Is Targeting the Folate Receptor in Ovarian Cancer Coming of Age?

Abstract

Prognosis for women with epithelial ovarian cancer remains poor. One new molecular target in epithelial ovarian cancer is folate receptor alpha (FRα). This commentary discusses the characteristics that contribute to its attractiveness as a candidate for therapeutic intervention.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer‐related mortality, and the prognosis for many women, particularly those with advanced or recurrent disease, remains poor. Median survival outcomes have improved over the last decade, in large part because of a shift away from broad‐based cytotoxic use to more tailored therapeutic interventions. Indeed, the integration of agents, like bevacizumab and PARP inhibitors, alongside traditional chemotherapy has dramatically altered the therapeutic landscape for EOC management.

One actively pursued molecular target in EOC is folate (FR) α, a member of the folate receptor family of high affinity folate‐binding proteins [1], [2]. FRα is a transmembrane glycoprotein that facilitates the unidirectional transport of folate into cells via receptor‐mediated endocytosis (Fig. 1). A number of important characteristics contribute to its attractiveness as a candidate for therapeutic intervention in EOC. FRα is a tumor‐associated antigen in this malignancy, with over 80% of ovarian carcinomas constitutively expressing the receptor and elevated FRα expression is often associated with more poorly differentiated, aggressive tumors. In contrast, FRα shows a highly restricted distribution pattern in normal tissues, with expression limited to a variety of polarized epithelia, such as those found in the choroid plexus, kidney, lung, and placenta [3]. Of relevance, in all normal tissues apart from the kidney, FRα is confined to the apical surface of the epithelium and out of direct contact with circulation—an anatomical feature that may confer a lower potential for off‐target toxicities from systemically administered FR‐targeting agents. Moreover, studies have shown that FRα expression is retained in recurrent and metastatic tumors and is not significantly altered in response to chemotherapy [4], [5], providing further support for targeting this receptor in the treatment of EOC, whether newly diagnosed or at the time of recurrence.

Figure 1.

Model of folate internalization and trafficking via FRα‐mediated endocytosis. Folate binding to FRα creates a receptor‐ligand complex that, through invagination and budding off in caveolae‐type vesicles, give rise to early endosomes. These undergo acidification and subsequent fusion with lysosomes, ultimately resulting in folate release that is required for metabolic synthesis of DNA and RNA.

Abbreviation: FR, folate receptor.

Early efforts to therapeutically target FRα included the humanized anti‐FRα monoclonal antibody, farletuzumab, which exerts its antitumor activity primarily through antibody‐dependent cell‐mediated cytotoxicity and complement‐dependent cytotoxicity [6]. Despite a good safety profile shown in the first‐in‐human monotherapy trial (NCT00428766) and a promising response in combination with conventional carboplatin/taxane regimen in a subsequent phase II study (NCT00318370) [7], farletuzumab failed to achieve a relevant efficacy both in a platinum‐sensitive population (NCT00849667) [8] and in the setting of platinum‐resistant disease (NCT00738699). A potential contributing factor to these contradictory and disappointing results was a lack of a priori patient selection for FRα expression, underscoring the importance of incorporating patient selection, based on receptor expression status, into the design of FR‐targeting clinical trials.

An alternative modality consisted of the covalent conjugation of cytotoxic compounds directly to folate to form small molecule drug conjugates (SMDCs). The folate‐SMDC binds with high affinity to folate receptors (all isoforms, not only FRα) and enters the cell via endocytosis, where active drug is released following reductive activity within the endosome. Indeed, folate is one of the most studied ligands in targeted drug delivery [9], and a variety of folate‐SMDCs have been developed with therapeutic intent in EOC, including conjugates of platinum, paclitaxel, maytansinoids, and epothilone (BMS‐748285; epofolate) [2]. The most successful of the SMDC class is vintafolide (EC145), consisting of a folate conjugate of the vinca alkaloid desacetylvinblastine monohydrazide (DAVLBH), a potent microtubule destabilizing agent (Fig. 2A) [10]. The early clinical evaluations of vintafolide were encouraging, particularly the results of the phase II PRECEDENT trial (NCT00722592) evaluating the use of vintafolide in combination with pegylated liposomal doxorubicin (PLD) versus PLD alone in women with platinum‐resistant ovarian cancer (Table 1) [11]. This was the first randomized study to show a statistically significant improvement over standard therapy, with the greatest benefit seen in patients whose tumors were 100% positive for FR expression (median progression‐free survival (PFS) of 5.5 months for the combination compared with 1.5 months for PLD alone). A key component of this (and other vintafolide) trials was use of a companion diagnostic agent containing a ^99mTc‐based imaging group, known as etarfolatide [12]. Whole‐body, noninvasive imaging with etarfolatide at baseline allowed for selection of patients with FR‐positive lesions, and the relationship between receptor status and PFS was determined through threshold analysis. Unfortunately, the subsequent phase III trial (PROCEED; NCT01170650) was discontinued at interim analysis because the combination did not meet the prespecified criteria for required PFS improvement (Table 1). DAVLBH, the toxic drug conjugated to folate, is a P‐glycoprotein (P‐gp) substrate, and it has subsequently been suggested that P‐gp‐mediated efflux of the payload is a mechanism of vintafolide resistance that may have contributed to this poor outcome [13].

Figure 2.

Chemical structures of the folate‐small molecule drug conjugate vintafolide and the FRα‐targeting antibody‐drug conjugate mirvetuximab soravtansine. Vintafolide (A). Mirvetuximab soravtansine (B).

Abbreviations: FR, folate receptor; mAb, monoclonal antibody.

Table 1. Select clinical trials of FR‐targeting experimental therapeutics in advanced ovarian cancer.

