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Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors:

Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors: 584763 TAM0010.1177/1758834015584763Therapeutic Advances in Medical OncologyVergote research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Vintafolide: a novel targeted therapy for 2015, Vol. 7(4) 206 –218 DOI: 10.1177/ the treatment of folate receptor expressing © The Author(s), 2015. Reprints and permissions: tumors http://www.sagepub.co.uk/ journalsPermissions.nav Ignace Vergote and Christopher P. Leamon Abstract: Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early- stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents. Keywords: folate receptor, lung neoplasms, neoplasms, ovarian neoplasms, small molecule drug conjugate, vintafolide Correspondence to: Introduction 2006; Stegmeier et  al. 2010]. Targeted therapies Christopher P. Leamon, There is an ongoing need for the development of are associated with a low toxicity profile, though PhD Endocyte, Inc., 3000 Kent new cancer therapies that can effectively target they often have low single-agent responses [Imai Avenue, West Lafayette, IN tumor cells without harming normal cells or tissue and Takaoka, 2006]. However, a key consideration 47906, USA chrisleamon@endocyte. [Miller et  al. 2013]. Recent treatment advances for targeted therapy is to establish predictive bio- com include the use of combination chemotherapy, markers and/or imaging techniques to determine Ignace Vergote, MD, PhD which has had a significant impact on the treat- which patients would benefit most from a particu- Leuven Cancer Institute, Leuven, Belgium ment of most cancer types [DeVita and Chu, lar targeted-therapy combination [Bicknell, 2005; 2008]. Targeted cancer therapies such as monoclo- Stegmeier et  al. 2010]. Furthermore, like tradi- nal antibodies and small molecule tyrosine kinase tional chemotherapy, the emergence of resistance inhibitors have also had a significant impact on to targeted therapies is a major challenge often cancer treatment, demonstrating increased efficacy faced in the clinic, particularly in patients with with improvements in progression-free survival advanced tumors [Miller et al. 2013]. Thus, there (PFS) over conventional chemotherapeutics alone is a clear need for new strategies and targeted in many tumor types [Bottsford-Miller et al. 2012; approaches to cancer treatment, particularly when Feliz and Tsimberidou, 2013; Giuliano and Pages, combating resistance. Two major categories of cur- 2013; Miller et  al. 2013; Tang et  al. 2013; Tejpar rently used targeted therapies include monoclonal et al. 2012]. These therapies have the potential to antibodies (e.g. trastuzumab, bevacizumab) and achieve durable antitumor effects without overlap- small molecule therapies (e.g. tyrosine kinase ping toxicity [Bicknell, 2005; Imai and Takaoka, inhibitors, bortezomib) [Miller et al. 2013]. Drug 206 http://tam.sagepub.com I Vergote and CP Leamon conjugates are another major group of targeted Capdevila, 1986; Tian et al. 2012]. After binding therapies that involve a promising approach to the FR, folate uptake occurs through receptor- whereby targeted agents are created by linking a mediated endocytosis [Kamen and Capdevila, drug or a prodrug to a tissue-targeting molecule 1986; Vlahov et al. 2006]. It is important to note or carrier; this group can be further separated that FRα plays a critical role in the uptake of into antibody-drug conjugates (ADCs) and small serum folates by cells expressing the receptor by molecule-drug conjugates (SMDCs). The folate binding 5-MeTHF with high affinity and FA with receptor (FR) is overexpressed in many epithelial even higher affinity [Antony, 1996; Kamen and tumors and has been established as a tumor cellu- Capdevila, 1986; Kamen and Smith, 2012; Tian lar-surface marker for targeted drug delivery [Teng et al. 2012; Westerhof et al. 1995]. et al. 2012]. This has led to the development of a number of FR-targeted agents, including anti-FR FRβ is expressed in placenta, colon, thymus, monoclonal antibodies, FR-binding ADCs, and spleen, and various leukemic myelomonocytic folic acid (FA)-based SMDC (FA-SMDC). The cells [Elnakat and Ratnam, 2004; Ratnam et  al. aim of this paper is to review the role of the FR as 1989; Ross et al. 1994; Shen et al. 1994; Weitman a target in cancer progression and resistance and to et al. 1992a]. In contrast, FRα is expressed mostly consider agents in development that target the FR in epithelial cells of the uterus, placenta, choroid with a focus on the SMDC vintafolide. plexus, retina, and kidney [Gonen and Assaraf, 2012], and it is expressed at very high levels in several tumor types, including ovarian, lung, kid- The FR and its role in cancer progression ney, and breast cancer, making it a prime candi- and resistance date for targeted anticancer therapy [Christoph et al. 2013; Crane et al. 2012; Elnakat and Ratnam, The FR and folate metabolism 2006; Nunez et al. 2012; Parker et al. 2005; T offoli Folate is essential for DNA replication and the et al. 1997; Weitman et al. 1992a]. FRα expression synthesis of nucleotide precursors [Gonen and is notably restricted to the apical surfaces of polar- Assaraf, 2012]. Folates can be found in an oxi- ized epithelial cells in the kidney (facing the lumen dized form, FA, or as naturally occurring reduced of the tubule) and therefore is not exposed to the folates [Gonen and Assaraf, 2012]. However, the bloodstream [Parker et  al. 2005]. Similarly, lung major circulating form of folate is 5-methyltet- alveolar lining cells (type I and II pneumocytes) rahydrofolate (5-MeTHF), which is found at low, and epithelial cells of the bronchi stain intensely yet sufficient, physiological concentrations of for FRα on the apical membranes facing the air- 5–30 nM in sera [Gonen and Assaraf, 2012; way, which are not accessible to blood-borne Ifergan and Assaraf, 2008]. folates [Parker et  al. 2005; Salazar and Ratnam, 2007; Weitman et  al. 1992b]. It is important to Folates can be taken up into cells first by carrier note that FRα expression in normal cells of the proteins, such as the transmembrane-reduced uterus, choroid plexus, retina, and kidney is con- folate carrier, which is ubiquitously expressed in siderably lower than FRα expression at sites not most normal tissues and malignant tumors, or by exposed to the bloodstream and in cancer [Parker the proton-coupled folate transporter in low pH et al. 2005; Ross et al. 1994; Weitman et al. 1992a, environments, such as the intestine [Zhao et  al. 1992b]. Based on these observations, targeting the 2009], and second, through membrane-bound FRα may be an effective therapeutic option for the FRs [Gonen and Assaraf, 2012]. FRs are high- treatment of cancer [Salazar and Ratnam, 2007]. affinity folate-binding glycoproteins, of which there are three principal isoforms (α, β, and γ) [Gonen and Assaraf, 2012]. A fourth isoform, The FR and cancer progression and resistance FRδ, has also been identified, but it has been dif- The FR appears to play a critical role in cancer ficult to detect in human tissues; therefore, it is progression and resistance. For instance, FRα suggestive of a highly restricted expression pat- expression appears to be a negative prognostic tern, a splice variant, or a pseudogene [Spiegelstein factor in patients with ovarian cancer [Kalli et al. et al. 2000; Tian et al. 2012]. FRα and FRβ bind 2008; Toffoli et  al. 1998] and may represent a FA as well as 5-MeTHF with high affinity, marker for resistance to conventional chemother- whereas FRγ is a secreted protein that is not apy. In addition, FRα expression is a negative- involved in cellular uptake [Antony, 1996; Dosio prognostic factor in breast [Hartmann et  al. et al. 2010; Gonen and Assaraf, 2012; Kamen and 2007], endometrial [Brown et  al. 2008], uterine http://tam.sagepub.com 207 Therapeutic Advances in Medical Oncology 7(4) [Allard et  al. 2007], and colorectal cancer [Shia IMGN853 is an FRα-targeting ADC that is com- et  al. 2008]. It is important to note that FRα posed of three parts: an anti-FRα antibody that expression does not appear to be influenced by targets the compound to FRα-expressing cancer chemotherapy in ovarian and endometrial cancer cells; DM4, a potent cell-killing agent that inhibits [Despierre et  al. 2013]. Taken together, these tubulin polymerization; and a disulfide-based studies further support the rationale for targeting linker [Ab et  al. 2011]. IMGN853 is in phase I the FRα in cancer treatment. clinical development for patients with ovarian can- cer and other FOLR1+ solid tumors [ClinicalTrials. gov identifier: NCT01609556] [Ab et  al. 2011]. Targeting the FRα in tumors Preliminary results recently reported