Kathleen N. Moore, MD, MS, discusses the clinical implications of the potential FDA approval of mirvetuximab soravtansine, observations from other antibody-drug conjugates under investigation in clinical trials, and the rationale of examining PARP inhibitor–based combinations in ovarian cancer.
Kathleen N. Moore, MD, MS
Although the antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) is the closest to potential FDA approval for the treatment of patients with folate receptor alpha (FRα)–high, platinum-resistant ovarian cancer, other ADCs are also generating promise in the ovarian cancer space, such as upifitamab rilsodotin (UpRi; XMT-1536) and DS-6000a, according to Kathleen N. Moore, MD, MS.
“We are seeing this pipeline of ADCs come to fruition in ovarian cancer, which is exciting. This is a way to give potent molecules of chemotherapy to tumors with a very differentiated safety profile [compared with] regular chemotherapy. This provides a great alternative for patients who need active drugs in the [platinum-resistant] setting,” Moore said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on ovarian cancer, which she chaired.
In the interview, Moore discussed the clinical implications of the potential FDA approval of mirvetuximab soravtansine, observations from other ADCs under investigation in clinical trials, and the rationale of examining PARP inhibitor–based combinations in ovarian cancer. Moore is an associate director of Clinical Research at the Oklahoma University (OU) Health Stephenson Cancer Center, the director of the Oklahoma TSET Phase I Program, and a professor in the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine in Oklahoma City.
Moore: ADCs are a class of drug that allows us to [direct] the highly potent molecules of chemotherapy, similar to standard systemic chemotherapies that we may already use, directly to tumor cells via surface antigens that are either exclusively expressed on the tumor cell or markedly overexpressed on the tumor cell as related to normal tissue. [ADCs] are targeted therapy, but they are targeted chemotherapy that we are developing. There are a number [of ADCs] that are already FDA approved in hematologic malignancies and in solid tumors, most notably in breast cancer, where we have seen tremendous responses and benefit from HER2-targeting ADCs. That possibility is on the doorstep for us in ovarian cancer, where we have a number of ADCs in development in clinical trials.
The ADC that is closest to FDA approval is mirvetuximab soravtansine, which targets FRα. FRα is a transmembrane protein that is ubiquitously found on high-grade serous ovarian cancer, and it is found in about 40% of high-grade serous ovarian cancer, which is the population that the current indication [for mirvetuximab soravtansine] will address. The study that is before the FDA right now is the SORAYA trial, which was a single-arm trial that demonstrated a 32.4% overall response rate and a durable duration of response of 6.9 months amongst tumors that were platinum resistant, bevacizumab [Avastin] pretreated, and exposed to 1 to 3 prior lines of therapy.
The confirmatory trial for mirvetuximab soravtansine will be the phase 3 MIRASOL trial [NCT04209855], a randomized study with similar inclusion [to SORAYA], although it does not require prior bevacizumab. Patients will be randomized to [mirvetuximab soravtansine] or investigator’s choice of chemotherapy. That trial is expected to read out in the first quarter of 2023.
We are awaiting the FDA’s decision on SORAYA and mirvetuximab soravtansine. The Prescription Drug User Fee Act date is November 28, 2022. We are hoping it will be earlier, but that is when we should know [about potential FDA approval]. Mirvetuximab soravtansine will hopefully be available soon, and providers can start using the companion diagnostic to send archival tissue for FRα testing, which is an immunohistochemistry test, to see if patients are eligible.
Several [ADCs] are coming right behind [mirvetuximab soravtansine]. Up next is likely UpRi, which is an ADC targeting the sodium-dependent phosphate transporter, which we call NaPi2b. UpRi has been tested in patients with platinum-resistant ovarian cancer who were biomarker unselected [in the phase 1/2 UPLIFT trial (NCT03319628)] and [showed] a nice response rate in data presented by Debra Richardson, MD, FACS, FACOG, of OU Health, at the 2022 SGO Annual Meeting on Women’s Cancer. We will see what the response is across all comers vs a biomarker-selected population, then what that application [for accelerated approval] looks like as data mature.
The confirmatory trial for that agent is called the [phase 3] UP-NEXT trial [NCT05329545], which is evaluating the agent as maintenance therapy in the platinum-sensitive setting. Here they are restricting [enrollment] to patients who are NaPi2b high, which is a little more common than FRα high, [occurring in] about two-thirds of patients with high-grade serous ovarian cancer. That study has just activated and is up and running.
