ADC shows favourable signals for difficult-to-treat ovarian cancer

Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC), showed antitumour activity in women with platinum-resistant ovarian cancer* (PROC) with high folate receptor alpha (FRα) expression, findings from the phase III SORAYA study have shown.

“The investigator-assessed objective response rate (ORR) for the entire population was 32.4 percent, with five complete responders. Median duration of response (DOR) was 6.9 months, ranging from 2.8 to 18 months on study,” said Dr Robert Coleman from the US Oncology Research, Texas Oncology, The Woodlands, Texas, US, at SGO 2023.

“Benchmarking against the primary endpoint in the overall population, ORR was slightly higher when MIRV was administered as first treatment in the PROC setting and in patients who had previously received bevacizumab in a platinum-sensitive setting,” he added. The respective ORRs for these subgroups were 34.8 percent and 34.0 percent. [SGO 2023, abstract LBA4]

Among patients with RECIST-evaluable disease who had a post-baseline treatment tumour assessment (n=102), 71 percent had some tumour reduction on therapy and 51 percent had disease control.

A final data cut for overall survival (OS) was made in December 2022, reflecting 59 percent data maturity. Median OS was 15 months, and over a third of patients were alive at 2 years. Median OS was longer in patients who had 1–2 prior therapies as opposed to those who have had three prior lines (18.7 vs 11.6 months).

Most adverse events (AEs) were low-grade and reversible. The most common grade ≥3 treatment-related AEs (TRAEs) were ocular, represented by keratopathy (9 percent), blurred vision (6 percent), and dry eye (2 percent), as well as gastrointestinal-related AEs.

Over half of participants experienced any-grade blurred vision or keratopathy. “In general, the onset of symptoms was predictable, occurring in the second or third week of the second cycle. [But these were] reassuringly reversible in nearly all patients. Management with steroids and lubricating eye drops mitigated both the severity and duration of symptoms,” said Coleman.

Only one patient discontinued therapy due to an ocular TRAE. “Vision returned to baseline and corneal changes resolved to grade 0 within 15 days. There were no corneal ulcerations or perforations in the study,” he continued.

Overall, about a third of participants had dose delays owing to TRAEs, while 20 percent had dose reductions. Nine percent discontinued treatment due to TRAEs.

 

FRα tied to poor outcomes

In patients with drug-resistant cancers, the motivation to develop new treatment alternatives stems from the unacceptably poor performance of available treatments hallmarked by low ORRs, short DORs, and frequently accumulating toxicities, noted Coleman.

More than 90 percent of ovarian cancers overexpress FRα, which is associated with poor outcomes. [Cell Oncol (Dordr) 2012;35:9-18; Gynecol Oncol 2008;108:619-626; Mol Oncol 2012;6:360-369] MIRV, a first-in-class ADC that delivers the maytansine analogue DM4 into ovarian cancer cells localized by high FRα expression, has been given the FDA nod in November 2022 for the treatment of adults with FRα-high PROC who have previously received 1–3 systemic regimens.

“Since the clinical efficacy of chemotherapy generally decreases with each line of therapy, we sought to evaluate the antitumour activity of MIRV when given as [first-line therapy] or in subsequent lines of therapy for platinum-resistant disease,” Coleman said.

The study enrolled 106 women (median age 62 years) with measurable FRα-high PROC* who had received 1–3 prior lines of therapy. MIRV 6 mg/kg (adjusted to ideal body weight) was administered intravenously once Q3W. Nearly 40 percent of participants had stage IV disease. About half had previous PARPi** therapy and over half had three prior lines of treatment. Roughly two-thirds of women received MIRV as first treatment for platinum-resistant disease.

Prior bevacizumab use was required for all participants. Apart from six patients who received bevacizumab in both the platinum-sensitive and platinum-resistant settings, bevacizumab was mostly administered with chemo in a platinum-sensitive setting, predominantly in the frontline.

Despite being a particularly poor-risk subgroup, those who received bevacizumab in the platinum-resistant setting (n=17) had an ORR of about 18 percent. Nearly half of these patients had stage IV disease at diagnosis and about 60 percent had received MIRV as fourth-line therapy. “To put this into context, a [previous study showed] a response rate for chemo in the third- or fourth-line setting between 3 and 8 percent in a bevacizumab-naïve population,” Coleman noted.

 

Practice-changing?

Taken together, MIRV demonstrates clinically meaningful antitumour activity in this difficult-to-treat population, noted Coleman and colleagues in their published report. [J Clin Oncol 2023;doi:10.1200/JCO.22.01900]

“The ORR in patients receiving this treatment as their first regimen following platinum resistance and in those who received bevacizumab as part of a platinum-sensitive regimen had high activity,” Coleman said. “Overall responses in each subgroup exceeded our expectations for single-agent chemo and safety was consistent with early reports.”

“The totality of these data supports the regulatory action that made this drug available to us under an accelerated approval … These results position MIRV to become a practice-changing, biomarker driven, standard-of-care treatment option for patients with FRα-positive PROC,” he concluded.

Data from the confirmatory MIRASOL trial are expected next quarter.