indicate that Three general strategies have been used to target IMGN853 was well tolerated at doses up to 3.3 therapeutics to FR-expressing tumors: an anti-FR mg/kg and provided evidence of antitumor activity antibody approach, a humanized FRα-binding– [Kirkjian et al. 2013; Moore et al. 2014]. ADC approach, and a FA-SMDC approach [Beck et  al. 2012; Teng et  al. 2012; Vlahov and FA-SMDCs were developed because they are Leamon, 2012]. smaller than monoclonal antibodies and have a higher affinity for FRs on cancer cells; therefore, Several anti-FRα antibodies have been developed they may potentially improve blood clearance and for targeting of FRα antibodies, including the tumor penetration of the attached drug [Pribble monoclonal antibody farletuzumab [Armstrong and Edelman, 2012; Vlahov and Leamon, 2012]. et al. 2013; Konner et al. 2010; Teng et al. 2012], The proposed mechanism of action of FA-SMDCs which has a mechanism of action distinct from is shown in Figure 1 [Vlahov and Leamon, 2012]. that of drug conjugates. Farletuzumab is a fully First, the FA-based SMDC extravasates from the humanized antibody derived from the murine circulation and binds the high-affinity FR on the antibody LK26, which binds FRα to promote cell tumor cell. The FR and conjugate then enter the lysis by both complement-dependent cytotoxicity cell by endocytosis. The FA-SMDC is sequestered and antibody-dependent cell-mediated cytotoxic- in an endosome, where the pH is lower (because ity [Farrell et  al. 2012; Jelovac and Armstrong, of the presence of proton pumps), causing the 2012; Teng et al. 2012]. In addition, the binding SMDC to be released from the FR. Reductive of farletuzumab to FRα also suppresses the pro- activity inside the endosome then cleaves the liferation and growth of FRα-expressing cells and disulfide-based linker of the FA-SMDC to release tumors by preventing the phosphorylation of sub- the active drug. Finally, the drug escapes from the strates specific for Lyn kinase [Jelovac and endosome to enter the cytosol while the FR recy- Armstrong, 2012]. Farletuzumab is being investi- cles back to the cell surface. The whole process is gated as a single agent or in combination with then repeated. Several folate-conjugated cytotoxic chemotherapy in epithelial-ovarian carcinoma agents have been, or are being, evaluated as anti- [Armstrong et  al. 2013; Jelovac and Armstrong, cancer therapy, including folate-conjugated 2012; Konner et  al. 2010] and in combination 5-fluro-2′deoxyuridine-5′-O-monophosphate, with chemotherapy in lung cancer [Thomas et al. folate-conjugated carboplatin, and folate-conju- 2013]. Farletuzumab was evaluated as a single gated microtubule poisons [Teng et  al. 2012]. agent and in combination with carboplatin and a These include EC0225 [Leamon et  al. 2007a], taxane in a phase II study in patients with plati- folate conjugated to both a vinca alkaloid and num-sensitive ovarian cancer [Armstrong et  al. mitomycin; BMS-753493 (epofolate) [Gokhale 2013]. As a single agent, farletuzumab was well et  al. 2012] [ClinicalTrials.gov identifiers: tolerated without additive toxicity when adminis- NCT00546247 and NCT00550017] folate con- tered with chemotherapy. Further, when com- jugated to epothilone; and EC0489 [ClinicalTrials. bined with chemotherapy, 75% of patients gov identifier: NCT00852189], an analogue of achieved complete response (CR) or partial vintafolide (vide infra). response (PR). Results from the phase III FAR- 121 study in patients with platinum-sensitive ovarian cancer in first relapse showed that farletu- Patient selection and biomarker analyses zumab in combination with carboplatin and a The noninvasive, folate-targeted, single-photon taxane (paclitaxel or docetaxel) unfortunately did emission computed tomography based compan- 99m not meet the study’s primary endpoint of PFS ion imaging agent, Tc-etarfolatide (EC20), [Vergote et al. 2013]. offers the potential to rationally select patients for 208 http://tam.sagepub.com I Vergote and CP Leamon Figure 1. Schematic presentation of tumor cellular uptake of a FA–based, small-molecule drug conjugate. FA, folic acid; FR, folate receptor. treatment with vintafolide without the need for is a vinca alkaloid that disrupts the formation of biopsy [Morris et al. 2014; Pribble and Edelman, the mitotic spindle, thereby inhibiting cell divi- 2012]. The use of imaging with etarfolatide sion and inducing cell death [Pribble and allows identification of patients whose disease Edelman, 2012]. FA and DAVLBH are connected expresses functionally active FR and, therefore, through a peptide spacer and a reducible, self- has the potential to respond to FR-targeted immolative disulfide-linker system to form vinta- treatment [Morris et  al. 2014]. Using this folide [Dosio et  al. 2010; Pribble and Edelman, technique, patients are generally categorized 2012]. The disulfide linker enables the release of as FR++ (100%; all lesions positive), FR+ DAVLBH inside the cancer cell after receptor- (10–90%; at least one lesion positive, but not all mediated endocytosis [Pribble and Edelman, positive), and FR– (0%; no lesions positive) 2012]. This is an important feature because the (Figure 2) [Naumann et  al. 2013]. Because high affinity of FA for the FR can result in ligands EC20 is a noninvasive, real-time assessment of remaining attached to the FR for long periods of functionally active and anatomically accessible time, which can reduce the potency of folate-tar- FRs, it has been evaluated as a biomarker of geted chemotherapeutic agents [Dosio et  al. response to FA-SMDCs, such as vintafolide 2010]. Vintafolide was designed specifically to [Leamon et al. 2012]. bind to high-affinity FR present on the surfaces of cancer cells and to release its active component, DAVLBH, once it enters the endosome of the tar- Vintafolide get cell (Figure 3). Chemistry and mechanism of action Vintafolide is a water-soluble derivative of FA and Preclinical studies the vinca alkaloid desacetylvinblastine hydrazide Preclinical studies have shown that vintafolide (DAVLBH) (Figure 3) [Dosio et al. 2010; Pribble binds to the FRα with high affinity [Leamon and Edelman, 2012; Vlahov et al. 2006]. DAVLBH et  al. 2007b]; accordingly, it has highly potent http://tam.sagepub.com 209 Therapeutic Advances in Medical Oncology 7(4) Figure 2. Etarfolatide imaging. Etarfolatide imaging can be used to divide patients into three categories: FR++ (100%; all lesions positive), FR+ (10–90%; at least one lesion positive but not all positive), or FR– (0%; no lesions positive). FR, folate receptor. and specific antitumor activity against FRα+ found to completely block the activity of vinta- tumors [Dosio et al. 2010; Leamon et al. 2007b, folide, and FR– cells are resistant to vintafo- 2012; Reddy et  al. 2007]. FRα expression is lide. Specificity for FR-containing cells has critical for vintafolide activity, and cytotoxicity also been demonstrated in FRα-expressing is dose dependent with an IC (concentration tumors in M109 tumor-bearing BALB/C mice that inhibits 50% of activity) in the single-digit [Leamon et al. 2012]. nanomolar range [Leamon et  al. 2007b]. Preclinical studies conducted to optimize the dosing regimen have shown that vintafolide is Pharmacodynamic and pharmacokinetic studies most efficacious when administered on a more In a nonrandomized, open-label, dose-compari- frequent schedule and at low-dose levels son, phase I study in patients with refractory or [Reddy et  al. 2007], exploiting the natural metastatic solid tumors, vintafolide was adminis- recycling mechanism of the FR to keep greater tered as an intravenous bolus injection or as a 1 h pressure on the tumor cell. Specificity for infusion on days 1, 3, and 5 (week 1) and days 15, FR-containing cells has been demonstrated by 17, and 19 (week 3) of a 28-day cycle [Li et  al. the fact that the binding affinity of vintafolide 2009; LoRusso et al. 2012]. The maximum toler- for the FR is slightly less than the affinity of ated dose (MTD) of vintafolide was 2.5 mg, and folate for the FR (0.47 relative to the binding the maximum concentration and area under affinity of FA for the FR) [Leamon et  al. the curve for vintafolide increased in a dose- 2007b]. Furthermore, excess free FA has been proportional manner across the dose range studied 210 http://tam.sagepub.com I Vergote and CP Leamon Figure 3. Molecular design and structure of vintafolide. Each molecule of vintafolide contains one FA moiety, which serves as a stable high-affinity binding ligand for the FR (Kd ~0.1 nM), and one vinca alkaloid unit (DAVLBH). Unlike the untargeted DAVLBH molecule, vintafolide is readily soluble in aqueous solutions because of the hydrophilic peptide spacer unit that is placed between the folic acid and DAVLBH moieties. This