^aFR‐targeting conjugate.

^bPatients with platinum‐resistant EOC, fallopian tube, or primary peritoneal cancer, medium/high FRα expression, and 1–3 prior lines of therapy.

Abbreviations: EOC, epithelial ovarian cancer; FR, folate receptor; IC, investigator's choice; mPFS, median progression‐free survival; ORR, objective response rate; PLD, pegylated liposomal doxorubicin.

The transition of farletuzumab and vintafolide into pivotal trials represented a significant inflection point for the feasibility of FR targeting in ovarian cancer. In view of the modest single‐agent activity seen with each and inability to confirm the superiority of FR‐targeted combinations over conventional chemotherapy in phase III studies, these results were undoubtedly disappointing. Although the full promise of FR‐based therapy is yet to be realized, it is important to remember that appropriate targets cannot be judged by the failure of one (or two) agents. The keys to success are building on the lessons learned and overcoming the limitations of these pioneering approaches.

Helping drive renewed enthusiasm for FRα‐targeting in EOC is the maturing clinical profile of mirvetuximab soravtansine (IMGN853), an antibody‐drug conjugate (ADC) recently granted fast track designation by the Food and Drug Administration (Fig. 2B). ADCs are complex engineered molecules comprised of a monoclonal antibody, directed toward tumor‐associated antigens, conjugated via a stable linker to a cytotoxic agent. Mirvetuximab soravtansine consists of a humanized anti‐FRα antibody linked to the maytansinoid DM4 [14], a potent tubulin‐targeting agent. As an ADC, mirvetuximab soravtansine possesses several therapeutic advantages over both farletuzumab and vintafolide. First, the capacity of FRα to internalize large molecule ligands makes it well suited for ADC‐based therapeutic approaches and the ADC molecule itself couples the pharmacokinetic features of an antibody with the cancer‐killing impact of a cytotoxic agent. Second, in contrast to folate‐SMDCs, use of an antibody as the targeting vehicle provides not only antigen specificity but also an extended half‐life to ensure adequate delivery of the payload to the site of tumors. Importantly, the cleavable linker incorporated into mirvetuximab soravtansine allows active DM4 metabolites to diffuse from the initial cell into proximal tumor cells and kill them, an effect termed “bystander” killing [15]. Unlike the requirement of uniformly high tumoral receptor expression for vintafolide activity, this characteristic is likely to be advantageous in tumors with heterogeneous FRα expression.

As with farletuzumab and vintafolide, mirvetuximab soravtansine is well tolerated. The safety profile of this ADC consists of primarily low grade, manageable gastrointestinal as well as reversible ocular events and a low incidence of toxicities commonly seen with chemotherapy, such as myelosuppression and alopecia. Favorable tolerability and encouraging signals of antitumor activity emerged from the phase I clinical experience with mirvetuximab soravtansine [16]. These early trends identified the dose, schedule, and target population for a randomized phase III study comparing monotherapy to investigators’ choice chemotherapy in patients with platinum‐resistant disease (FORWARD I; NCT02631876) that completed enrollment in April 2018 (Table 1). Dose escalation defined 6 mg/kg (based on adjusted ideal body weight) given once every 3 weeks as the appropriate phase III dose.

As compared with its predecessors, mirvetuximab soravtansine presents several advantages. Particularly, an association was identified between FRα expression and the depth and duration of response in phase I evaluations [17], and an expansion study in patients with platinum‐resistant EOC revealed superior efficacy outcomes (objective response rate [ORR] and PFS) in less‐heavily pretreated individuals [18]. In a retrospective pooled analysis of EOC patients enrolled in the first‐in‐human study, the strongest signals of efficacy were seen in the subset of women with 1–3 prior lines of therapy and medium/high FRα expression (ORR, 47%; PFS, 6.7 months), values that compared favorably with agents presently used in the second line setting for relapsed EOC [16].

Moreover, the tolerability and safety profile made this ADC an ideal candidate for combination‐based therapeutic approaches. A test of this strategy is underway, with initiation of the FORWARD II combination trial (NCT02606305). Although the data are still preliminary, early findings suggest that combinations of mirvetuximab soravtansine with bevacizumab or pembrolizumab in platinum‐resistant patients, or carboplatin in the platinum‐sensitive setting, are all well tolerated and active [19]. Overall, given its similar mode of action to taxanes (microtubule disruption), a clinical picture is beginning to emerge in which this agent may be substituted for paclitaxel in patients with FRα‐positive tumors in order to provide more manageable and effective treatment options for women with advanced ovarian cancer.

With top‐line results from FORWARD I expected in the first half of 2019 and an ongoing focus on novel combinatorial strategies, mirvetuximab soravtansine may become the first FRα‐directed investigational agent to have a defined role in the management of EOC. If successful, this coming of age for FR‐targeting will help guide treatment decisions for personalized oncological care in EOC. Furthermore, FRα is also a candidate for tumor‐directed drug delivery in other solid tumors (Table 2). In this regard, another FRα‐targeting ADC, MORAb‐202 (farletuzumab conjugated to eribulin) [20] has just entered phase I evaluation, with plans to expand the study in triple‐negative breast cancer and endometrial cancer. Therefore, it is reasonable to envision the eventual application of ADC‐based, FR‐targeted therapy in other indications.

Table 2. Select tumor types with reported FR overexpression.

Abbreviations: FR, folate receptor; TNBC, triple‐negative breast cancer.

Disclosures

Michael J. Birrer: Tesaro, Clovis, Merck Sharp & Dome, Genentech USA, AstraZeneca (C/A); Kathleen Moore: AstraZeneca, Clovis, Immunogen, Genentech/Roche, Tesaro, VBL Therapeutics, Janssen, Aravive (C/A). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board