Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer

Highlights

• Combining mirvetuximab soravtansine and bevacizumab is a promising approach for platinum-resistant ovarian cancer.

• The combination is well tolerated, with a differentiated safety profile compared to bevacizumab with chemotherapy.

• The efficacy measures compare favorably to reported outcomes for bevacizumab/chemotherapy in similar patient populations.

Abstract

Purpose

To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer.

Methods

Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined.

Results

Sixty-six patients, with a median of 3 prior lines of therapy (range, 1–8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1–2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months).

Conclusion

The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.

Introduction

The incorporation of molecularly targeted agents into the treatment armamentarium for epithelial ovarian carcinoma (EOC; including epithelial ovarian, fallopian tube, and primary peritoneal cancer) [1,2] has had a meaningful impact in terms of disease control, particularly for individuals in early treatment lines considered at high risk of further relapse [3]. Despite this progress, most women diagnosed with advanced EOC ultimately develop, and succumb to, platinum-resistant recurrences [4]. The dismal prognosis imparted by platinum-resistant disease underscores the substantial unmet need for more effective and tolerable therapeutic agents and innovative approaches to improve outcomes in this clinically challenging population.

The first targeted agent indicated for use in EOC was the angiogenesis inhibitor bevacizumab [5]. Initial approval in the U.S. and E.U. was based on findings from the AURELIA/ENGOT-ov3 trial, which showed that addition of bevacizumab to chemotherapy significantly improved progression-free survival (PFS) over chemotherapy alone in patients with platinum-resistant EOC [6]. Bevacizumab approval was subsequently expanded into the platinum-sensitive, recurrent, and front-line settings, in combination with chemotherapy followed by a maintenance period of single-agent bevacizumab. This occurred in response to additional randomized phase III studies performed in patients with recurrent platinum-sensitive disease (OCEANS and GOG-0213) [7,8] and newly diagnosed, advanced EOC (GOG-218 and ICON7) [9,10], all of which demonstrated prolonged PFS when bevacizumab was combined with chemotherapy.

Another molecular target of interest in EOC is folate receptor alpha (FRα) [11], a transmembrane protein involved in cellular folate transport [12]. FRα expression is highly restricted in normal tissues and absent from normal ovarian epithelium. However, FRα expression has been reported in approximately 80% of EOC tumors; methods to assess FRα expression include immunohistochemistry and imaging with radiolabeled conjugates [13]. This differential distribution pattern makes FRα an attractive candidate for antibody-drug conjugate (ADC)-based therapeutic strategies [14]. ADCs comprise a monoclonal antibody, directed toward tumor-associated antigens, to which a potent cytotoxic agent (‘payload’) is conjugated via chemical linkage [15]. ADCs are also a clinically validated class of therapeutics, with four currently approved for cancer therapy and >60 others being evaluated in a variety of tumor indications [16].

Mirvetuximab soravtansine is an ADC composed of an anti-FRα antibody coupled via a cleavable disulfide linker to the maytansinoid DM4 [17,18], a potent tubulin-targeting agent [19,20]. Mirvetuximab soravtansine is currently in clinical development for EOC, where it has exhibited encouraging signals of activity and favorable tolerability as monotherapy [21], underscoring its potential as a suitable partnering agent for combination-based strategies. The distinct and complementary mechanisms of action of mirvetuximab soravtansine and bevacizumab, along with nonoverlapping toxicity profiles, provided a rationale for combining the two agents as a novel avenue for therapeutic intervention in EOC. Additional support for this approach was provided by preclinical studies which showed superior antitumor activity for the combination over single-agent regimens, including in patient-derived models of EOC [22]. Here we report results from the Phase Ib combination trial FORWARD II (NCT02606305) designed to evaluate the safety, tolerability, and clinical activity of mirvetuximab soravtansine when co-administered with bevacizumab to patients with FRα-positive, platinum-resistant EOC.