physical property enables vintafolide to be dosed intravenously without the aid of coadministered solubilizing or dispersing agents. A self-immolative linker system allows for efficient release of the DAVLBH moiety inside the endosome of the targeted FR-expressing tumor cell. DAVLBH, desacetylvinblastine hydrazide; FA, folic acid; FR, folate receptor. [Li et  al. 2009; LoRusso et  al. 2012]. The phar- regimen for “maintenance”) [Li et  al. 2009; macokinetics of vintafolide are characterized by a Morris et al. 2014]. rapid distribution and elimination phase, which includes a short distribution half life (i.e. uptake In the nonrandomized, open-label, dose-compar- of the conjugate by FR-expressing tissues in vivo ison, phase I study in patients with refractory or is rapid) [Paulos et al. 2004], a volume of distri- metastatic solid tumors, the MTD of vintafolide bution that is larger than blood volume, and was 2.5 mg administered as an intravenous bolus rapid clearance by the kidney and liver [Li et al. on days 1, 3, and 5 (week 1) and days 15, 17, and 2009; Paulos et  al. 2004]. On the basis of these 19 (week 3) of a four-week cycle [LoRusso et al. results, a dose-dense regimen was proposed for 2012]. Preliminary evidence of antitumor activity phase II studies, in which the same cumulative was demonstrated in two patients with ovarian dose (2.5 mg × six doses per month) was divided cancer; one patient had a PR, and the other into smaller doses of 1.0 mg/day as an intravenous patient had disease stabilization for longer than bolus injection (Monday–Friday) for 3 weeks 5 months [LoRusso et al. 2012]. Vintafolide dem- of a four-week cycle, with a total dose of onstrated an acceptable safety profile with no 15 mg/month (this was an induction-style design; evidence of myelosuppression. Constipation, after two cycles, patients returned to the three nausea, fatigue, and vomiting were the most times a week, every other week, four-week cycle commonly reported adverse events. http://tam.sagepub.com 211 Therapeutic Advances in Medical Oncology 7(4) Clinical studies: ovarian cancer clinical activity compared with PLD alone, with a The efficacy and safety of vintafolide was first median PFS (primary endpoint) of 5.0 months in assessed in 2007 in a nonrandomized trial [Morris the vintafolide plus PLD arm compared with et  al. 2014], and a number of phase II and III 2.7 months in the PLD-alone arm (HR 0.63; 95% clinical studies have since been conducted in CI 0.41–0.96; p = 0.031) (Figure 4, Table 1). patients with ovarian and lung cancer [Edelman Furthermore, this benefit with combination et  al. 2012a, 2012b; Naumann et  al. 2013]. The therapy was maintained in FR+ (i.e. 10–100% main characteristics and key findings of these FR+ target tumor lesions) patients (5.7 versus clinical trials are described in the following sec- 1.7 months; HR 0.547; 95% CI 0.304–0.983; tions and are summarized in Table 1. p = 0.041) (Table 1); the greatest benefit was in FR++ patients (HR 0.381; 95% CI 0.172–0.845; Study EC-FV-02 was an open-label, phase II trial p = 0.013). No significant differences in the of vintafolide monotherapy in patients with plati- Response Evaluation Criteria in Solid Tumors– num-resistant or -refractory advanced epithelial confirmed objective response rate (ORR; 18% ovarian, primary peritoneal, or endometrial can- versus 12%; p = 0.479) and the secondary end- cer who underwent scanning with EC20 to assess point of OS (HR 1.010; 95% CI 0.679–1.503; their FR status [Morris et  al. 2014]. Vintafolide p = 0.957) were noted between the combination treatment consisted of an induction phase, fol- therapy and the PLD-alone treatment arms. lowed by a maintenance phase for responders Overall, the drug combination was well tolerated. (patients achieving CR or PR) or patients who No cumulative treatment-emergent adverse events had stable disease (SD) without unacceptable (TEAEs) were reported, except palmar-plantar toxicity (Table 1). The disease control rate (DCR) erythrodysesthesia syndrome, which increased in for all evaluable patients (primary endpoint), incidence with subsequent cycles in both treat- regardless of EC20 status, was 40% [95% confi- ment arms. Most TEAEs in both treatment arms dence interval (CI) 25.7–55.7%; CR, 0%; PR, were grade 1 or 2, with higher incidence rates 4%; SD, 36%]. Superior outcomes were demon- of leukopenia, abdominal pain, peripheral sensory strated in patients who demonstrated EC20 neuropathy (all p = 0.026) and neutropenia uptake with DCRs of 57% in those with all FR+ (p = 0.021) in the vintafolide plus PLD arm than target tumor lesions (FR++) and 43% in those in the PLD-alone arm; the incidence of nausea who had at least one but not all FR+ target lesions was higher in the PLD-alone arm (p = 0.036). For (FR+), compared with 25% in patients who were grade 3 or 4 TEAEs, the difference in the inci- FR–. Two patients experienced PR; both patients dence of leukopenia between treatment arms was were FR+, with one FR++. A similar benefit in nominally statistically significant (p = 0.031). median overall survival (OS) was seen when However, the difference in leukopenia incidence patients were assessed by EC20 status, with between treatment arms was not clinically signifi- FR++ patients demonstrating significant cant because no increase in febrile neutropenia or improvement in OS compared with FR– patients infection was reported. [hazard ratio (HR) 0.170; p = 0.001]. The most common drug-related vintafolide toxicity (all The recently completed randomized, double- grades) was constipation, followed by fatigue, blind, placebo-controlled, phase III PROCEED nausea, anorexia, and neuropathy. The most com- trial (EC-FV-06) [ClinicalTrials.gov identifier: mon grade 3 vintafolide-related toxicities were NCT01170650] evaluated vintafolide in combina- constipation and fatigue; no grade 4 vintafolide- tion with PLD compared with PLD alone in related toxicities were reported. patients with FR+, platinum-resistant ovarian cancer. Patients with primary or secondary plati- The open-label, randomized, phase II num-resistant, pathology-confirmed epithelial PRECEDENT study (EC-FV-04) evaluated the ovarian, fallopian tube, or primary peritoneal can- use of vintafolide in combination with pegylated cer were eligible for the study and had their FR liposomal doxorubicin (PLD) versus PLD alone in status determined by EC20 scans. The primary 162 women with platinum-resistant recurrent endpoint of this study was PFS in patients with ovarian cancer who had received at least two pre- FR+ tumors. At a prespecified interim futility vious cytotoxic regimens (Table 1); the assessment analysis, the Data Safety Monitoring Board of FR status using the companion imaging diag- (DSMB) recommended that the study be stopped nostic, EC20, was optional [Naumann et al. 2013]. because vintafolide in combination with PLD ver- Vintafolide demonstrated significantly improved sus PLD alone did not meet the prespecified 212 http://tam.sagepub.com I Vergote and CP Leamon Table 1. Summary of efficacy and safety clinical trial data for vintafolide [Edelman et al. 2012a, 2012b; Morris et al. 2014; Naumann et al. 2013]. Trial Study design Participants Interventions Key efficacy and safety results Ovarian cancer trials Study EC-FV-02 Phase II, Patients with Vintafolide monotherapy: Efficacy [ClinicalTrials. single-arm, OL, platinum-resistant induction phase (1 mg DCR* (primary endpoint): gov identifier: MC or -refractory intravenously, Monday Overall: 40% (95% CI 25.7–55.7%) NCT00507741] advanced epithelial to Friday for 3 weeks, By FR status : FR++ (57%; 95% CI [Morris et al. 2014] ovarian, primary every 28 days for two 28.9–82.3%); FR+ (43%; 95% CI 27.1– peritoneal, or cycles) followed by a 60.5%); FR– (25%; 95% CI 0.6-80.6%) endometrial cancer maintenance phase OS: (N = 45); patients (2.5 mg intravenously, By FR status : FR++ (14.6 months); were scanned with Monday, Wednesday, and FR+ (11.6 months); FR– EC20 to assess FR Friday during weeks 1 (2.7 months) status and 3, every 28 days) in FR++ versus FR+ (HR 0.708; p = 0.420) responders (CR or PR) FR++ versus FR– (HR 0.170; p = 0.001) and patients with SD Safety without unacceptable Common vintafolide-related AE (all toxicity grades): nausea (29%), anorexia (22%), and neuropathy (20%) PRECEDENT Phase II, R, OL, Patients with Combination therapy: Efficacy (EC-FV-04) MC platinum-resistant, vintafolide (2.5 mg Combination therapy versus PLD [ClinicalTrials. recurrent ovarian intravenously, three monotherapy gov identifier: cancer who received times per week during Median PFS (primary endpoint): NCT00722592] up to two previous weeks 1 and 3, every Overall: 5.0 versus 2.7 months (HR [Naumann et al. cytotoxic regimens 28 days) + PLD 0.63; 95% CI 0.41–0.96; p = 0.031) 2013] (N = 162); EC20 (50 mg/m intravenously FR+ patients: 5.7 versus 1.7 months scans were optional on day 1, every 28 days) (HR 0.547; 95% CI 0.304–0.983; or p = 0.041) PLD monotherapy RECIST-confirmed ORR: Overall: 18% versus 12% (p = 0.479) DCR*: Overall: 73% versus 53% (p = 0.018) Median OS: Overall: HR 1.010 (95% CI 0.679– 1.503; p = 0.957) Safety TEAE more common with combination therapy: leukopenia (23% versus 8%), abdominal pain (36% versus 18%), and peripheral sensory neuropathy (29% versus 12%; all p = 0.026); neutropenia (44% versus 24%; p = 0.021) TEAE more common with PLD monotherapy: nausea (8.0% versus 0.9%; p = 0.036) PROCEED Phase III, R, Patients with FR+, Combination Primary endpoint: PFS (EC-FV-06) DB, PBC platinum-resistant therapy: vintafolide Secondary endpoints: OS, tolerability [ClinicalTrials. epithelial ovarian, (intravenously, three Results of this trial are anticipated gov identifier: fallopian tube, or times per week during in 2015 NCT01170650] primary peritoneal weeks 1 and 3, every cancer; all patients 28 days) + PLD were scanned with (50 mg/m , every 28 days) EC20 to assess FR or status PLD monotherapy (Continued) http://tam.sagepub.com 213 Therapeutic Advances in Medical Oncology 7(4) Table 1. (Continued) Trial Study design Participants Interventions Key efficacy and safety results Lung cancer trials Study EC-FV-03 Phase II, Patients with Vintafolide monotherapy: Efficacy [ClinicalTrials. single-arm, OL, progressive induction phase (1 mg Clinical benefit response (primary gov identifier: MC adenocarcinoma intravenously, daily × endpoint): NCT00511485] of the lung who 5 days for 3 weeks, every Overall: 26% (95% CI 14–41%) [Edelman et al. previously received 28 days) followed by a $ By FR status : FR++ versus FR+ 2012a, 2012b] at least two maintenance phase (50% versus 14%; p = 0.10) cytotoxic-containing (2.5 mg intravenously, DCR* at 8 weeks: chemotherapeutic three times per week Overall: 35% (95% CI 0–12%) regimens (N = during weeks 1 and 3, Median PFS: 43); at least one 1 every 28 days) Overall: 7.4 weeks EC20+ tumors $ By FR status : FR++ versus FR+ (31.1 versus 7.3 weeks; HR 0.326; p = 0.034) Median OS: Overall: 42.9 weeks By FR status : FR++ versus FR+ (47.2 versus 14.9 weeks; HR 0.539; p = 0.101) Safety Common drug-related AEs: fatigue (37.2%), constipation (32.6%), nausea (14.0%), and anemia (14.0%) TARGET Phase II, R, OL, Patients with Vintafolide monotherapy: Primary endpoint: PFS (EC-FV-07) MC NSCLC whose 2.5 mg twice per week Secondary endpoint: ORR, DCR, [ClinicalTrials. condition failed during weeks 1 and 2, duration of response, duration of gov identifier: to respond to every 21 days disease control, tolerability NCT01577654] one previous or The study is ongoing chemotherapy Combination therapy: regimen; all vintafolide + docetaxel patients have FR++ (75 mg/m intravenously, tumors as assessed day 1, every 21 days) by EC20 scans or Docetaxel monotherapy *DCR is defined as the proportion of patients achieving CR, PR, or SD. FR status was determined by EC20-based single-photon emission computed tomography to identify patients with FR++ (all target lesions FR+), FR+ (⩾1FR+ target tumor lesion), or FR– (no FR+ target tumor lesions). Clinical benefit response is defined as the ability to receive more than four cycles of therapy, indicating that patients had responded to therapy (SD or radiographic response) and had tolerated therapy well. 99m AE, adverse event; CI, confidence interval; CR, complete response; DB, double blind; DCR, disease control rate; EC20, Tc-etarfolatide; FR, folate receptor; HR, hazard ratio; MC, multicenter; NSCLC, non-small cell lung cancer; OL, open label; ORR, objective response rate; OS, overall survival; PBC, placebo controlled; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PR, partial response; R, randomly as- signed; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TEAE, treatment-emergent AE. criteria for PFS to allow continuation of the study. The primary objective, clinical benefit response The DSMB did not identify any safety concerns [the ability to receive more than four cycles of ther- for the patients enrolled in the PROCEED trial. apy, indicating that patients had responded (SD or Final results are anticipated to be available in 2015. radiographic response) and had tolerated therapy well], was not met (26%; 95% CI 14–41%); a PR was reported in one patient (2.3%; 95% CI Clinical studies: lung cancer 0–12%). In an exploratory analysis, FR++ patients Study EC-FV-03 was a single-arm, open-label trial demonstrated a superior clinical benefit response that evaluated vintafolide in patients with progres- of 50% compared with 14% in FR+ patients sive adenocarcinoma of the lung who had previ- (p = 0.10). Median PFS was 7.4 weeks and median ously received at least two cytotoxic-containing OS was 42.9 weeks for the whole study population. chemotherapeutic regimens and were identified An exploratory analysis of survival outcomes dem- as EC20+ (Table 1) [Edelman et al. 2012a, 2012b]. onstrated a significant improvement in median PFS 214 http://tam.sagepub.com I Vergote and CP Leamon Figure 4. Kaplan–Meier curve of PFS by treatment arm. PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; Vinta, vintafolide. Reprinted with permission from Naumann et al. [2013]. © 2013 American Society of Clinical Oncology. All rights reserved. in patients with FR++ tumors compared with associated with vinca alkaloid therapy, with no those with FR+ tumors (31.1 versus 7.3 weeks; HR new or unique TEAE reported [Dosio et al. 2010; 0.326; p = 0.034) and a trend toward improvement Pribble and Edelman, 2012]. Although FRα is in median OS (47.2 versus 14.9 weeks; HR 0.539; highly expressed in the kidney [Parker et al. 2005], p = 0.101) [Edelman et al. 2012a]. no renal toxicities have been observed [Dosio et al. 2010]. The randomized, open-label, phase II TARGET trial (EC-FV07) [ClinicalTrials.gov identifier: NCT01577654] is also being conducted to com- Conclusion pare vintafolide as second-line treatment with vin- Vintafolide has a unique target, the FR, which has tafolide plus docetaxel and docetaxel alone in several unique properties that make it a rational patients with non-small cell lung cancer (NSCLC) target for cancer treatment, including high expres- who have FR++ tumors. The primary endpoint of sion in cancer cells of several tumor types and a this study is PFS, and secondary endpoints include restricted pattern of tissue-specific expression ORR, DCR, duration of response, OS, and safety. allowing for selective delivery of FR-targeted Preliminary data for vintafolide in combination agents. Use of the companion diagnostic (etar- with docetaxel showed clinically meaningful folatide; EC20) allows the selection of patients improvement across all efficacy endpoints over who are most likely to benefit from vintafolide single-agent docetaxel [Hanna et  al. 2014]. The treatment. Vintafolide has been investigated in median (95% CI) PFS of the vintafolide plus doc- ongoing phase II and phase III studies in NSCLC etaxel and docetaxel groups was 4.2 (2.8–5.4) and and ovarian cancer, respectively, and its favorable 3.3 (1.7–4.2) months, respectively (p = 0.07); the toxicity profile provides the potential for combi- median (95% CI) OS was 11.5 (7.3–13.4) and 8.8 nation with other standard approved agents (5.4–12.6) months, respectively (p = 0.29). The [Reddy et  al. 2014]. For example, a study com- best improvement was observed in the predefined paring vintafolide in combination with PLD and adenocarcinoma patient subgroup with a PFS HR PLD alone indicated that combination therapy of 0.68 (95% CI 0.41–1.14) and an OS HR of may be an effective and safe treatment option for 0.51 (95% CI 0.28–0.94). The safety profile was FR+, platinum-resistant disease [Naumann et al. manageable and consistent with the AEs observed 2013], further supporting the investigation of with both therapies. vintafolide in combination with other agents. Additional agents have been investigated, such as the FRα-targeted monoclonal antibody farletu- Safety across clinical studies zumab, which has provided disappointing results In general, the TEAEs observed across clinical to date, as well as the ADC IMG853, which is studies to date are consistent with the TEAEs being investigated in phase I studies. http://tam.sagepub.com 215 Therapeutic Advances in Medical Oncology 7(4) Crane, L., Arts, H., van Oosten, M., Low, P., van Acknowledgements der Zee, A., van Dam, G. et al. (2012) The effect of Medical writing assistance was provided by chemotherapy on expression of folate receptor-alpha Mark English, PhD, and Matt Grzywacz, PhD, in ovarian cancer. Cell Oncol 35: 9–18. of ApotheCom (Yardley, PA, USA). 