farletuzumab (MORAB-003) / Eisai - LARVOL DELTA

Establishment and characterization of a panel of ovarian XPDX models from patients with clinical resistance to anti-folate receptor therapies (AACR 2025) - "These models were characterized by DNA and RNA sequencing, folate receptor expression, and in vivo sensitivity to various therapies including MIRV. Four post-FRα ovarian XPDX models were established and characterized: ST409 was from a 59-year-old Hispanic female pretreated with chemotherapy and eleven months of farletuzumab; ST6205B and ST6205D were collected two months apart from a 74-year-old Hispanic female pretreated with chemotherapy, four months of niraparib, and seven months of MIRV; STM476 was from a 65-year-old Caucasian female pretreated with chemotherapy, eleven months of rucaparib, and two months of MIRV. We have established and characterized a panel of ovarian XPDX models from patients with clinical resistance to anti-folate receptor therapies. These models can be utilized as a valuable tool in better understanding mechanisms of resistance to FRα-targeting therapies and in developing novel therapies for patients who progress clinically on MIRV or similar..."

Clinical • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • FOLR1 • RB1 • TP53

Efficacy and Safety of Farletuzumab in Ovarian Cancer: A Systematic Review and Single-Arm Meta-Analysis. (PubMed, Cureus) - "However, the treatment is associated with a high incidence of gastrointestinal and hematological AEs, raising the need for careful patient selection. Further studies are required to refine the therapeutic regimen and ensure an optimal balance between efficacy and safety."

Journal • Retrospective data • Review • Gastrointestinal Disorder • Hematological Disorders • Neutropenia • Oncology • Ovarian Cancer • Solid Tumor • FOLR1

Preclinical testing of FOLR1-CAR T cells against osteosarcoma (OS). (ASCO 2023) - "A 2nd generation FOLR1-CAR T cell was created by fusing the ScFv from farletuzumab (anti-FOLR1 monoclonal antibody) with a 4-1BB costimulatory and CD3z cytotoxicity domain... FOLR1-CAR T cells appear to have in vivo activity against U2OS cell line and support further testing of safety and feasibility in an early phase clinical trial for relapsed/refractory OS. >"

CAR T-Cell Therapy • Preclinical • Oncology • Osteosarcoma • Pulmonary Disease • Respiratory Diseases • Sarcoma • Solid Tumor • FOLR1 • PTPRC

AFVT-2101: A FRα × CD16A bispecific innate cell engager for the treatment of solid tumors (AACR 2023) - "Further, AFVT-2101 is more efficacious and potent in both ADCC and ADCP assays than farletuzumab, an Fc-competent monoclonal antibody targeting FRα, which shares the same VH/VL sequence as AFVT-2101. Moreover, the innate immune engager significantly restrains in vivo tumor growth and induces pharmacodynamic changes in line with TME repolarization. AFVT-2101 engages innate immune cells in a target-restricted manner and potentially imparts an efficacious clinical profile with favorable tolerability."

Oncology • Solid Tumor • FCGR3A • FOLR1

Integrating antibody drug conjugates in the management of gynecologic cancers. (PubMed, Int J Gynecol Cancer) - "The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor...In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens...We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination..."

Journal • Review • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • Uterine Cancer • FOLR1 • HER-2

Randomized phase II trial of farletuzumab plus chemotherapy versus placebo plus chemotherapy in low CA-125 platinum-sensitive ovarian cancer. (PubMed, Gynecol Oncol) - P2 | "Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950)."

Journal • P2 data • Oncology • Ovarian Cancer • Solid Tumor • FOLR1 • MUC16

MORAb003-004: Efficacy and Safety of Farletuzumab (MORAb-003) in Combination With Carboplatin and Taxane in Participants With Platinum-sensitive Ovarian Cancer in First Relapse (clinicaltrials.gov) - P3 | N=1100 | Terminated | Sponsor: Morphotek | Completed ➔ Terminated; Lack of efficacy

Combination therapy • Trial termination • Oncology • Ovarian Cancer • Solid Tumor • MUC16

