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Associate Director, Clinical Research
Department of Gynecologic Oncology
Stephenson Cancer Center
University of Oklahoma
Oklahoma City, Oklahoma
Kathleen Moore, MD: consultant/advisor/speaker: AstraZeneca, Aravive, Alkermes, BluePrint Pharma, Eisai, EMD Serono, Elevar, Genentech/Roche, Jiangsu Hengrui, Immunogen, INXmed, I-Mab, Mereo, Mersana, Myriad, Novartis, Onconova, Oncxerna, Tarveda, Verastem, VBL Therapeutics; researcher: PTC Therapeutics, Lilly, Merck, GlaxoSmithKline/Tesaro.
The treatment of ovarian cancer is continually evolving with significant advances. In this commentary, I highlight new agents in development for relapsed/refractory platinum-resistant ovarian cancer (PROC).
The Main Challenge in Managing Patients With PROC
PROC has long been an area of unmet need. Although approximately 15% of women with ovarian cancer are cured with frontline therapy using standard therapies, the majority of patients should expect recurrence. Eventually, after exposure to many lines of platinum-containing chemotherapy, ovarian tumors will develop multiple mechanisms of resistance and stop responding to platinum. After a patient’s tumor progresses on platinum, it is usually no longer a therapeutic option.
The original definition of platinum resistance that was established almost 3 decades ago—and is still used in clinical trials today—is that recurrence within 6 months indicates such poor response that nonplatinum agents are needed. However, this cutoff point was chosen when only 4 drugs were available for ovarian cancer, and maintenance treatment had not yet been approved. More recently, tumors that receive initial treatment with platinum therapy may receive maintenance therapy with PARP inhibitors or might be in continuous treatment with bevacizumab, but the 6-month cutoff point is still used to determine whether retreatment with platinum might be beneficial. I expect that this outdated definition will be updated because the agents that are now available are very active and being used in earlier lines of treatment.
Current Standard of Care for Patients With Ovarian Cancer Who Become Refractory to Platinum Therapy Either in First Line or in Later Lines
There is a meaningful clinical difference between tumors that are primary platinum refractory (progression within 3 months of completing frontline treatment) and primary platinum resistant (recurrence or progression within 6 months). Both subsets are challenging to treat. The current standard of care for both is any of the approved nonplatinum therapies, such as weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan with or without bevacizumab. Gemcitabine is a viable option as well but is not approved by the FDA as a monotherapy in this setting.
Unfortunately, both primary platinum-refractory and primary platinum-resistant disease portend a poor prognosis in ovarian cancer, with an expected median survival of less than 2 years. By comparison, for the overall ovarian cancer population, nearly one half will remain alive at 5 years. It is unclear what drives primary resistance or refractoriness to platinum in ovarian cancer, but preliminary studies suggest factors such as cyclin E amplification (CCNE1), MYC overexpression, and homologous recombination proficiency (HRP), also known as negative for homologous recombination deficiency (HRD). These markers tend to cluster in patients with platinum resistance but are not absolute indicators of resistance. Some patients with CCNE1 amplification do just fine, for instance. Nevertheless, patients with ovarian cancer who no longer respond to platinum represent a very high unmet need.
Patients are defined as having acquired platinum resistance if they recur within 6 months after their second, third, or even fourth platinum rechallenge. Some physicians consider platinum resistance a spectrum, and I think it is a tumor type we need to understand better. Of importance, ovarian cancer that becomes resistant to second-line platinum vs fourth-line platinum tends to behave more aggressively and have a worse prognosis as the disease progresses.
BRCA Mutations or HRD as Predictive Biomarker for Platinum Sensitivity in Ovarian Cancer
Ovarian tumors that have mutated BRCA and tumors that are HRD tend to respond to platinum agents longer, receive more lines of platinum therapy, and eventually can develop acquired platinum resistance. However, it has been noted in clinical trials that some patients with ovarian cancer who respond to second-line or third-line platinum therapy can respond even if they are HRP. This means that HRD is not a perfect marker of sensitivity to platinum, but nevertheless, it does indicate tumors that have more deficient DNA repair capability.
Antibody–Drug Conjugates in Development for PROC
Among the many drug classes being evaluated for platinum-resistant ovarian cancer, I am particularly enthused about antibody–drug conjugates (ADCs). The 2 farthest along in clinical development are mirvetuximab soravtansine and upifitamab rilsodotin.
Mirvetuximab soravtansine targets the folate receptor α (FRα), which is nearly ubiquitously expressed in high-grade serous ovarian cancer, albeit at varying levels. It works best in patients with high FRα expression. Mirvetuximab soravtansine delivers a potent tubulin-targeting maytansinoid (DM4) to ovarian tumor cells via FRα.