[It is also worth noting] that mirvetuximab soravtansine has moved into [investigation] in a platinum-sensitive population with the [phase 3] GLORIOSA trial [NCT05445778], evaluating [the ADC] in combination with bevacizumab maintenance vs bevacizumab alone for those with FRα-high disease.
Daiichi Sankyo has an ADC with a different payload than either UpRi or mirvetuximab soravtansine, both of which have microtubule toxin–variety conjugates. The Daiichi Sankyo compound is DS-6000a, which is a topoisomerase inhibitor and targets cadherin. Data were presented at the 2022 ASCO Annual Meeting and look good.
Moreover, we are expecting data to read out with fam-trastuzumab deruxtecan-nxki [Enhertu] in HER2-positive ovarian cancer in the phase 2 DESTINY-PanTumor02 trial [NCT04482309]. We are anxiously awaiting that readout and are anticipating that it will look promising. [HER2-positive disease] is a small subset of ovarian cancer, but it will be important.
TROP2, tissue factor, and ALPPL2 are other antigens that all have differentiated ADCs [under investigation] in phase 1 trials.
Navicixizumab is a novel monoclonal antibody that targets DLL4, which is part of notch signaling in VEGF. It has been tested as monotherapy in a phase 1 trial [NCT02298387], as well as in combination with weekly paclitaxel in a phase 1 trial [NCT03030287] in the platinum-resistant setting.
Moreover, navicixizumab has a novel biomarker for potential selection of patients who will benefit from this agent, according to data presented at the European Society of Gynecologic Oncology in 2021. A phase 3 trial [NCT05043402] is coming and will hopefully launch in 2023 in the platinum-resistant space with weekly paclitaxel vs weekly paclitaxel plus navicixizumab.
[Enrollment] will not be selected by the biomarker yet because [the biomarker] has to be validated first. There is a novel trial for this registration-enabling study that will allow us to hopefully validate that. It is exciting to be able to identify the tumors that are more or less likely to respond to an agent so we can optimize who gets that agent and when.
PARP inhibitors are firmly established as frontline maintenance for patients in response to chemotherapy, following frontline paclitaxel and carboplatin. That is where PARP inhibitors are most effective and where the current studies would indicate that they have their best efficacy. If a patient missed that opportunity, is platinum-sensitive, and responds again to platinum-based chemotherapy, then they should receive [the PARP inhibitor] as platinum-sensitive maintenance. Unless patients have missed both of those opportunities and have biomarkers indicating that they would respond to PARP inhibitors, [we are not recommending] that PARP inhibitors are used instead of chemotherapy in treatment.
Combinations are of interest, and there are several under study to try to address whether we can improve the response or duration of benefit of PARP inhibitors amongst biomarker-negative tumors, such as BRCA wild-type or homologous recombination deficient [HRD] groups, where there still is a benefit to PARP; however, that benefit is not as robust as it is for tumors that are biomarker positive. Or, for tumors that have progressed on a PARP inhibitor, can you re-sensitize to the combination?
A number of these combinations have been tested, with promising results presented by Shannon Westin, MD, MPH, of the University of Texas MD Anderson Cancer Center, on [the combination of] olaparib [Lynparza] and adavosertib, a Wee1 kinase inhibitor, in the phase 2 EFFORT trial [NCT03579316]. This trial was conducted in patients who had PARP-resistant tumors with response rates of 39% in the combination arm in patients who were BRCA wild-type. That is a strong signal of efficacy that is plagued a bit by the toxicity of the combination. There are ongoing trials, led by Timothy Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center, looking at how to sequence [olaparib and adavosertib], so that may come back in the future.
We have seen preclinical and early clinical work by Fiona Simpkins, MD, of Penn Medicine, and Stephanie Wethington, MD, MSc, of Johns Hopkins Medicine, with the combination of olaparib, and ceralasertib [AZD6738], which is an ATR inhibitor. [This combination has also produced] a strong signal of efficacy but was plagued by sequencing issues that have kept it from moving forward.
The combination with the most momentum right now is olaparib, plus the PI3K inhibitor copanlisib (Aliqopa). This is based on the work of major National Cancer Institute–designated cancer centers. [Work] coming out of Dana-Farber Cancer Institute has identified the idea of a metabolic intervention with PI3K inhibition by inducing DNA damage repair deficiency in a setting where it did not otherwise exist. For example, in a PARP-resistant tumor where the tumor has become resistant to PARP inhibition and good at fixing its DNA, you reintroduce that deficiency that makes [tumors] more vulnerable to PARP inhibitors or potentially other things. This [method] is irrespective of whether there’s a PI3K mutation, because it makes no difference. It’s a complete metabolic intervention to induce this loss of DNA repair capability.
