Initial data from the FORWARD II study, a phase Ib/II study evaluating the antiboy-drug conjugate (ADC) mirvetuximab soravtansine (also known as IMGN853), in combination with bevacizumab (Avastin®; Genentech/Roche) in patients with medium and high folate receptor alpha (FRα)-expressing recurrent ovarian cancer for whom a non-platinum based combination regimen, demonstrates encouraging outcomes relative to available regimens.

Mirvetuximab soravtansine is a targeted anti-cancer drug comprising a folate receptor alpha (FRα)-binding antibody a cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent.

The findings from the FORWARD II, funded by ImmunoGen, the developer of mirvetuximab soravtansine, were presented in an oral presentation at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program. [1]

“The data presented at the 2020 virtual ASCO meeting demonstrates the potential of mirvetuximab soravtansine to serve as the combination agent of choice for both platinum-sensitive and platinum-resistant recurrent ovarian cancer,” noted Anna Berkenblit, M.D., Senior Vice President and Chief Medical Officer of ImmunoGen.

“We are particularly encouraged by the overall response rate of 64% observed in patients with high FRα expression, regardless of platinum status. We look forward to the continued evaluation of mirvetuximab with bevacizumab in this increasing population of recurrent ovarian cancer patients for whom a non-platinum based regimen would be appropriate,” she added.

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“Despite the advances with PARP inhibitors and anti-angiogenic agents in newly diagnosed ovarian cancer, active, well-tolerated therapies for women with recurrent disease regardless of platinum status are still needed,” said Lucy Gilbert, M.D., Professor, and Director of the Gynecologic Oncology Division at McGill University Health Center in Montreal, Canada.

“With this combination, the overall response rate in the platinum-resistant subset is more than twice the usual response rate for this population and similarly, in the platinum-sensitive subset, the overall response rate is higher than previously seen with platinum-based doublets. Given these responses and the favorable tolerability profile of this combination, these data are exciting and demonstrate the potential of mirvetuximab to address the growing unmet need in this patient population,” Gilbert further explained.

Recurrent ovarian cancer
Ovarian cancer remains the second most common gynecologic malignancy. The American Cancer Society estimates that 21,750 new cases of ovarian cancer will be diagnosed in the United States in 2020. Because the disease is generally diagnosed in an advanced stage, the disease has a poor prognosis. And while most patients achieve a complete remission, approximately 80% to 85% of patients will eventually experience recurrence.

The current standard of care includes debulking surgery which is followed by platinum-taxane chemotherapy. However, most patients will, over time, develop resistance to platinum therapy. As a result, a major unmet need remains for patients resistant to platinum-based chemotherapy diagnosed with recurrent ovarian cancer. Given the median overall survival of about 13 months post recurrence, several different strategies, including a combination of mirvetuximab soravtansine with bevacizumab, are currently under evaluation.

Study design and results
In the FORWARD II study, a cohort enrolled 60 patients with a median age of 60 and a median number of 2 prior lines of therapy (range 1-4). Thirty-two patients (53%) had platinum-resistant disease with a platinum-free interval (PFI) of less than or equal to 6 months. Twenty-eight (28) patients (47%) had a platinum-sensitive disease – of which 20 patients (33%) had a PFI greater than 6 months and less than or equal to 12 months and 8 patients (13%) had a PFI greater than 12 months.

In this cohort, the combination of mirvetuximab soravtansine with bevacizumab demonstrates promising anti-tumor activity with a favorable tolerability profile, particularly among patients with high levels of FRα expression. According to the investigators, this is encouraging relative to outcomes with available therapies reported in similar populations.

During the virtual ASCO presentation, key updated data included the overall patient population, objective responses seen in 28 patients confirming an overall response rate (ORR) 47% (95% CI, 34, 60).

In patients with high FRα expression (n=33), the confirmed ORR was 64% (95% CI, 45, 80), with an ORR of 59% (95% CI, 33, 82) in the platinum-resistant subgroup (n=17), and 69% (95% CI, 41, 89) in the platinum-sensitive subgroup (n=16). With a median follow-up of 8.5 months and nearly half of patients with high FRα expression remaining on the study, the duration of response and progression-free survival data are still immature.

The adverse events (AEs) observed with the doublet were manageable and consistent with the side effect profiles of each agent. The most common treatment-related AEs were low-grade, including diarrhea, blurred vision, fatigue, and nausea; grade 3+ AEs were infrequent.

“Effective, tolerable treatment options for patients with recurrent ovarian cancer, unfortunately, remain limited,” explained David O’Malley, MD, Professor, Division Director of Gynecology Oncology and Co-Director of the Gyn Onc Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center, and FORWARD II Principal Investigator.

“These promising results confirm previously reported mirvetuximab soravtansine plus bevacizumab data demonstrating a deeper and more durable tumor burden reduction in women whose tumors express high levels of FRα. These results add to the body of evidence that mirvetuximab can potentially be used to treat a broader patient population. I look forward to further evaluating these data as they mature.”

Other combinations
In addition to bevacizumab, the FORWARD II study also evaluates mirvetuximab soravtansine in combination with carboplatin and, pembrolizumab (Keytruda®; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co) in patients with FRα-positive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancers, as well as a triplet combination of mirvetuximab plus carboplatin and bevacizumab in patients with FRα-positive platinum-sensitive ovarian cancer.

Clinical trials
Study of Mirvetuximab Soravtansine in Comb. With Bevacizumab, Carboplatin, PLD, Pembrolizumab, or Bevacizumab + Carboplatin in Adults With FRa + Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer – NCT02606305
Mirvetuximab Soravtansine (IMGN853) and Bevacizumab in Patients With Endometrial Cancer – NCT03836157

[1] Gilbert L, Oaknin A, Matulonis UA, Mantia-Smaldone G, Lim PC, Castro CM, Provencher DM, Memarzadeh S. et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer. J Clin Oncol 38: 2020 (suppl; abstract 6004). 10.1200/JCO.2020.38.15_suppl.6004 [Abstract]

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