AFVT-2101, an innate immune-cell engager that selectively targets FOLR1 expressing tumor cells to safely harness potent anti-cancer responses (SITC 2022) - "Further, AFVT-2101 is demonstrated to be more efficacious and potent in both ADCC and ADCP assays than farletuzumab, an Fc competent monoclonal antibody targeting FOLR1 which shares the same VH/VL sequence as AFVT-2101. We show that AFVT-2101 induces moderate concentration-dependent pro-inflammatory cytokine release in a target-restricted manner, confirming a potent but safe in vitro profile of AFVT-2101. Download figure Open in new tab Download powerpoint Abstract 1212 Figure 1 Structure of AFVT-2101"

Oncology • FCGR3A • FOLR1 • IFNG • TNFA

Safety and efficacy of MORAb-202 in patients (pts) with platinum-resistant ovarian cancer (PROC): Results from the expansion part of a phase 1 trial. (ASCO 2022) - P1 | "Background: MORAb-202 is an antibody-drug conjugate consisting of farletuzumab (an antibody that binds to folate receptor alpha [FRα]) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin-B–cleavable linker. In the PROC population, antitumor activity was seen with both the MORAb-202 0.9 mg/kg and 1.2 mg/kg doses. While pt numbers were small, efficacy was observed irrespective of FRα-expression levels. ILD/pneumonitis was the most common TEAE and was low grade in most pts."

Clinical • P1 data • Inflammation • Interstitial Lung Disease • Oncology • Ovarian Cancer • Pain • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CTSB • FOLR1

Dose optimization for MORAb-202, an antibody-drug conjugate (ADC) highly selective for folate receptor-alpha (FRα), using population pharmacokinetic (PPK) and exposure-response (E-R) efficacy and safety analyses. (ASCO 2022) - P1 | "Background: MORAb-202 is an ADC consisting of farletuzumab (an antibody that binds to FRα) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin B-cleavable linker. Based on this assessment, BSA-based dosing is predicted to lower the exposure-dependent ILD risk in patients with higher BW and is being further evaluated in ongoing clinical studies."

Clinical • PK/PD data • Interstitial Lung Disease • Oncology • Ovarian Cancer • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CTSB • FOLR1

"#Eisai Presents New Findings for #AntibodyDrugConjugate #FarletuzumabEcteribulin at #ASCO22 https://t.co/NIzh8riXFD" (@1stOncology)

Expert Point of View: Deborah K. Armstrong, MD (THE ASCO POST) - "'There is limited expression [of folate receptor alpha] in normal tissues, limited to the choroid plexus, proximal renal tubules, placenta, and endometrium,' said Dr. Armstrong. 'On the other hand, the high-level expression of folate receptor alpha in ovarian cancer correlates with advanced stages of disease and more malignant phenotypes. Alternate cellular folate uptake by the reduced folate carrier circumvents folate deficiency when folate receptor alpha is targeted.'"

Media quote

Project Stella: Development and Preclinical Assessment of FOLR1-Directed Chimeric Antigen Receptor T Cells in CBF2AT3-GLIS2/RAM AML (ASH 2021) - " We generated a FOLR1-directed CAR using anti-FOLR1 binder (Farletuzumab), IgG4 intermediate spacer and 41-BB/CD3zeta signaling domains... We tested the target specificity of FOLR1-directed CAR T cells against FOLR1-positive (CBF/GLIS-CB, WSU-AML, Kasumi-1 FOLR1+ ) and FOLR1-negative (Kasumi-1) cells. CD8 FOLR1 CAR T cells demonstrated cytolytic activity against FOLR1 positive but not FOLR1 negative cells ( Figure 1B ). Furthermore, both CD8 and CD4 FOLR1 CAR T cells produced higher levels of IL-2, IFN-"

CAR T-Cell Therapy • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CBFA2T3 • CD34 • CD8 • FOLR1 • GLIS2 • IL2

MORAb-202, an antibody-drug-conjugate (ADC) targeting folate receptor alpha (FRα), exhibits durable anti-tumor efficacy in PDx models of TNBC (SABCS 2021) - "Background MORAb-202 is an ADC consisting of a FRα-targeting antibody (farletuzumab) paired with a cathepsin B-cleavable linker and an eribulin payload. The major toxicity observed with MORAb-202 treatment was hematologic toxicity. Conclusion These findings suggest MORAb-202 may be a promising ADC for TNBC and warrants further clinical investigation in this setting."

Clinical • Breast Cancer • Endometrial Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Triple Negative Breast Cancer • CTSB • FOLR1

MORAb-003-002A: An Open Label Extension Study of the Efficacy of MORAb-003 (clinicaltrials.gov) - P2; N=3; Terminated; Sponsor: Morphotek; Completed ➔ Terminated; Study was terminated by sponsor due to futile results in NCT00849667 study.

