thymic carcinoma derived cell lines. Anetumab ravtansine inhibits growth of MSLN positive thymic carcinoma in our preclinical model; when combined with SoC cisplatin, ARav confers enhanced tumor growth inhibition."

P1/2, N=1, Terminated, Mayo Clinic | Completed --> Terminated; slow accrual

Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

P1/2, N=1, Completed, Mayo Clinic | Active, not recruiting --> Completed | Trial completion date: Oct 2020 --> Jan 2020

P1/2, N=134, Recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2020 --> Feb 2022 | Trial primary completion date: Feb 2020 --> Feb 2022

P2; Active, not recruiting --> Completed

P1, N=36, Completed, Bayer | Active, not recruiting --> Completed

P1b, N=348, Recruiting, Bayer | Trial completion date: Jul 2021 --> Nov 2021 | Trial primary completion date: Feb 2020 --> Feb 2021

P2; N=248; Completed; Sponsor: Bayer; Active, not recruiting --> Completed

P1; N=54; Completed; Sponsor: Bayer; Active, not recruiting --> Completed

P2; Recruiting --> Active, not recruiting | N=30 --> 18

P1, N=147, Completed, Bayer | Active, not recruiting --> Completed

P1; N=147; Active, not recruiting; Sponsor: Bayer; Trial primary completion date: Dec 2018 --> Dec 2016