anetumab ravtansine (BAY 94-9343) / Bayer, AbbVie, Novartis - LARVOL DELTA

Pharmacologic and pharmacometric studies of factors affecting the pharmacokinetics and pharmacodynamics of antibody drug conjugate anetumab ravtansine in patients with solid tumors. (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • PK/PD data • Oncology • Solid Tumor

Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin. (PubMed, Sci Rep) - "We investigated the effects of sMSLN on anetumab, an antibody-based therapy against MSLN, anetumab ravtansine, an antibody drug conjugate, and mechanisms to decrease sMSLN...Overall, sMSLN could represent a predictive biomarker for MSLN directed therapies. TPE may be more reliable than PIs to reduce sMSLN and ultimately restore sensitivity to these therapies in patients with high sMSLN."

Journal • Mesothelioma • Oncology • Solid Tumor • MSLN

Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer. (PubMed, Clin Transl Sci) - "In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0-inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response."

Journal • PK/PD data • Mesothelioma • Oncology • Ovarian Cancer • Solid Tumor

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Tumor mutational burden • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial). (PubMed, Clin Cancer Res) - "Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care."

Journal • P2 data • Hematological Disorders • Neutropenia • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL6 • MSLN

NCI-2018-01503: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Patients With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • MSLN

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=49 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Sep 2025

Trial completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN • PD-L1

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma. (PubMed, Lung Cancer) - "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."

IO biomarker • Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma (Lung Cancer) - P1/2 | N=46 | NCT03126630 | "In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1–not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months."

P1/2 data • Mesothelioma

Soluble mesothelin neutralizes mesothelin antibody-based therapies. (ASCO 2024) - P1/2 | "We found that high sMSLN levels are associated with shorter PFS for anetumab ravtansine, but not pembrolizumab. Additionally, anetumab binds to sMSLN in the plasma, which suggests that sMSLN can sequester anti-MSLN antibodies and may limit the efficacy of MSLN-targeted therapies. High levels of sMSLN could potentially be used as a biomarker to select which patients should not receive MSLN-targeting therapies."

IO biomarker • Hematological Disorders • Immunology • Mesothelioma • Oncology • Solid Tumor • MSLN

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2024 ➔ Jan 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

NCI-2018-01503: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Patients With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Oct 2024

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • MSLN

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1 ➔ P1/2

Combination therapy • IO biomarker • Metastases • Phase classification • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • MSLN

Phase 1/2 Randomized Trial of Anetumab Ravtansine and Pembrolizumab Compared to Pembrolizumab for Pleural Mesothelioma - NCT03126630 (IASLC-WCLC 2023) - P1/2 | "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."

Clinical • IO biomarker • P1/2 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN

Protocol # 10107: Phase 1 Safety Run-In and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine and Pembrolizumab (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-Positive Malignant Pleural Mesothelioma (National Cancer Institute)

CME

A Clinical Study of Anetumab Ravtansine in Adults With Solid Tumors Who Have Been Treated in Previous Bayer-sponsored Anetumab Ravtansine Studies (clinicaltrials.gov) - P2 | N=9 | Terminated | Sponsor: Bayer | Completed ➔ Terminated; Due to strategic company decisions, the development of anetumab ravtansine was stopped.

Trial termination • Oncology • Solid Tumor

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=46 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=110 ➔ 46 | Trial completion date: Mar 2023 ➔ Jul 2024 | Trial primary completion date: Mar 2023 ➔ Jul 2023

Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • CCL2 • MSLN • PD-L1

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1/2 ➔ P1

Combination therapy • IO biomarker • Metastases • Phase classification • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • MSLN

Immunotherapy in MPM (WCLC 2017) - P2,P3; "...Finally, the JAVELIN study of Avelumab, a PD-L1 inhibitor, in patients with prior therapy reported a PR rate of 9.4% and DCR of 57%(6)...Ongoing clinical trials of single agent checkpoint blockade included the randomised phase III CONFIRM trial, comparing nivolumab with placebo in 336 previously treated patients (NCT03063450), and the randomised phase III PROMISE-Meso study, comparing pembrolizumab with chemotherapy in the second line (plus) setting in 142 patients (NCT02991482)...The completed NIBIT-Meso 1 trial is a phase II study of tremelimumab and durvalumab for which results are likely to be available soon (NCT02588131), with a further phase II trial of the same agents and similar design open in the USA (NCT03075527)...Two single arm phase II clinical trials of identical design are combining cisplatin and pemetrexed first line chemotherapy with durvalumab, one Australian (ACTRN 12616001170415) and one in the USA (NCT02899195). A randomised phase II study in Canada

Biomarker • CAR T-Cell Therapy • Checkpoint inhibition • Clinical • Mesothelioma

Con - Raphael Bueno Is Right (It Does Not Work) (IASLC-WCLC 2019) - P1, P2, P2/3, P3; "...Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%...The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features...The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year...The phase III CheckMat

IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer

Anetumab ravtansine has monotherapy efficacy in mesothelin positive patient-derived NSCLC tumor models and in a syngeneic tumor model in immunocompetent mice (AACR 2019) - P1, P1/2, P1b; "Here, we describe the mesothelin targeting antibody drug conjugate anetumab ravtansine (ARav) with the maytansinoid payload (DM4) as a novel treatment option for NSCLC.In the NSCLC cell line-derived xenograft model NCI-H322, ARav dosed at 2.5 mg/kg or 10 mg/kg, Q3Dx3, i.v., showed significant antitumor activity and was superior to cisplatin (dosed 3 mg/kg, Q3Dx12, ip). The combination led to increased frequency of TFS compared to each monotherapy (12/12 TFS in the combination versus 7/12 for the anti PD-L1 and 2/12 for ARav). Further studies are currently ongoing to optimize the combination dosing and schedule as well as to characterize the immune cells involved in the response.In summary, the data supports the development of ARav in NSCLC and further exploration of ARav in combination with immune checkpoint inhibitors in MSLN-positive cancer indications.Anetumab ravtansine clinical activity is currently assessed at phase I studies in ovarian cancer in combination

IO biomarker • Monotherapy • PD(L)-1 Biomarker • Colorectal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer

Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Malignant Pleural Mesothelioma (WCLC 2017) - P2; "Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS."

Clinical • P2 data • Mesothelioma

Phase 1b Multi-Indication Study of the Antibody Drug Conjugate Anetumab Ravtansine in Patients with Mesothelin-Expressing Advanced or Recurrent Malignancies (WCLC 2017) - P1b; "Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m2 IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m2 IV day 1 and 8 on a 21-day cycle). Section not applicable"

Biomarker • Clinical • Combination therapy • P1 data • Biliary Cancer • Mesothelioma • Non Small Cell Lung Cancer • Ovarian Cancer • Pancreatic Cancer • Triple Negative Breast Cancer

Phase 1b multi-indication study of the antibody drug conjugate anetumab ravtansine in patients with mesothelin-expressing advanced or recurrent malignancies (ESMO 2017) - P1b; "Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m2 IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m2 IV day 1 and 8 on a 21-day cycle). Secondary objectives include safety, disease control rate, duration of response, durable response rate, and progression-free survival. Approximately 348 patients will be enrolled."

Biomarker • Clinical • Combination therapy • P1 data • Biliary Cancer • Mesothelioma • Non Small Cell Lung Cancer • Ovarian Cancer • Pancreatic Cancer • Triple Negative Breast Cancer

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • IO biomarker • Metastases • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • MSLN