The U.S. Food and Drug Administration (FDA) has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere®; ImmunoGen), previously known as IMGN853, for the treatment of patients diagnosed with treatment of adult patients diagnosed with folate receptor α (Frα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.
Ovarian cancer is the eighth most common cancer in women worldwide and patients often have advanced disease when diagnosed. The disease is also the leading cause of death from gynecological cancers in the United States.
Each year, an estimated 20,000 patients are diagnosed with the disease, and 13,000 patients will die.
Most patients present with late-stage disease and will typically undergo surgery followed by platinum-based chemotherapy. Unfortunately, the majority of patients eventually develop platinum-resistant disease, which is difficult to treat. In this setting, standard of care single-agent chemotherapies are associated with low response rates, short durations of response, and significant toxicities.
Despite improvements in primary therapy, mortality rates remain high, and 80% of patients with advanced EOC will have their disease recur. The five-year relative survival rate for all stages of invasive EOC is 49%.
The FDA’s accelerated approval program was based on objective response rate (ORR) and duration of response (DOR) data from the global, single-arm, pivotal phase 3 SORAYA trial (NCT04296890). However, continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate (ADC) directed against the folate receptor 1 protein (FOLR1), also known as receptor α (Frα)–positive, a cell-surface protein highly expressed in ovarian cancer, and is the first FDA approved ADC for platinum-resistant disease. The drug comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin-targeting agent to kill the targeted cancer cells.
Eligible for treatment
To be eligible for treatment, patients need to be selected for therapy based on the outcome of the Ventana FOLR1 (FOLR1-2.1) RxDx Assay, the first immunohistochemistry (IHC) companion diagnostic test. This test, developed by Ventana Medical Systems and approved by the FDA, will inform clinicians about the likelihood of the potential patient benefit from FOLR1 therapy. The test also enables clinicians to make more informed treatment decisions for patients with ovarian cancer by quickly determining whether they qualify for mirvetuximab soravtansine therapy and potentially improving their outcomes.
The qualitative immunohistochemical assay, using mouse monoclonal anti-FOLR1 clone FOLR1-2.1, is intended for use in the assessment of FRɑ in formalin-fixed, paraffin-embedded epithelial ovarian cancer (EOC), including primary peritoneal cancer and primary fallopian tube cancer, tissue specimens by light microscopy.
Difficult to treat
“Platinum-resistant ovarian cancer is a notoriously challenging disease to treat. Given there have been no new therapies approved by FDA for this indication since 2014, mirvetuximab soravtansine’s accelerated approval is a tremendous advance in the ovarian cancer treatment paradigm,” explained Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.
“The approval of mirvetuximab soravtansine is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes,” noted Ursula Matulonis, MD, Chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, Professor of Medicine at the Harvard Medical School, and SORAYA Co-Principal Investigator.
“Mirvetuximab soravtansine’s impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with [this new treatment option],” Matulonis added.
In the SORAYA trial mirvetuximab soravtansine elicited a confirmed investigator-assessed objective response rate (ORR) of 31.7% (95% confidence interval [CI]: 22.9%-41.6%). This included a complete response rate (CR) of 4.8% and a partial response rate of 26.9%. Furthermore, the median duration of response (DOR), the key secondary endpoint, was 6.9 months (95% CI, 5.6-9.7) as assessed per investigator.
The SORAYA trial enrolled a total of 106 patients with platinum-resistant ovarian cancer whose tumors expressed high levels of FRα. Participating patients were allowed to have received up to 3 prior lines of systemic treatment, and all were required to have received bevacizumab (Avastin®; Genentech/Roche).
In this study, participants received intravenous mirvetuximab soravtansine at 6 mg/kg once every 3 weeks until progressive disease or unacceptable toxicity. Investigators conducted tumor response assessments every 6 weeks for the first 36 weeks, and every 12 weeks thereafter.