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584763 TAM0010.1177/1758834015584763Therapeutic Advances in Medical OncologyVergote research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Vintafolide: a novel targeted therapy for 2015, Vol. 7(4) 206 –218 DOI: 10.1177/ the treatment of folate receptor expressing © The Author(s), 2015. Reprints and permissions: tumors http://www.sagepub.co.uk/ journalsPermissions.nav Ignace Vergote and Christopher P. Leamon Abstract: Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early- stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents. Keywords: folate receptor, lung neoplasms, neoplasms, ovarian neoplasms, small molecule drug conjugate, vintafolide Correspondence to: Introduction 2006; Stegmeier et  al. 2010]. Targeted therapies Christopher P. Leamon, There is an ongoing need for the development of are associated with a low toxicity profile, though PhD Endocyte, Inc., 3000 Kent new cancer therapies that can effectively target they often have low single-agent responses [Imai Avenue, West Lafayette, IN tumor cells without harming normal cells or tissue and Takaoka, 2006]. However, a key consideration 47906, USA chrisleamon@endocyte. [Miller et  al. 2013]. Recent treatment advances for targeted therapy is to establish predictive bio- com include the use of combination chemotherapy, markers and/or imaging techniques to determine Ignace Vergote, MD, PhD which has had a significant impact on the treat- which patients would benefit most from a particu- Leuven Cancer Institute, Leuven, Belgium ment of most cancer types [DeVita and Chu, lar targeted-therapy combination [Bicknell, 2005; 2008]. Targeted cancer therapies such as monoclo- Stegmeier et  al. 2010]. Furthermore, like tradi- nal antibodies and small molecule tyrosine kinase tional chemotherapy, the emergence of resistance inhibitors have also had a significant impact on to targeted therapies is a major challenge often cancer treatment, demonstrating increased efficacy faced in the clinic, particularly in patients with with improvements in progression-free survival advanced tumors [Miller et al. 2013]. Thus, there (PFS) over conventional chemotherapeutics alone is a clear need for new strategies and targeted in many tumor types [Bottsford-Miller et al. 2012; approaches to cancer treatment, particularly when Feliz and Tsimberidou, 2013; Giuliano and Pages, combating resistance. Two major categories of cur- 2013; Miller et  al. 2013; Tang et  al. 2013; Tejpar rently used targeted therapies include monoclonal et al. 2012]. These therapies have the potential to antibodies (e.g. trastuzumab, bevacizumab) and achieve durable antitumor effects without overlap- small molecule therapies (e.g. tyrosine kinase ping toxicity [Bicknell, 2005; Imai and Takaoka, inhibitors, bortezomib) [Miller et al. 2013]. Drug 206 http://tam.sagepub.com I Vergote and CP Leamon conjugates are another major group of targeted Capdevila, 1986; Tian et al. 2012]. After binding therapies that involve a promising approach to the FR, folate uptake occurs through receptor- whereby targeted agents are created by linking a mediated endocytosis [Kamen and Capdevila, drug or a prodrug to a tissue-targeting molecule 1986; Vlahov et al. 2006]. It is important to note or carrier; this group can be further separated that FRα plays a critical role in the uptake of into antibody-drug conjugates (ADCs) and small serum folates by cells expressing the receptor by molecule-drug conjugates (SMDCs). The folate binding 5-MeTHF with high affinity and FA with receptor (FR) is overexpressed in many epithelial even higher affinity [Antony, 1996; Kamen and tumors and has been established as a tumor cellu- Capdevila, 1986; Kamen and Smith, 2012; Tian lar-surface marker for targeted drug delivery [Teng et al. 2012; Westerhof et al. 1995]. et al. 2012]. This has led to the development of a number of FR-targeted agents, including anti-FR FRβ is expressed in placenta, colon, thymus, monoclonal antibodies, FR-binding ADCs, and spleen, and various leukemic myelomonocytic folic acid (FA)-based SMDC (FA-SMDC). The cells [Elnakat and Ratnam, 2004; Ratnam et  al. aim of this paper is to review the role of the FR as 1989; Ross et al. 1994; Shen et al. 1994; Weitman a target in cancer progression and resistance and to et al. 1992a]. In contrast, FRα is expressed mostly consider agents in development that target the FR in epithelial cells of the uterus, placenta, choroid with a focus on the SMDC vintafolide. plexus, retina, and kidney [Gonen and Assaraf, 2012], and it is expressed at very high levels in several tumor types, including ovarian, lung, kid- The FR and its role in cancer progression ney, and breast cancer, making it a prime candi- and resistance date for targeted anticancer therapy [Christoph et al. 2013; Crane et al. 2012; Elnakat and Ratnam, The FR and folate metabolism 2006; Nunez et al. 2012; Parker et al. 2005; T offoli Folate is essential for DNA replication and the et al. 1997; Weitman et al. 1992a]. FRα expression synthesis of nucleotide precursors [Gonen and is notably restricted to the apical surfaces of polar- Assaraf, 2012]. Folates can be found in an oxi- ized epithelial cells in the kidney (facing the lumen dized form, FA, or as naturally occurring reduced of the tubule) and therefore is not exposed to the folates [Gonen and Assaraf, 2012]. However, the bloodstream [Parker et  al. 2005]. Similarly, lung major circulating form of folate is 5-methyltet- alveolar lining cells (type I and II pneumocytes) rahydrofolate (5-MeTHF), which is found at low, and epithelial cells of the bronchi stain intensely yet sufficient, physiological concentrations of for FRα on the apical membranes facing the air- 5–30 nM in sera [Gonen and Assaraf, 2012; way, which are not accessible to blood-borne Ifergan and Assaraf, 2008]. folates [Parker et  al. 2005; Salazar and Ratnam, 2007; Weitman et  al. 1992b]. It is important to Folates can be taken up into cells first by carrier note that FRα expression in normal cells of the proteins, such as the transmembrane-reduced uterus, choroid plexus, retina, and kidney is con- folate carrier, which is ubiquitously expressed in siderably lower than FRα expression at sites not most normal tissues and malignant tumors, or by exposed to the bloodstream and in cancer [Parker the proton-coupled folate transporter in low pH et al. 2005; Ross et al. 1994; Weitman et al. 1992a, environments, such as the intestine [Zhao et  al. 1992b]. Based on these observations, targeting the 2009], and second, through membrane-bound FRα may be an effective therapeutic option for the FRs [Gonen and Assaraf, 2012]. FRs are high- treatment of cancer [Salazar and Ratnam, 2007]. affinity folate-binding glycoproteins, of which there are three principal isoforms (α, β, and γ) [Gonen and Assaraf, 2012]. A fourth isoform, The FR and cancer progression and resistance FRδ, has also been identified, but it has been dif- The FR appears to play a critical role in cancer ficult to detect in human tissues; therefore, it is progression and resistance. For instance, FRα suggestive of a highly restricted expression pat- expression appears to be a negative prognostic tern, a splice variant, or a pseudogene [Spiegelstein factor in patients with ovarian cancer [Kalli et al. et al. 2000; Tian et al. 2012]. FRα and FRβ bind 2008; Toffoli et  al. 1998] and may represent a FA as well as 5-MeTHF with high affinity, marker for resistance to conventional chemother- whereas FRγ is a secreted protein that is not apy. In addition, FRα expression is a negative- involved in cellular uptake [Antony, 1996; Dosio prognostic factor in breast [Hartmann et  al. et al. 2010; Gonen and Assaraf, 2012; Kamen and 2007], endometrial [Brown et  al. 2008], uterine http://tam.sagepub.com 207 Therapeutic Advances in Medical Oncology 7(4) [Allard et  al. 2007], and colorectal cancer [Shia IMGN853 is an FRα-targeting ADC that is com- et  al. 2008]. It is important to note that FRα posed of three parts: an anti-FRα antibody that expression does not appear to be influenced by targets the compound to FRα-expressing cancer chemotherapy in ovarian and endometrial cancer cells; DM4, a potent cell-killing agent that inhibits [Despierre et  al. 2013]. Taken together, these tubulin polymerization; and a disulfide-based studies further support the rationale for targeting linker [Ab et  al. 2011]. IMGN853 is in phase I the FRα in cancer treatment. clinical development for patients with ovarian can- cer and other FOLR1+ solid tumors [ClinicalTrials. gov identifier: NCT01609556] [Ab et  al. 2011]. Targeting the FRα in tumors Preliminary results recently reported indicate that Three general strategies have been used to target IMGN853 was well tolerated at doses up to 3.3 therapeutics to FR-expressing tumors: an