Trial termination • Oncology • Ovarian Cancer • Solid Tumor

First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors. (ASCO 2019) - P1; "Background: MORAb-202 is an antibody drug conjugate consisting of farletuzumab (a humanized monoclonal antibody that binds to FRA) paired with a cathepsin B-cleavable linker to eribulin mesylate (a microtubule dynamics inhibitor). MORAb-202 escalation to 0.9mg/kg was manageable with encouraging initial antitumor activity in pts with FRA-positive solid tumors. Clinical trial information: NCT03386942"

Clinical • P1 data

[VIRTUAL] A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA125 pl (SGO 2021) - P2 | "The combination of FAR-CT did not show signals of superior efficacy compared with PLB-CT in improving PFS or other efficacy parameters in subjects with platinum-sensitive recurrent ovarian cancer in first relapse who had low CA-125 levels. No new safety concerns were identified with the combination of FAR-CT. Since FAR binds to the folate receptor alpha, a novel antibody-drug conjugate has been developed and clinical studies are ongoing to assess the safety/efficacy of this modification."

Clinical • Combination therapy • P2 data • Interstitial Lung Disease • Oncology • Ovarian Cancer • Respiratory Diseases • Solid Tumor • FOLR1

Folate receptor α increases chemotherapy resistance through stabilizing MDM2 in cooperation with PHB2 that is overcome by MORAb-202 in gastric cancer. (PubMed, Clin Transl Med) - "The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα-expressing tumor."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FOLR1 • MDM2

"Didn't farletuzumab / MORAb-202 already fail in phase 3? $BMY" (@JacobPlieth)

P3 data

First-in-human Phase 1 Study of MORAb-202, An Antibody-drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-positive Advanced Solid Tumors. (PubMed, Clin Cancer Res) - P1 | "The maximum tolerated dose of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202."

Clinical • Journal • P1 data • Hematological Disorders • Interstitial Lung Disease • Leukopenia • Neutropenia • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CTSB

Antibody-Drug-Conjugate MORAb-202 exhibits long-lasting antitumor efficacies against TNBC PDx Models. (PubMed, Cancer Sci) - "The antibody drug conjugate MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed on various tumor types. Toxicology studies (Q3Wx2) in non-human primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTSB • FOLR1

Farletuzumab/Chemo Fails to Improve PFS in Platinum-Sensitive, Recurrent Ovarian Cancer With Low CA-125 (OncLive) - P=NA, N=214; "The addition of farletuzumab to carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin did not demonstrate superiority over placebo plus chemotherapy in patients with platinum-sensitive recurrent ovarian cancer who are in their first relapse and have low cancer antigen-125 levels....'Is there a future for farletuzumab in ovarian cancer? Perhaps, but not likely as a monoclonal antibody alone,' Herzog concluded. 'A derivative compound, MORAb-202 is an antibody-drug conjugate with farletuzumab linked to eribulin as the cytotoxic payload. Promising phase 1 Japanese data have spurred ongoing trials for ovarian, endometrial, and endometrial cancers.'"

Clinical data • Media quote

Eisai to Present Investigational Data from Oncology Pipeline at the Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women's Cancer (PRNewswire) - "Eisai will present two abstracts at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women's Cancer, March 19-25 (#SGOMtg). These investigational data include the first presentation of efficacy and safety results from the KEYNOTE-775/Study 309 study, a multi-center, randomized, open-label, Phase 3 trial (NCT03517449) evaluating KEYTRUDA in combination with LENVIMA in certain patients with advanced endometrial cancer...Additional data to be presented in the Focused Plenary V: Ovary – Time to Return to the Drawing Board session include an abstract (Plenary Session ID # 10240) on results from a randomized, double-blind, placebo-controlled, Phase 2 study evaluating the efficacy and safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin in women with low CA125 platinum-sensitive ovarian cancer (NCT02289950)."

P2 data • P3 data • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer

[VIRTUAL] A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA125 platinum-sensitive ovarian cancer (SGO 2021) - No abstract available

Clinical • Combination therapy • P2 data • Oncology • Ovarian Cancer • Solid Tumor

Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors (AACR 2018) - "FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3).In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules.We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Cancer Discov. 4, 998-1013 (2014)."

Triple Negative Breast Cancer