Phase 1 dose‐escalation study of mirvetuximab soravtansine (<scp>IMGN853</scp>), a folate receptor α‐targeting antibody‐drug conjugate, in patients with solid tumors

Moore, Kathleen N.; Borghaei, Hossein; O’Malley, David M.; Jeong, Woondong; Seward, Shelly; Bauer, Todd M.; Perez, Raymond P.; Matulonis, Ursula A.; Running, Kelli L.; Zhang, Xiaoyan; Ponte, Jose F.; Ruiz-Soto, Rodrigo; Birrer, Michael J.

doi:10.1002/cncr.30736

Cited by 104 publications

(85 citation statements)

References 30 publications

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Section: Antibody-drug Conjugatesmentioning

confidence: 99%

“…on day 1 of a 21-day cycle (i.e., once every 3 weeks) to patients with FRα-positive solid tumors, which included individuals with ovarian, endometrial, cervical, renal and NSCLC [64]. A total of 44 patients were enrolled, with the first 30 receiving mirvetuximab soravtansine at escalating doses from 0.15 to 7.0 mg/kg calculated on total body weight.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

“…Importantly, the terminal half life determined at doses ≥1.0 mg/kg showed no dose dependence with respect to clearance or volume of distribution parameters. Cycle 3 exposure metrics indicated that there was no meaningful accumulation of mirvetuximab soravtansine after multiple doses [64].Phase I clinical experience Dose escalation in the first-in-human Phase I trial (NCT01609556) evaluated mirvetuximab soravtansine administered iv. on day 1 of a 21-day cycle (i.e., once every 3 weeks) to patients with FRα-positive solid tumors, which included individuals with ovarian, endometrial, cervical, renal and NSCLC [64].…”

mentioning

confidence: 99%

“…Cycle 3 exposure metrics indicated that there was no meaningful accumulation of mirvetuximab soravtansine after multiple doses [64].…”

mentioning

confidence: 99%

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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: Antibody-drug Conjugatesmentioning

confidence: 99%

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

mentioning

confidence: 99%

“…Cycle 3 exposure metrics indicated that there was no meaningful accumulation of mirvetuximab soravtansine after multiple doses [64].…”

mentioning

confidence: 99%

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

et al. 2017

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“…The first-in-human, Phase I study of single-agent mirvetuximab soravtansine in patients with EOC and other FRα-positive solid tumors established the recommended Phase II dose (RP2D) as 6.0 mg/kg, using adjusted ideal body weight (AIBW), administered once every 3 weeks [37]. The use of AIBW to calculate mirvetuximab soravtansine dosing was shown to reduce intracohort variability in pharmacokinetic exposure metrics.…”

Section: Background and Rationalementioning

confidence: 99%

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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Improving the Safety Profile of ADCs

Guffroy

Falahatpisheh

Finkelstein

2018

Cancer Drug Discovery and Development

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Phase 1 dose‐escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α‐targeting antibody‐drug conjugate, in patients with solid tumors

Cited by 104 publications

References 30 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

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

Improving the Safety Profile of ADCs

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