anti-FR mg/kg and provided evidence of antitumor activity antibody approach, a humanized FRα-binding– [Kirkjian et al. 2013; Moore et al. 2014]. ADC approach, and a FA-SMDC approach [Beck et  al. 2012; Teng et  al. 2012; Vlahov and FA-SMDCs were developed because they are Leamon, 2012]. smaller than monoclonal antibodies and have a higher affinity for FRs on cancer cells; therefore, Several anti-FRα antibodies have been developed they may potentially improve blood clearance and for targeting of FRα antibodies, including the tumor penetration of the attached drug [Pribble monoclonal antibody farletuzumab [Armstrong and Edelman, 2012; Vlahov and Leamon, 2012]. et al. 2013; Konner et al. 2010; Teng et al. 2012], The proposed mechanism of action of FA-SMDCs which has a mechanism of action distinct from is shown in Figure 1 [Vlahov and Leamon, 2012]. that of drug conjugates. Farletuzumab is a fully First, the FA-based SMDC extravasates from the humanized antibody derived from the murine circulation and binds the high-affinity FR on the antibody LK26, which binds FRα to promote cell tumor cell. The FR and conjugate then enter the lysis by both complement-dependent cytotoxicity cell by endocytosis. The FA-SMDC is sequestered and antibody-dependent cell-mediated cytotoxic- in an endosome, where the pH is lower (because ity [Farrell et  al. 2012; Jelovac and Armstrong, of the presence of proton pumps), causing the 2012; Teng et al. 2012]. In addition, the binding SMDC to be released from the FR. Reductive of farletuzumab to FRα also suppresses the pro- activity inside the endosome then cleaves the liferation and growth of FRα-expressing cells and disulfide-based linker of the FA-SMDC to release tumors by preventing the phosphorylation of sub- the active drug. Finally, the drug escapes from the strates specific for Lyn kinase [Jelovac and endosome to enter the cytosol while the FR recy- Armstrong, 2012]. Farletuzumab is being investi- cles back to the cell surface. The whole process is gated as a single agent or in combination with then repeated. Several folate-conjugated cytotoxic chemotherapy in epithelial-ovarian carcinoma agents have been, or are being, evaluated as anti- [Armstrong et  al. 2013; Jelovac and Armstrong, cancer therapy, including folate-conjugated 2012; Konner et  al. 2010] and in combination 5-fluro-2′deoxyuridine-5′-O-monophosphate, with chemotherapy in lung cancer [Thomas et al. folate-conjugated carboplatin, and folate-conju- 2013]. Farletuzumab was evaluated as a single gated microtubule poisons [Teng et  al. 2012]. agent and in combination with carboplatin and a These include EC0225 [Leamon et  al. 2007a], taxane in a phase II study in patients with plati- folate conjugated to both a vinca alkaloid and num-sensitive ovarian cancer [Armstrong et  al. mitomycin; BMS-753493 (epofolate) [Gokhale 2013]. As a single agent, farletuzumab was well et  al. 2012] [ClinicalTrials.gov identifiers: tolerated without additive toxicity when adminis- NCT00546247 and NCT00550017] folate con- tered with chemotherapy. Further, when com- jugated to epothilone; and EC0489 [ClinicalTrials. bined with chemotherapy, 75% of patients gov identifier: NCT00852189], an analogue of achieved complete response (CR) or partial vintafolide (vide infra). response (PR). Results from the phase III FAR- 121 study in patients with platinum-sensitive ovarian cancer in first relapse showed that farletu- Patient selection and biomarker analyses zumab in combination with carboplatin and a The noninvasive, folate-targeted, single-photon taxane (paclitaxel or docetaxel) unfortunately did emission computed tomography based compan- 99m not meet the study’s primary endpoint of PFS ion imaging agent, Tc-etarfolatide (EC20), [Vergote et al. 2013]. offers the potential to rationally select patients for 208 http://tam.sagepub.com I Vergote and CP Leamon Figure 1. Schematic presentation of tumor cellular uptake of a FA–based, small-molecule drug conjugate. FA, folic acid; FR, folate receptor. treatment with vintafolide without the need for is a vinca alkaloid that disrupts the formation of biopsy [Morris et al. 2014; Pribble and Edelman, the mitotic spindle, thereby inhibiting cell divi- 2012]. The use of imaging with etarfolatide sion and inducing cell death [Pribble and allows identification of patients whose disease Edelman, 2012]. FA and DAVLBH are connected expresses functionally active FR and, therefore, through a peptide spacer and a reducible, self- has the potential to respond to FR-targeted immolative disulfide-linker system to form vinta- treatment [Morris et  al. 2014]. Using this folide [Dosio et  al. 2010; Pribble and Edelman, technique, patients are generally categorized 2012]. The disulfide linker enables the release of as FR++ (100%; all lesions positive), FR+ DAVLBH inside the cancer cell after receptor- (10–90%; at least one lesion positive, but not all mediated endocytosis [Pribble and Edelman, positive), and FR– (0%; no lesions positive) 2012]. This is an important feature because the (Figure 2) [Naumann et  al. 2013]. Because high affinity of FA for the FR can result in ligands EC20 is a noninvasive, real-time assessment of remaining attached to the FR for long periods of functionally active and anatomically accessible time, which can reduce the potency of folate-tar- FRs, it has been evaluated as a biomarker of geted chemotherapeutic agents [Dosio et  al. response to FA-SMDCs, such as vintafolide 2010]. Vintafolide was designed specifically to [Leamon et al. 2012]. bind to high-affinity FR present on the surfaces of cancer cells and to release its active component, DAVLBH, once it enters the endosome of the tar- Vintafolide get cell (Figure 3). Chemistry and mechanism of action Vintafolide is a water-soluble derivative of FA and Preclinical studies the vinca alkaloid desacetylvinblastine hydrazide Preclinical studies have shown that vintafolide (DAVLBH) (Figure 3) [Dosio et al. 2010; Pribble binds to the FRα with high affinity [Leamon and Edelman, 2012; Vlahov et al. 2006]. DAVLBH et  al. 2007b]; accordingly, it has highly potent http://tam.sagepub.com 209 Therapeutic Advances in Medical Oncology 7(4) Figure 2. Etarfolatide imaging. Etarfolatide imaging can be used to divide patients into three categories: FR++ (100%; all lesions positive), FR+ (10–90%; at least one lesion positive but not all positive), or FR– (0%; no lesions positive). FR, folate receptor. and specific antitumor activity against FRα+ found to completely block the activity of vinta- tumors [Dosio et al. 2010; Leamon et al. 2007b, folide, and FR– cells are resistant to vintafo- 2012; Reddy et  al. 2007]. FRα expression is lide. Specificity for FR-containing cells has critical for vintafolide activity, and cytotoxicity also been demonstrated in FRα-expressing is dose dependent with an IC (concentration tumors in M109 tumor-bearing BALB/C mice that inhibits 50% of activity) in the single-digit [Leamon et al. 2012]. nanomolar range [Leamon et  al. 2007b]. Preclinical studies conducted to optimize the dosing regimen have shown that vintafolide is Pharmacodynamic and pharmacokinetic studies most efficacious when administered on a more In a nonrandomized, open-label, dose-compari- frequent schedule and at low-dose levels son, phase I study in patients with refractory or [Reddy et  al. 2007], exploiting the natural metastatic solid tumors, vintafolide was adminis- recycling mechanism of the FR to keep greater tered as an intravenous bolus injection or as a 1 h pressure on the tumor cell. Specificity for infusion on days 1, 3, and 5 (week 1) and days 15, FR-containing cells has been demonstrated by 17, and 19 (week 3) of a 28-day cycle [Li et  al. the fact that the binding affinity of vintafolide 2009; LoRusso et al. 2012]. The maximum toler- for the FR is slightly less than the affinity of ated dose (MTD) of vintafolide was 2.5 mg, and folate for the FR (0.47 relative to the binding the maximum concentration and area under affinity of FA for the FR) [Leamon et  al. the curve for vintafolide increased in a dose- 2007b]. Furthermore, excess free FA has been proportional manner across the dose range studied 210 http://tam.sagepub.com I Vergote and CP Leamon Figure 3. Molecular design and structure of vintafolide. Each molecule of vintafolide contains one FA moiety, which serves as a stable high-affinity binding ligand for the FR (Kd ~0.1 nM), and one vinca alkaloid unit (DAVLBH). Unlike the untargeted DAVLBH molecule, vintafolide is readily soluble in aqueous solutions because of the hydrophilic peptide spacer unit that is placed between the folic acid and DAVLBH moieties. This physical property enables vintafolide to be dosed intravenously without the aid of coadministered solubilizing or dispersing agents. A self-immolative