Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models

Ponte, Jose F.; Ab, Olga; Lanieri, Leanne; Lee, Jenny S.W.; Coccia, Jennifer A.; Bartle, Laura M.; Themeles, Marian; Zhou, Yinghui; Pinkas, Jan; Ruiz-Soto, Rodrigo

doi:10.1016/j.neo.2016.11.002

Cited by 77 publications

(53 citation statements)

References 57 publications

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“…Preclinical data suggested that mirvetuximab soravtansine and PLD exert synergistic antitumor effects on ovarian cancer cells and, importantly, these effects translated to improved and durable efficacy over respective single-agent treatments alone (with good tolerability) in platinum-resistant, patient-derived xenografts [79]. Dose-escalation results from FORWARD II demonstrated that the combination was practical, with the highest dosing level evaluated being 6.0 mg/kg (AIBW) mirvetuximab soravtansine and 40 mg/kg PLD administered on day 1 of a 4-week cycle (n = 16) [82].…”

Section: Mirvetuximab Soravtansine Plus Pldmentioning

confidence: 99%

“…(2018) 14(2) future science group A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer Drug Evaluation treatment (including carboplatin, PLD and bevacizumab) in preclinical models [79]. These observations provided a framework for an ongoing Phase Ib/II study evaluating mirvetuximab soravtansine in combination with bevacizumab, carboplatin, PLD or pembrolizumab in patients with ovarian cancer (FORWARD II, NCT02606305).…”

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A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

et al. 2017

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Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy. Ovarian cancer landscapeOvarian cancer remains a leading cause of gynecological cancer mortality, responsible for 152,000 deaths annually worldwide [1]. In the USA alone, it is estimated that 22,440 women will be diagnosed with ovarian cancer in 2017 and more than 14,000 will die due to this disease [2]. The remarkable degree of cellular and molecular heterogeneity exhibited by tumors of the ovary (including those arising from the fallopian tubes and primary peritoneum) is such that ovarian cancer is no longer considered a single disease entity with variable morphology, but rather a collection of neoplasms each associated with their own distinct histological subtypes and response to therapy [3,4]. Among these, epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [5,6]. The foundation of current standard-of-care treatment for women diagnosed with EOC is cytoreductive (debulking) surgery and chemotherapy using a platinum-based combination regimen, most commonly the carboplatin-paclitaxel doublet. This strategy has largely reached a plateau of effectiveness in improving overall patient survival [7,8]. The continuing high mortality is associated, at least in part, with the fact that EOC is overwhelmingly diagnosed at an advanced stage. Furthermore, while EOC is highly chemosensitive and most individuals achieve remission with front-line therapy, up to 80% of patients relapse and require further treatment without the expectation of cure [9].The development of platinum resistance in EOC appears to be a dynamic and multifactorial process, although the underlying molecular mechanisms remain poorly defined [10,11]. Recurrent EOC is classified based on the length Drug Evaluation Moore, Martin, O'Malley et al. of time, empirically divided into 6-month blocks, since receiving treatment with a platinum agent, known as the platinum-free interval [7,12]. The classification is as follows:r Refractory: progression during or within 4 weeks of platinum-based chemotherapy; r Primary resistant: relapse within 6 months of completing initial platinum therapy; r Partially platinum sensitive: relapse between 6 and 12 months; r Platinum sensitiv...

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Section: Mirvetuximab Soravtansine Plus Pldmentioning

confidence: 99%

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confidence: 99%

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

et al. 2017

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“…Once the average group size tumor volume was approximately 0.159 cm 3 , the mice were randomized into treatment groups (ie, 6 to 7 per group); each group was treated with either IMGN853 (5 mg/kg), isotype control (5 mg/kg), M9346A (5 mg/kg) or PBS. Drug dosages were chosen according to previous studies conducted on xenograft models (18,32). All treatment drugs were given as retro-orbital intravenous (IV) weekly injections for two doses based on prior literature (18,32).…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Activity of IMGN853, an Antibody–Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers

Altwerger

Bonazzoli

Bellone

et al. 2018

Molecular Cancer Therapeutics

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Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (Type II) endometrial cancers, and evaluate FRα as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient derived xenograft (PDX) models. Semi-quantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (ie, 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared to control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors (p< 0.001). Treatment with IMGN853 in USC PDX model (BIO(K)1), expressing 2+ FRα, induced 2-fold increase in median survival (p< 0.001). IMGN853 shows impressive anti-tumor activity in biologically aggressive FRα 2+ uterine cancers. This preclinical data suggests that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment.

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“…Moreover, mirvetuximab soravtansine exhibited robust single-agent antitumor activity in vivo (at doses well below its maximum-tolerated dose) in multiple cell line and patient-derived xenograft models of ovarian and other FRα-positive cancers [35]. Preclinical activity of this ADC in combination with standard-of-care therapeutics used in the management of ovarian cancer has also been reported [36] and those data provided the framework for an ongoing combination Phase Ib trial in patients with advanced ovarian cancer (FORWARD II). …”

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confidence: 92%

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

Moore

Vergote²,

Oaknin

et al. 2018

Future Oncol.

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Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinumresistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response. Ovarian cancer is a leading cause of gynecologic cancer mortality worldwide, responsible for over 150,000 deaths each year [1]. Family history and the presence of penetrant mutations in genes such as BRCA1 and BRCA2 are significant risk factors for the development of ovarian cancer; epidemiological research has also identified a variety of hormonal and reproductive factors that can either increase (e.g., older age at menopause, hormone replacement therapy) or decrease (e.g., parity, lactation, oral contraceptive use) the likelihood of disease (reviewed in [2]). Epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer malignancies [3,4]. EOC is highly chemosensitive, with the current standard-of-care treatment for newly diagnosed cases involving debulking surgery and adjuvant platinum-and taxane-based combination chemotherapy. Most individuals achieve remission with front-line therapy; unfortunately up to 80% of patients will relapse during or after treatment with eventual drug-resistant disease [5]. Disease recurring within 6 months of platinum-based chemotherapy is classified as platinum-resistant, whereas disease recurring >6 months after therapy is considered platinum sensitive. Patients with platinum-sensitive disease have a high likelihood of responding to additional platinum-based therapy; however, almost all will eventually develop acquired (secondary) platinum resistance [5,6] ovarian cancer typically receive single-agent chemotherapy at relapse. Outcomes for these patients remain poor, with low response rates to further chemotherapy (15-20%), progression-free survival (PFS) of 3-4 months [7][8][9], and a median overall survival rate of less than a year [5]. In addition, this treatment approach is associated with additional, cumulative toxicities and limited tolerability for patients. It has been suggested that natural compounds, such as phytochemicals, may alleviate chemotherapy-induced side effects and therefore may be useful as adjuvants to standard treatment [10]; however, this field remains in its infancy. These measures underscore a critical need for innovative and effective therapeutic stra...

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Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models

Cited by 77 publications

References 57 publications

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

In Vitro and In Vivo Activity of IMGN853, an Antibody–Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers

FORWARD I: A Phase III Study of Mirvetuximab Soravtansine Versus Chemotherapy in Platinum-Resistant Ovarian Cancer

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