SORAYA was a single-arm phase III study of mirvetuximab soravtansine in patients with PROC, 1-3 prior regimens including bevacizumab, and high FRα expression (N = 106). Patients received mirvetuximab soravtansine 6 mg/kg weekly, with dosing adjusted per ideal body weight. This patient group has few options after bevacizumab, and chemotherapy monotherapy has a response rate of only approximately 15%. Results showed an ORR of 32% with a median duration of response of 7 months. This is clearly an active, well-tolerated agent and I am optimistic the FDA will grant it accelerated approval. Of note, MIRASOL is an ongoing confirmatory randomized phase III study of mirvetuximab soravtansine in the same population, except previous bevacizumab is not required.
I have treated more than 100 patients with mirvetuximab soravtansine, and most of them report feeling better on this ADC than on chemotherapy. Of importance, there’s no hair loss, very minimal effect on blood counts (ideal for platinum-resistant patients with low blood counts), and far less neuropathy than with paclitaxel. However, mirvetuximab soravtansine and certain other ADCs are associated with ocular toxicity, and patients need to be made aware of this risk. This usually occurs after cycle 2 and can include vision disturbances, dry eyes, and blurry vision, but only rarely eye pain. Ocular toxicity can be kept at a low grade with lubricating eyedrops and steroid eyedrops and occasionally dose modification of mirvetuximab soravtansine. In trials to date, and in my clinical experience, fewer than 1% of patients discontinue mirvetuximab soravtansine because of ocular toxicity.
Oncologists need to have a partnership with local ophthalmologists and optometrists so that patients with symptoms are rapidly evaluated. Patients need to consistently take their eyedrops and know to notify their care team if they develop ocular toxicity.
Upifitamab rilsodotin is an ADC that targets the sodium-dependent phosphate transport protein NaPi2b. The ongoing first-in-human phase Ib/II study of upifitamab rilsodotin in multiple tumor types likely to express NaPi2b has completed the dose-escalation and dose-expansion portions. In early results from the dose-expansion cohort presented at the Society of Gynecologic Oncology 2022 meeting, the overall response rate was as high as 44% in patients with ovarian cancer and high NaPi2b expression and as low as 17% with any NaPi2b expression level (depending on dose). The UPLIFT segment of this study is evaluating upifitamab rilsodotin 36-80 mg/m2 in patients with high-grade PROC and any NaPi2b expression level and is intended as a registrational study to support accelerated approval. The phase I/II UPGRADE trial (NCT04907968) and the phase III UP-NEXT trial (NCT05329545) are evaluating upifitamab rilsodotin in patients with platinum-sensitive and recurrent platinum-sensitive ovarian cancer, respectively.
Other Novel Agents in Development for Previously Treated Ovarian Cancer
Numerous ongoing clinical trials are evaluating novel agents in combination with weekly paclitaxel for the treatment of ovarian cancer. The phase III OVAL study is assessing the addition of the anticancer viral gene therapy ofranergene obadenovec to weekly paclitaxel in patients with recurrent PROC (NCT03398655). Although results showed no benefit to adding ofranergene to paclitaxel, the median progression-free survival of approximately 5.3 months highlights the power of weekly paclitaxel. I think this study is particularly important regarding patients with PROC because it really does establish what your best option is in the platinum‑resistant setting once you are beyond bevacizumab, other than mirvetuximab soravtansine, which I think is better.
Other novel agents are making their way through clinical trials in various ovarian cancer settings. These include the ADC farletuzumab ecteribulin (MORAb-202) that combines the FRα antibody farletuzumab with eribulin mesylate, a microtubule inhibitor. In the dose-expansion phase of a recent phase I study in PROC (N = 45), the overall response rate was 25% to 52% with antitumor activity seen across FRα expression levels. A multicenter phase I/II trial is underway in ovarian cancer and other solid tumors (estimated N = 55; NCT04300556).
REGN5668 is a bispecific antibody that targets both MUC16 and CD28. It is currently being evaluated in a phase I/II study in combination with the PD-1 antibody cemiplimab or the MUC16/CD3-targeted bispecific antibody ubamatamab in patients with recurrent ovarian cancer (NCT04590326). Ubamatamab is also being evaluated alone or with cemiplimab in a phase I/II study in recurrent ovarian cancer (estimated N = 554; NCT03564340).
Your Thoughts?Have you used any of these novel agents in your clinic to treat patients with PROC? Answer the polling question and share your experience in the comment box below.