That has been demonstrated nicely in phase 1 [NCT01623349] work in platinum-resistant ovarian cancer, published in The Lancet by Panagiotis A. Konstantinopoulos, MD, PhD, of Dana-Farber Cancer Institute. There is a study that was just launched through the National Clinical Trials Network called the [phase 2] NRG-GY029 trial [NCT05295589] in [patients who are] platinum resistant and PARP exposed. [This trial is evaluating] copanlisib plus olaparib vs chemotherapy with a progression-free survival [primary] end point.
We are expecting a decision on mirvetuximab soravtansine any day, although the deadline is November 28, 2022. There is widespread familiarity with mirvetuximab soravtansine in the United States because of the number of trials that have been ongoing.
Investigators have some familiarity with mirvetuximab soravtansine, but as it rolls out nationwide, as we hope it will, it does require FRα testing. There will be a companion [immunohistochemistry] diagnostic that takes about a week to turn around. Patients’ tumors must be FRα high to participate at this time. The drug is given intravenously every 3 weeks, and it has [negligible] hematologic toxicity. There is no hair loss and far less neuropathy than weekly paclitaxel, which was a comparator. Though, [mirvetuximab soravtansine] still has low-grade neuropathy.
It does require premedication with antiemetics. If those are used, patients do quite well from a nausea standpoint, and there is common but low-grade diarrhea that patients need to be warned about so they can use over-the-counter medications.
The biggest adverse effect [AE] that differentiates mirvetuximab soravtansine is ocular toxicity. About 50% of patients will have some manifestation of anything from dry eyes to blurry vision. We do have steroid eyedrops that are used as mitigation strategies for ocular toxicity, and there will be required ophthalmologic exams, at least early on, to monitor eye [toxicities]. In almost 500 patients treated, we have seen full reversibility of the ocular toxicity, so it is not permanent. If it does happen, it is low grade, and we usually hold the drug, [the ocular toxicity resolves], and then depending on how severe the AE was, we will restart the drug without further issue, or sometimes we will dose modify and then restart.
Only 1% of patients discontinued mirvetuximab soravtansine because of eye toxicity. We take the eye toxicity seriously, and providers need to have a relationship with an ophthalmologist or an optometrist, and we must counsel patients about using preservative-free lubricating eyedrops and steroid eyedrops to mitigate that toxicity. We want to preserve [vision], and we can, as this is reversible and should not be limiting for anyone except patients that have baseline corneal abnormalities, which is uncommon. However, if patients do have baseline corneal abnormalities, they are excluded from receiving mirvetuximab soravtansine. Again, that is very uncommon, and we do baseline eye exams to rule that out.
Oncologists are used to dealing with ocular toxicities, since several medications that are FDA approved have ocular toxicities. I have zero concerns that [ocular toxicities] will be problematic [for patients who receive mirvetuximab soravtansine].
We have an enormous portfolio of clinical trials open for women with either frontline or recurrent ovarian cancer that are either built on standard of care or in places where standard of care is not expected to work well. Just because [a treatment] is the standard of care does not mean [the treatment] works [in all patients], and this is often a hard thing to understand.
We have a lot of options other than [standard of care], including a palette of ADCs that are in clinical trials, several novel immunotherapies, and other build-ons from PARP inhibitors and DNA mismatch repair deficiency–inducing drugs. There are a number of trials available for our patients to consider. When they are considering options in the recurrent setting, they can make informed choices about what sounds best to them.
As a medical oncologist who takes care of women with ovarian cancer, [I can say our patients] are wonderful. We are doing things together that are curing more patients in the frontline. We have seen indications of that from recent meetings. We are certainly doing things together that are prolonging overall survival, due to better supportive care and access to these novel drugs that are beneficial and provide effective options for patients.
These advances all come through participation in clinical trials and referral to clinical trial centers. We have a great community of providers taking care of women with ovarian cancer who are willing to do this in the best interest of their patients. This is how we move the field forward and figure out which of these medicines work. Everyone should have some indications of what trials are open, and that is how we ultimately improve equitable access to patients.