Exploring the Nuances of Regulatory Approval Vs Optimal Use of a New Antineoplastic Agent

Maurie Markman, MD

The recent regulatory approval of mirvetuximab soravtansine-gynx (Elahere)—a novel folate receptor α–directed antibody and microtubule inhibitor conjugate—for the treatment of platinum-resistant ovarian cancer is a welcome event.¹ Oncologists and, most importantly, patients in this clinical situation now have another option to consider during the disease management journey.

It is also important to mention that the drug’s accelerated approval follows a highly laudatory practice adopted by the FDA in recent years to allow for routine clinical use of promising antineoplastic agents in the absence of data from randomized trials, with additional data pending.

As with other antineoplastic strategies employed in cancer care, the benefits and toxicities experienced by individual patients will not be known until after the drug is delivered and its positive and negative effects are observed and measured. In this regard, it is critical to note that participants in clinical trials are likely to have physiologic characteristics and medical histories, including the presence or absence of comorbidities, that may only modestly, or even minimally, reflect those of the real-world populations who will be receiving this novel agent.

Furthermore, its somewhat unique adverse effect profile, which includes ocular toxicity, will require oncologists to understand that they may need to refer patients to an ophthalmologist. None of which should diminish the hope that this drug may provide clinically meaningful and prolonged responses with acceptable toxicities.

However, the present focus is neither the approval nor the unknown efficacy and toxicity of mirvetuximab soravtansine, but rather the discussion that follows focuses on the question of the optimal sequencing of potential drug strategies in the clinical setting where current regulatory approval for this new drug has been provided.

Challenging Therapeutic Decision-Making

In the not-so-distant-past, evidence-based recommendations for sequencing antineoplastic drugs in the management of epithelial ovarian cancer were fairly straightforward. The standard of care for individuals with advanced disease, was— and remains—primary platinum chemotherapy (carboplatin or cisplatin) plus a taxane (most commonly paclitaxel), delivered either after cytoreductive surgery or upon diagnosis, followed by surgery.

If disease progression or stable disease is observed as the best response or the patients initially experience a response but have disease recurrence relatively quickly (within 6 months from the completion of approximately 6 cycles of chemotherapy) the tumor is classified as being platinum-resistant. If a response is observed and recurrence is noted more than 6 months following the end of primary chemotherapy the cancer is platinum-sensitive.

One can argue with the terminology; for instance, is the cancer completely resistant to platinum if an excellent response is initially observed but evidence for recurrence is discovered 5 months after chemotherapy discontinuation? Nevertheless, this simple classification scheme has value both for patient management and the design of ovarian cancer clinical trials of new antineoplastic agents in the platinum-resistant and platinum-sensitive groupings.

Unfortunately, accelerated regulatory approvals in the past 10 to 15 years, both of novel drugs and their use as part of newer strategies (eg, maintenance therapy) present a challenge to the relatively simple drug development and clinical use paradigms mentioned. Consider, for example, a patient who receives the FDA-approved regimen of 6 cycles of carboplatin and paclitaxel with bevacizumab (Avastin) and exhibits an excellent response but experiences recurrence during the bevacizumab maintenance phase, approximately 7 or 8 months after the cytotoxic agents have been discontinued. What is the evidence that this patient should then be considered to have platinum-sensitive disease or, indeed, platinum-resistant disease?

Substituting an FDA-approved PARP inhibitor maintenance strategy, the same question can be asked of a patient with a BRCA germline mutation who experiences disease recurrence approximately 7 or 8 months after completion of the carboplatin/paclitaxel regimen when she is receiving an FDA-approved PARP inhibitor as maintenance therapy. Should this cancer be considered platinum-sensitive or platinum-resistant?

Returning to the optimal use of mirvetuximab soravtansine, there are a number of questions to be asked when considering its use in the context of previously published data about bevacizumab in platinum-resistant disease.

First, what is the clinical activity (objective response rate) of the combination of bevacizumab with the individual drugs employed in the AURELIA trial (NCT00976911) in patients with the required biomarker that led to FDA approval of the conjugate?² Knowing whether the chemotherapy/bevacizumab regimen is effective in this setting may assist oncologists in their decision-making process.

In addition, if a clinician were to assume that patient with ovarian cancer who has received bevacizumab during primary chemotherapy would not benefit from receiving this agent again in combination with a cytotoxic agent, the assumption would be incorrect. In fact, previously reported data from an ovarian cancer randomized trial revealed that prior delivery of bevacizumab does not prevent its favorable effect if administered with a cytotoxic agent in a subsequent line of therapy.³

Therefore, given the documented improvement in progression-free survival² and the possibly meaningful and favorable effect on overall survival (specifically with weekly paclitaxel plus bevacizumab) shown in the landmark AURELIA study,⁴ and in the absence of contraindications to additional administration of the antiangiogenic agent, would it be appropriate to administer this bevacizumab plus paclitaxel to women with platinum-resistant disease prior to mirvetuximab soravtansine?

Although individual ovarian cancer experts and practicing clinicians may have their own opinions about the optimal approach, including carefully considering the severity of prior bevacizumab-associated toxicities experienced by the patient, the absence of evidence-based comparative data about the 2 different approaches is problematic. Add this to the growing list of unresolved relevant issues associated with our rapidly expanding armamentarium of beneficial antineoplastic strategies that complicate clinical decision-making.

References

1. Moore KN, Martin LP, O’Malley DM, et al. A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018;14(2):123-136. doi:10.2217/fon-2017-0379
2. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum- resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489
3. Pignata S, Lorusso D, Joly F, et al; MITO16b/MANGO–OV2/ENGOT–ov17 Investigators. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomized, phase 3 trial. Lancet Oncol. 2021;22(2):267-276. doi:10.1016/S1470-2045(20)30637-9
4. Poveda AM, Selle F, Hilpert F, et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol. 2015;33(32):3836-3838. doi:10.1200/JCO.2015.63.1408