linker system allows for efficient release of the DAVLBH moiety inside the endosome of the targeted FR-expressing tumor cell. DAVLBH, desacetylvinblastine hydrazide; FA, folic acid; FR, folate receptor. [Li et  al. 2009; LoRusso et  al. 2012]. The phar- regimen for “maintenance”) [Li et  al. 2009; macokinetics of vintafolide are characterized by a Morris et al. 2014]. rapid distribution and elimination phase, which includes a short distribution half life (i.e. uptake In the nonrandomized, open-label, dose-compar- of the conjugate by FR-expressing tissues in vivo ison, phase I study in patients with refractory or is rapid) [Paulos et al. 2004], a volume of distri- metastatic solid tumors, the MTD of vintafolide bution that is larger than blood volume, and was 2.5 mg administered as an intravenous bolus rapid clearance by the kidney and liver [Li et al. on days 1, 3, and 5 (week 1) and days 15, 17, and 2009; Paulos et  al. 2004]. On the basis of these 19 (week 3) of a four-week cycle [LoRusso et al. results, a dose-dense regimen was proposed for 2012]. Preliminary evidence of antitumor activity phase II studies, in which the same cumulative was demonstrated in two patients with ovarian dose (2.5 mg × six doses per month) was divided cancer; one patient had a PR, and the other into smaller doses of 1.0 mg/day as an intravenous patient had disease stabilization for longer than bolus injection (Monday–Friday) for 3 weeks 5 months [LoRusso et al. 2012]. Vintafolide dem- of a four-week cycle, with a total dose of onstrated an acceptable safety profile with no 15 mg/month (this was an induction-style design; evidence of myelosuppression. Constipation, after two cycles, patients returned to the three nausea, fatigue, and vomiting were the most times a week, every other week, four-week cycle commonly reported adverse events. http://tam.sagepub.com 211 Therapeutic Advances in Medical Oncology 7(4) Clinical studies: ovarian cancer clinical activity compared with PLD alone, with a The efficacy and safety of vintafolide was first median PFS (primary endpoint) of 5.0 months in assessed in 2007 in a nonrandomized trial [Morris the vintafolide plus PLD arm compared with et  al. 2014], and a number of phase II and III 2.7 months in the PLD-alone arm (HR 0.63; 95% clinical studies have since been conducted in CI 0.41–0.96; p = 0.031) (Figure 4, Table 1). patients with ovarian and lung cancer [Edelman Furthermore, this benefit with combination et  al. 2012a, 2012b; Naumann et  al. 2013]. The therapy was maintained in FR+ (i.e. 10–100% main characteristics and key findings of these FR+ target tumor lesions) patients (5.7 versus clinical trials are described in the following sec- 1.7 months; HR 0.547; 95% CI 0.304–0.983; tions and are summarized in Table 1. p = 0.041) (Table 1); the greatest benefit was in FR++ patients (HR 0.381; 95% CI 0.172–0.845; Study EC-FV-02 was an open-label, phase II trial p = 0.013). No significant differences in the of vintafolide monotherapy in patients with plati- Response Evaluation Criteria in Solid Tumors– num-resistant or -refractory advanced epithelial confirmed objective response rate (ORR; 18% ovarian, primary peritoneal, or endometrial can- versus 12%; p = 0.479) and the secondary end- cer who underwent scanning with EC20 to assess point of OS (HR 1.010; 95% CI 0.679–1.503; their FR status [Morris et  al. 2014]. Vintafolide p = 0.957) were noted between the combination treatment consisted of an induction phase, fol- therapy and the PLD-alone treatment arms. lowed by a maintenance phase for responders Overall, the drug combination was well tolerated. (patients achieving CR or PR) or patients who No cumulative treatment-emergent adverse events had stable disease (SD) without unacceptable (TEAEs) were reported, except palmar-plantar toxicity (Table 1). The disease control rate (DCR) erythrodysesthesia syndrome, which increased in for all evaluable patients (primary endpoint), incidence with subsequent cycles in both treat- regardless of EC20 status, was 40% [95% confi- ment arms. Most TEAEs in both treatment arms dence interval (CI) 25.7–55.7%; CR, 0%; PR, were grade 1 or 2, with higher incidence rates 4%; SD, 36%]. Superior outcomes were demon- of leukopenia, abdominal pain, peripheral sensory strated in patients who demonstrated EC20 neuropathy (all p = 0.026) and neutropenia uptake with DCRs of 57% in those with all FR+ (p = 0.021) in the vintafolide plus PLD arm than target tumor lesions (FR++) and 43% in those in the PLD-alone arm; the incidence of nausea who had at least one but not all FR+ target lesions was higher in the PLD-alone arm (p = 0.036). For (FR+), compared with 25% in patients who were grade 3 or 4 TEAEs, the difference in the inci- FR–. Two patients experienced PR; both patients dence of leukopenia between treatment arms was were FR+, with one FR++. A similar benefit in nominally statistically significant (p = 0.031). median overall survival (OS) was seen when However, the difference in leukopenia incidence patients were assessed by EC20 status, with between treatment arms was not clinically signifi- FR++ patients demonstrating significant cant because no increase in febrile neutropenia or improvement in OS compared with FR– patients infection was reported. [hazard ratio (HR) 0.170; p = 0.001]. The most common drug-related vintafolide toxicity (all The recently completed randomized, double- grades) was constipation, followed by fatigue, blind, placebo-controlled, phase III PROCEED nausea, anorexia, and neuropathy. The most com- trial (EC-FV-06) [ClinicalTrials.gov identifier: mon grade 3 vintafolide-related toxicities were NCT01170650] evaluated vintafolide in combina- constipation and fatigue; no grade 4 vintafolide- tion with PLD compared with PLD alone in related toxicities were reported. patients with FR+, platinum-resistant ovarian cancer. Patients with primary or secondary plati- The open-label, randomized, phase II num-resistant, pathology-confirmed epithelial PRECEDENT study (EC-FV-04) evaluated the ovarian, fallopian tube, or primary peritoneal can- use of vintafolide in combination with pegylated cer were eligible for the study and had their FR liposomal doxorubicin (PLD) versus PLD alone in status determined by EC20 scans. The primary 162 women with platinum-resistant recurrent endpoint of this study was PFS in patients with ovarian cancer who had received at least two pre- FR+ tumors. At a prespecified interim futility vious cytotoxic regimens (Table 1); the assessment analysis, the Data Safety Monitoring Board of FR status using the companion imaging diag- (DSMB) recommended that the study be stopped nostic, EC20, was optional [Naumann et al. 2013]. because vintafolide in combination with PLD ver- Vintafolide demonstrated significantly improved sus PLD alone did not meet the prespecified 212 http://tam.sagepub.com I Vergote and CP Leamon Table 1. Summary of efficacy and safety clinical trial data for vintafolide [Edelman et al. 2012a, 2012b; Morris et al. 2014; Naumann et al. 2013]. Trial Study design Participants Interventions Key efficacy and safety results Ovarian cancer trials Study EC-FV-02 Phase II, Patients with Vintafolide monotherapy: Efficacy [ClinicalTrials. single-arm, OL, platinum-resistant induction phase (1 mg DCR* (primary endpoint): gov identifier: MC or -refractory intravenously, Monday Overall: 40% (95% CI 25.7–55.7%) NCT00507741] advanced epithelial to Friday for 3 weeks, By FR status : FR++ (57%; 95% CI [Morris et al. 2014] ovarian, primary every 28 days for two 28.9–82.3%); FR+ (43%; 95% CI 27.1– peritoneal, or cycles) followed by a 60.5%); FR– (25%; 95% CI 0.6-80.6%) endometrial cancer maintenance phase OS: (N = 45); patients (2.5 mg intravenously, By FR status : FR++ (14.6 months); were scanned with Monday, Wednesday, and FR+ (11.6 months); FR– EC20 to assess FR Friday during weeks 1 (2.7 months) status and 3, every 28 days) in FR++ versus FR+ (HR 0.708; p = 0.420) responders (CR or PR) FR++ versus FR– (HR 0.170; p = 0.001) and patients with SD Safety without unacceptable Common vintafolide-related AE (all toxicity grades): nausea (29%), anorexia (22%), and neuropathy (20%) PRECEDENT Phase II, R, OL, Patients with Combination therapy: Efficacy (EC-FV-04) MC platinum-resistant, vintafolide (2.5 mg Combination therapy versus PLD [ClinicalTrials. recurrent ovarian intravenously, three monotherapy gov identifier: cancer who received times per week during Median PFS (primary endpoint): NCT00722592] up to two previous weeks 1 and 3, every Overall: 5.0 versus 2.7 months (HR [Naumann et al. cytotoxic regimens 28 days) + PLD 0.63; 95% CI 0.41–0.96; p = 0.031) 2013] (N = 162); EC20 (50 mg/m intravenously FR+ patients: 5.7 versus 1.7 months scans were optional on day 1, every 28 days) (HR 0.547; 95% CI 