Mirvetuximab soravtansine (MIRV) in patients with platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression: Characterization of antitumor activity in the SORAYA study.

Abstract

5512 Background: SORAYA is a global single arm phase 3 study evaluating MIRV in patients (pts) with FRα high platinum-resistant ovarian cancer (PROC). MIRV is an antibody drug conjugate comprising a FRα-binding antibody, cleavable linker, and maytansinoid DM4, a potent tubulin-targeting agent. In this study, MIRV demonstrated activity in a broad population of PROC, regardless of number of prior lines of therapy or prior PARPi (Matulonis, SGO 2022). Here we describe details of response to treatment important for clinical decision making. Methods: SORAYA enrolled PROC pts with high FRα expression by immunohistochemistry (Roche FOLR1 Assay ≥ 75% of cells with PS2+ staining intensity) who had received 1-3 prior therapies, including required prior bevacizumab. Pts received intravenous MIRV at 6 mg/kg, adjusted ideal body weight, on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1 by investigator (INV) and the key secondary endpoint was duration of response (DOR); additional endpoints included time to response, CA-125 response, safety and tolerability. Results: 106 pts were enrolled; 51% had 3 prior lines; 48% had 1-2 prior lines of therapy; 48% received prior PARPi. ORR by INV was 32.4% (95% confidence interval [CI]: 23.6%, 42.2%), including five complete responses. Median time to response was 1.5 mos (range 1.0 to 5.6) and 71% of pts demonstrated tumor reduction. At the time of the protocol specified primary analysis (16 Nov 2021), the median DOR was 5.9 mos (95% CI: 5.6, 7.7). With 15 responders remaining on MIRV, the DOR continues to evolve. In the 86 response-evaluable patients for CA-125 (by Gynecologic Cancer Intergroup criteria), responses were observed in 46.5% (95% CI: 35.7, 57.6). Updated data will be presented including depth and duration of responses and impact of dose modifications. The most common treatment-related adverse events (TRAE; all grade, grade 3+) included blurred vision (41%, 6%), keratopathy (36%, 9%), and nausea (29%, 0%). TRAEs led to dose delays in 32%, dose reductions in 19%, and discontinuations in 7% of pts; one patient discontinued treatment due to an ocular event. The tolerability profile of MIRV consists of low-grade, reversible ocular and GI events, managed with dose modifications and supportive care. Conclusions: Treatment options for pts with PROC are limited. MIRV is the first biomarker-directed therapy demonstrating anti-tumor activity in pts with FRα high PROC. These results support the clinically meaningful impact MIRV has for pts with FRα high PROC, irrespective of prior therapies or dose modifications. Clinical trial information: NCT04209855.

Folate receptor alpha in ovarian cancer tissue and patient serum is associated with disease burden and treatment outcomes

“…A number of FRα-targeting therapeutics are currently in pre-clinical and clinical development [ 12 , 26 , 31 ], including our own FRα-specific IgE antibody (MOv18 IgE) [ 41 , 44 – 47 , 51 ]. Here we demonstrate that the patients with FRα-expressing tumours, which could be targeted with such therapies, are likely to have circulating sFRα.…”

“…In addition to its potential role as a clinical biomarker, there has been significant interest in using FRα as a therapeutic target in patients with ovarian cancer, with several FRα-targeted therapeutics, such as farletuzumab and mirvetuximab soravtansine, in latephase trials [26][27][28][29][30][31]. Despite promising results, FRα-targeted agents are yet to be approved for use in patients with cancer.…”

Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers

“…For example, results from the SORAYA Phase III trial evaluating Elahere ® in patients with platinum-resistant ovarian cancer pre-treated with one to three prior lines of systemic therapy, and with high tumour expression of FRα, revealed an overall response to Elahere ® of 32.4%. Most importantly, five complete responses out of a total of 106 patients were observed [ 171 ]. Commonly observed Elahere ® -related AEs observed in both trials included nausea, diarrhoea and fatigue, as well as blurred vision and keratopathy, which were largely managed with dose delays and/or reductions [ 170 , 171 ].…”

Review of calculation of conditional power, predictive power and probability of success in clinical trials with continuous, binary and time-to-event endpoints

“…Example 2: The single-arm SORAYA trial [28] was designed to assess the effect of investigational drug Mirvetuximab soravtansine (MIRV) in platinum-resistant ovarian cancer with high folatereceptor alpha (FRα) patients with sample size of 105 patients. The study was designed with primary endpoint of overall response rate (ORR).…”

“…Example 4: We will again consider the single-arm SORAYA trial [28] from Example 2, but this time we will re-imagine this trial with progression-free survival (PFS) as a primary endpoint and also add an interim analysis to illustrate the calculation of PoS, CP and PPoS. Assume that the study targets 60 events (= d) at interim analysis and 90 PFS events (= D) at final analysis to evaluate the following test of hypothesis for median PFS (mPFS):…”