By Charles Bankhead
Anti-folate fails phase III test, but key biomarker measurement may have been faulty.
An antibody-drug conjugate (ADC) targeting folate-receptor expression failed to improve progression-free survival (PFS) versus chemotherapy in patients with recurrent platinum-resistant ovarian cancer, according to a randomized trial reported here. But that may not spell doom for the product.
Treatment with mirvetuximab soravtansine led to median PFS of 4.1 months versus 4.4 months with investigators’ choice of chemotherapy. A prespecified analysis limited to patients with high folate receptor-alpha (FRα) expression yielded a slight advantage in favor of mirvetuximab, but the difference did not pass muster with the trial’s statistical requirements.
However, a methodologic and statistical post-mortem showed that use of an FRα expression measure from previous studies of mirvetuximab — instead of the one employed in the trial — would have produced a statistically significant PFS improvement with mirvetuximab, as reported at the European Society for Medical Oncology annual congress.
“We did see clear signals of efficacy with mirvetuximab and potential signals of superiority [with the assay used in the study],” said Kathleen Moore, MD, of the University of Oklahoma Stephenson Cancer Center in Oklahoma City. “We can also say that we observed a very differentiated toxicity, which compares favorably to investigator’s choice of chemotherapy. These make us believe that mirvetuximab would be an attractive asset to the armamentarium for the care of patients with recurrent ovarian cancer.”
Findings from the exploratory analysis with the alternative method for assessing FRα expression warrant a follow-up randomized trial, which has already been planned, she added.
For years, patients with ovarian cancer had only chemotherapy treatment options. The introduction of PARP inhibitors has had a “transformative” impact on the treatment of recurrent disease. Incorporation of antiangiogenic agents and better supportive care have also contributed to better outcomes, including survival.
“We are living in an era now where women with ovarian cancer are living longer than ever have in our history,” said Moore. “Despite this, they still recur and develop resistance to platinum, PARP inhibitors, and our other active assets, and rely on the low response rates and relatively toxic monotherapy cytotoxic agents that are left as options for them.”
Mirvetuximab targets FRα, which is almost universally expressed by high-grade serous ovarian cancer, and delivers the microtubule-disrupting agent DM4 directly to the tumor. After internalization, DM4 releases a toxin that results in cell death.
Following promising results in preliminary clinical evaluations, the randomized, phase III FORWARD I trial compared mirvetuximab and chemotherapy in patients with recurrent, platinum-resistant ovarian cancer, associated with intermediate- or high-level FRα expression.
FRα expression is determined by histologic analysis of tumor tissue. In prior clinical evaluations of mirvetuximab, investigators relied on the PS2+ method to calculate FRα, a “cumbersome” process that involves determining staining intensity and the percentage of cells stained. An alternative method, known as 10x, merely counts stained cells visible at ≤10x magnification, a simpler process as compared with PS2+. Investigators performed a bridging study of the two methods and concluded that 10x scoring would be sufficient for patient selection in the FORWARD I trial.
Eligibility criteria included confirmed platinum-resistant ovarian cancer associated with at least one and a maximum of three prior systemic regimens and histology-confirmed medium or high FRα expression. By 10x scoring, medium FRα expression was defined as 50%-74% of cells staining positive and high expression as ≥75% of cells. Moore noted that 60% of patients in the trial had high FRα expression by this method, more than investigators anticipated from earlier trials with PS2+ methodology.
Investigators randomized 352 patients 2:1 to mirvetuximab soravtansine or to investigator’s choice of single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The trial’s primary endpoint was PFS by independent radiologic review in the intention-to-treat (ITT) and high-FRα populations. Secondary endpoints included overall response rate, overall survival (OS), and patient-reported outcomes (PROs). Statistical assumptions included a median PFS of 3.5 months in the control arm and power to detect a hazard ratio of 0.58 in favor of mirvetuximab.
The two treatment groups were balanced with respect to baseline characteristics, including stratification factors: FRα expression status (42% medium, 58% high), three prior lines of therapy (35%), and chemotherapy choice (paclitaxel 31%-32%; PLD 44%-46%; topotecan 23%).
Analysis of the primary endpoint in the ITT population showed the two groups in essentially a dead heat (HR 0.981, P=0.897). Among patients with high FRα expression, a trend favoring mirvetuximab was apparent: median PFS of 4.8 months versus 3.3 months for the control arm. The difference represented a 31% reduction in the hazard ratio with P=0.049. However, the trial design specified P<0.025 to define statistical significance.
Additional ITT analyses suggested other advantages for mirvetuximab: in objective response (22% vs 12%, P=0.015) and PROs (32% vs 14%, P=0.011). Analyses of the high-FRα population showed additional signals favoring the ADC: objective response (24% vs 10%, P=0.014), overall survival (16.4 vs 12.0 months, P=0.048), and PROs (28% vs 13%, P=0.096).
The safety analysis favored mirvetuximab, including fewer grade ≥3 treatment-emergent adverse events than with chemo (46% vs 61%). Patients randomized to mirvetuximab had substantially less neutropenia, anemia, thrombocytopenia, alopecia, and stomatitis but more diarrhea, nausea, and ophthalmologic events known to be associated with the drug (blurred vision, keratopathy, and dry eye).
Re-Examining FRα Expression
As investigators reviewed possible explanations for the unexpected findings, they decided to reanalyze the data using the PS2+ method of determining FRα expression, which required another review of all tumor specimens. Whereas 60% of patients had high FRα expression by 10x scoring, only 35% had high expression by PS2+ scoring. An additional 31% of the patients had medium expression, and 34% had FRα expression <50%, which would have qualified as low expression and excluded the patients from the trial.
Using the distribution of FRα expression by PS2+ scoring, the results looked very different, said Moore. A plot of hazard ratios showed that patients with high FRα expression by the more rigor method had significant improvement in PFS versus chemotherapy (5.6 vs 3.2 months, HR 0.549, P=0.015). Additionally, the analysis showed trends toward better OS (16.4 vs 11.4 months) and objective response (29% vs 6%).
Invited discussant Jonathan Ledermann, MD, of University College London, said the trial’s outcome underscored the “crucial” nature of correct biomarker analysis. Reanalysis of patients with high FRα expression by PS2+ scoring suggested mirvetuximab has activity similar to the combination of paclitaxel and bevacizumab (Avastin).
“However, cross-study comparisons are potentially misleading, especially in ‘platinum-resistant’ disease, which is a heterogeneous, nonbiologically defined grouping,” Ledermann added.
This article was published by MedPage Today.