0.304–0.983; or p = 0.041) PLD monotherapy RECIST-confirmed ORR: Overall: 18% versus 12% (p = 0.479) DCR*: Overall: 73% versus 53% (p = 0.018) Median OS: Overall: HR 1.010 (95% CI 0.679– 1.503; p = 0.957) Safety TEAE more common with combination therapy: leukopenia (23% versus 8%), abdominal pain (36% versus 18%), and peripheral sensory neuropathy (29% versus 12%; all p = 0.026); neutropenia (44% versus 24%; p = 0.021) TEAE more common with PLD monotherapy: nausea (8.0% versus 0.9%; p = 0.036) PROCEED Phase III, R, Patients with FR+, Combination Primary endpoint: PFS (EC-FV-06) DB, PBC platinum-resistant therapy: vintafolide Secondary endpoints: OS, tolerability [ClinicalTrials. epithelial ovarian, (intravenously, three Results of this trial are anticipated gov identifier: fallopian tube, or times per week during in 2015 NCT01170650] primary peritoneal weeks 1 and 3, every cancer; all patients 28 days) + PLD were scanned with (50 mg/m , every 28 days) EC20 to assess FR or status PLD monotherapy (Continued) http://tam.sagepub.com 213 Therapeutic Advances in Medical Oncology 7(4) Table 1. (Continued) Trial Study design Participants Interventions Key efficacy and safety results Lung cancer trials Study EC-FV-03 Phase II, Patients with Vintafolide monotherapy: Efficacy [ClinicalTrials. single-arm, OL, progressive induction phase (1 mg Clinical benefit response (primary gov identifier: MC adenocarcinoma intravenously, daily × endpoint): NCT00511485] of the lung who 5 days for 3 weeks, every Overall: 26% (95% CI 14–41%) [Edelman et al. previously received 28 days) followed by a $ By FR status : FR++ versus FR+ 2012a, 2012b] at least two maintenance phase (50% versus 14%; p = 0.10) cytotoxic-containing (2.5 mg intravenously, DCR* at 8 weeks: chemotherapeutic three times per week Overall: 35% (95% CI 0–12%) regimens (N = during weeks 1 and 3, Median PFS: 43); at least one 1 every 28 days) Overall: 7.4 weeks EC20+ tumors $ By FR status : FR++ versus FR+ (31.1 versus 7.3 weeks; HR 0.326; p = 0.034) Median OS: Overall: 42.9 weeks By FR status : FR++ versus FR+ (47.2 versus 14.9 weeks; HR 0.539; p = 0.101) Safety Common drug-related AEs: fatigue (37.2%), constipation (32.6%), nausea (14.0%), and anemia (14.0%) TARGET Phase II, R, OL, Patients with Vintafolide monotherapy: Primary endpoint: PFS (EC-FV-07) MC NSCLC whose 2.5 mg twice per week Secondary endpoint: ORR, DCR, [ClinicalTrials. condition failed during weeks 1 and 2, duration of response, duration of gov identifier: to respond to every 21 days disease control, tolerability NCT01577654] one previous or The study is ongoing chemotherapy Combination therapy: regimen; all vintafolide + docetaxel patients have FR++ (75 mg/m intravenously, tumors as assessed day 1, every 21 days) by EC20 scans or Docetaxel monotherapy *DCR is defined as the proportion of patients achieving CR, PR, or SD. FR status was determined by EC20-based single-photon emission computed tomography to identify patients with FR++ (all target lesions FR+), FR+ (⩾1FR+ target tumor lesion), or FR– (no FR+ target tumor lesions). Clinical benefit response is defined as the ability to receive more than four cycles of therapy, indicating that patients had responded to therapy (SD or radiographic response) and had tolerated therapy well. 99m AE, adverse event; CI, confidence interval; CR, complete response; DB, double blind; DCR, disease control rate; EC20, Tc-etarfolatide; FR, folate receptor; HR, hazard ratio; MC, multicenter; NSCLC, non-small cell lung cancer; OL, open label; ORR, objective response rate; OS, overall survival; PBC, placebo controlled; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PR, partial response; R, randomly as- signed; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TEAE, treatment-emergent AE. criteria for PFS to allow continuation of the study. The primary objective, clinical benefit response The DSMB did not identify any safety concerns [the ability to receive more than four cycles of ther- for the patients enrolled in the PROCEED trial. apy, indicating that patients had responded (SD or Final results are anticipated to be available in 2015. radiographic response) and had tolerated therapy well], was not met (26%; 95% CI 14–41%); a PR was reported in one patient (2.3%; 95% CI Clinical studies: lung cancer 0–12%). In an exploratory analysis, FR++ patients Study EC-FV-03 was a single-arm, open-label trial demonstrated a superior clinical benefit response that evaluated vintafolide in patients with progres- of 50% compared with 14% in FR+ patients sive adenocarcinoma of the lung who had previ- (p = 0.10). Median PFS was 7.4 weeks and median ously received at least two cytotoxic-containing OS was 42.9 weeks for the whole study population. chemotherapeutic regimens and were identified An exploratory analysis of survival outcomes dem- as EC20+ (Table 1) [Edelman et al. 2012a, 2012b]. onstrated a significant improvement in median PFS 214 http://tam.sagepub.com I Vergote and CP Leamon Figure 4. Kaplan–Meier curve of PFS by treatment arm. PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; Vinta, vintafolide. Reprinted with permission from Naumann et al. [2013]. © 2013 American Society of Clinical Oncology. All rights reserved. in patients with FR++ tumors compared with associated with vinca alkaloid therapy, with no those with FR+ tumors (31.1 versus 7.3 weeks; HR new or unique TEAE reported [Dosio et al. 2010; 0.326; p = 0.034) and a trend toward improvement Pribble and Edelman, 2012]. Although FRα is in median OS (47.2 versus 14.9 weeks; HR 0.539; highly expressed in the kidney [Parker et al. 2005], p = 0.101) [Edelman et al. 2012a]. no renal toxicities have been observed [Dosio et al. 2010]. The randomized, open-label, phase II TARGET trial (EC-FV07) [ClinicalTrials.gov identifier: NCT01577654] is also being conducted to com- Conclusion pare vintafolide as second-line treatment with vin- Vintafolide has a unique target, the FR, which has tafolide plus docetaxel and docetaxel alone in several unique properties that make it a rational patients with non-small cell lung cancer (NSCLC) target for cancer treatment, including high expres- who have FR++ tumors. The primary endpoint of sion in cancer cells of several tumor types and a this study is PFS, and secondary endpoints include restricted pattern of tissue-specific expression ORR, DCR, duration of response, OS, and safety. allowing for selective delivery of FR-targeted Preliminary data for vintafolide in combination agents. Use of the companion diagnostic (etar- with docetaxel showed clinically meaningful folatide; EC20) allows the selection of patients improvement across all efficacy endpoints over who are most likely to benefit from vintafolide single-agent docetaxel [Hanna et  al. 2014]. The treatment. Vintafolide has been investigated in median (95% CI) PFS of the vintafolide plus doc- ongoing phase II and phase III studies in NSCLC etaxel and docetaxel groups was 4.2 (2.8–5.4) and and ovarian cancer, respectively, and its favorable 3.3 (1.7–4.2) months, respectively (p = 0.07); the toxicity profile provides the potential for combi- median (95% CI) OS was 11.5 (7.3–13.4) and 8.8 nation with other standard approved agents (5.4–12.6) months, respectively (p = 0.29). The [Reddy et  al. 2014]. For example, a study com- best improvement was observed in the predefined paring vintafolide in combination with PLD and adenocarcinoma patient subgroup with a PFS HR PLD alone indicated that combination therapy of 0.68 (95% CI 0.41–1.14) and an OS HR of may be an effective and safe treatment option for 0.51 (95% CI 0.28–0.94). The safety profile was FR+, platinum-resistant disease [Naumann et al. manageable and consistent with the AEs observed 2013], further supporting the investigation of with both therapies. vintafolide in combination with other agents. Additional agents have been investigated, such as the FRα-targeted monoclonal antibody farletu- Safety across clinical studies zumab, which has provided disappointing results In general, the TEAEs observed across clinical to date, as well as the ADC IMG853, which is studies to date are consistent with the TEAEs being investigated in phase I studies. http://tam.sagepub.com 215 Therapeutic Advances in Medical Oncology 7(4) Crane, L., Arts, H., van Oosten, M., Low, P., van Acknowledgements der Zee, A., van Dam, G. et al. (2012) The effect of Medical writing assistance was provided by chemotherapy on expression of folate receptor-alpha Mark English, PhD, and Matt Grzywacz, PhD, in ovarian cancer. Cell Oncol 35: 9–18. of ApotheCom (Yardley, PA, USA). 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: May 21, 2015

Keywords: folate receptor; lung neoplasms; neoplasms; ovarian neoplasms; small molecule drug conjugate; vintafolide

References