In the efficacy-evaluable population (n = 104), the median age was 62 years (range, 35-85). Ninety-six percent of patients were White, 2% were Asian, and 2% did not have their race information reported; 2% of patients were Hispanic or Latino. Regarding ECOG performance status, 57% of patients had a status of 0 and the remaining 43% had a status of 1.
A total of ten percent of patients received 1 prior line of systemic treatment, 39% received 2 prior lines, and 50% received 3 or more prior lines. All patients previously received bevacizumab, as required, and 47% previously received a PARP inhibitor.
The safety of mirvetuximab soravtansine was evaluated in all 106 patients. The median duration of treatment with the agent was 4.2 months (range, 0.7-13.3)
The all-grade toxicities most commonly experienced with mirvetuximab soravtansine included vision impairment (50%), fatigue (49%), increased aspartate aminotransferase (50%), nausea (40%), increased alanine aminotransferase (39%), keratopathy (37%), abdominal pain (36%), decreased lymphocytes (35%), peripheral neuropathy (33%), diarrhea (31%), decreased albumin (31%), constipation (30%), increased alkaline phosphatase (30%), dry eye (27%), decreased magnesium (27%), decreased leukocytes (26%), decreased neutrophils (26%), and decreased hemoglobin (25%).
Thirty-one percent of patients experienced serious adverse reactions with the agent, which included intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Toxicities proved to be fatalfor 2% of patients, and these included small intestinal obstruction (1%) and pneumonitis (1%).
Twenty percent of patients required dose reductions due to toxicities while 11% of patients discontinued treatment with mirvetuximab soravtansine because of adverse reactions. Toxicities that resulted in more than 2% of patients discontinuing treatment included intestinal obstruction (2%) and thrombocytopenia (2%). One patient discontinued because of visual impairment.
Ongoing confirmatory trial
The MIRASOL study NCT04209855, an ongoing phase 3 confirmatory randomized trial, is designed to convert the FDA’s accelerated approval of mirvetuximab soravtansine to full approval. The study, which includes patients with FRα-high platinum-resistant ovarian cancer who have been treated with up to three prior regimens, is fully enrolled and top-line data are expected in early 2023.
Mirvetuximab soravtansine monotherapy is also being studied in later line platinum-sensitive ovarian cancer and in combination in both platinum-resistant and platinum-sensitive disease.
The safety of mirvetuximab soravtansine has been evaluated in a pooled analysis from three clinical studies which included a total of 464 patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received at least one dose of mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight (AIBW) administered intravenously once every 3 weeks).
Mirvetuximab soravtansine can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders, ocular conditions in need of ongoing treatment), dry eye, photophobia, eye pain, and uveitis.
Ocular adverse reactions occurred in 61% of patients with ovarian cancer treated with mirvetuximab soravtansine. Nine percent (9%) of patients experienced Grade 3 ocular adverse reactions, including visual impairment, keratopathy/keratitis (corneal disorders), dry eye, photophobia, and eye pain; and one patient (0.2%) experienced Grade 4 keratopathy.
The most common (≥5%) ocular adverse reactions were visual impairment (49%), keratopathy (36%), dry eye (26%), cataract (15%), photophobia (13%), and eye pain (12%).
The median time to onset for first ocular adverse reaction was 1.2 months (range: 0.03 to 12.9). Of the patients who experienced ocular events, 49% had complete resolution and 39% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of mirvetuximab soravtansine in 0.6% of patients.
Premedication and use of lubricating and ophthalmic topical steroids eye drops during treatment with mirvetuximab soravtansine are recommended. Advise patients to avoid use of contact lenses during treatment with mirvetuximab soravtansine unless directed by a healthcare provider.
Finally, the cytotoxic payload of mirvetuximab soravtansine, DM4, is a CYP3A4 substrate. As a result, concomitant use of mirvetuximab soravtansine with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of mirvetuximab soravtansine adverse reactions. Closely monitor patients for adverse reactions with mirvetuximab soravtansine when used concomitantly with strong CYP3A4 inhibitors.
A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (SORAYA) – NCT04296890
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (MIRASOL) – NCT04209855
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