ADCs Begin to Carve a Place in the Treatment Landscape for Ovarian Cancer

Patients with recurrent, platinum-resistant ovarian cancer have limited effective treatment options available, but a class of targeted antibody-drug conjugates (ADCs) represent a promising development for this population.¹

The treatment landscape for patients who experience disease progression following platinum-based chemotherapy include rechallenging with platinum chemotherapy or administering alternative targeted therapies, such as PARP inhibitors or VEGF inhibitors including bevacizumab (Avastin). However, there are limitations for these therapies including as use in their indicated use in the maintenance setting and/or the required presence of BRCA mutations or homologous recombination deficiency [HRD] status for approved PARP inhibitors including olaparib (Lynparza), rucaparib (Pluvicto), and niraparib (Zejula). Further, agents such as bevacizumab are contraindicated for patients at risk of gastrointestinal perforation.²

“[Approximately] 80% of patients with advanced ovarian cancer [have disease] recurrence,” Bradley J. Monk, MD, said in an interview with OncologyLive^®. “When they recur, we look at whether they recur in a setting that is eligible for platinum. We used to say that’s 6 months, or 183 days. We don’t say that anymore, because the most active agent in platinum-resistant recurrent ovarian cancer is platinum [chemotherapy]…. There’s good evidence that platinum doublets are better than single agents.” Monk is a professor of obstetrics and gynecology at The University of Arizona College of Medicine, Phoenix.

In an interview with OncologyLive^®, Ursula A, Matulonis, MD, agreed with Monk, adding that retreatment is appropriate in some instances in combination with carboplatin, bevacizumab, or alone. “We’re learning that although patients may technically have a platinum-resistant ovarian cancer, meaning that they have progression within 6 months of last receipt of platinum, that you can reuse platinum again in the future if the patient's cancer responded to platinum.” Matulonis said. “Sometimes patients need a therapy to get them out of trouble [because] they have a bowel obstruction or symptomatic ascites. Reuse of platinum, even in the platinum-resistant setting, may be used and there are guidelines around this, but it hasn’t quite moved into what the FDA would consider standard paradigms for ovarian cancer.” Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilson Family Chair at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

With poor prognosis and survival outcomes limited to 1 year post recurrence, investigators have focused on developing agents to fulfill the unmet need in platinum-resistant disease.

Biomarker-directed therapeutics have begun to gain traction in the field as actionable markers that would yield demonstrative results for this patient population. “[Over time] all patient if they recur, become platinum-resistant or ineligible,” Monk said. “That is the highest unmet medical need and the most exciting agent or agents in that are in development are antibody-drug conjugates.”

Establishing the Path Forward for ADCs in Ovarian Cancer

“The underlying thought behind ADCs is compelling. You have a very targeted therapy that goes to a specific cancer cell that overexpresses something that no other cells in the body do. The ADC delivers toxic poisons that we couldn’t normally give a patient [directly to the cancer cells],” Robert Wenham, MD, MS, said in an interview with OncologyLive^®.

“One of the Achilles’ heels of this program for several years was what links the antibody with the target to the poison itself. [Technological advances have made] linkers better so they release the poison when you want to. That has been what’s brought ADCs forward, because there have been a lot smart [individuals] working on this for a very long time, but it is the linker mechanism that has made this viable,” said Wenham, who is gynecologic oncologist and the chair of the Gynecologic Oncology Program at Moffitt Cancer Center in Tampa, Florida.

The development and success of ADCs in hematologic malignancies and breast cancer has resulted in their exploration in other solid tumors including ovarian cancer. Comprised of an antibody directed against a tumor antigen, a toxic payload, and a linker, investigators have sought to develop ADCs targeted against overexpressed antigens on tumor cells but not on normal tissue.³

“[ADCs] are really interesting. They have the potential to change how we practice,” John Nakayama, MD, said in an interview with OncologyLive^®. Nakayama is an assistant professor, Department of Reproductive Biology at Case Western Reserve University in Cleveland, Ohio. “You have a monoclonal antibody, and then you have a linker, and then you have a payload. In theory, using that antibody, you can go after a particular a particular antigen to help localize what you are doing. And the idea behind that is if you’re localizing [the target], you can limit off-target effects [allowing you to] use a payload that’s more toxic, because it’s so much more targeted. That is precision medicine at its finest.”

In ovarian cancer, targets with agents under development include folate receptor alpha (FRα), NaPi2B, tissue factor, and others.³

“In ovarian cancer there are not [many] targetable mutations except for BRCA mutations [and the] biomarkers that we use in in ovarian cancer are genetic ones, and that can be HRD. The other markers we use histology and then platinum sensitivity or resistance,” Matulonis said. “But if I think that tissue expression, extracellular expression of proteins, [that] will allow a whole new therapy to be used, and that would be ADCs.”

ADCs In Development

In September 2021, the FDA approved the tissue factor–directed antibody and microtubular inhibitor conjugate, tisotumab vedotin-tftv (Tivdak), for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.⁴ The approval was based on data from the phase 2 innovaTV 204 trial (NCT03438396). Among 101 patients the objective response rate was 24% (95% CI, 15.9%-33.3%), with a median duration of response of 8.3 months (95% CI, 4.2-not reached).

“Tissue factor is expressed on almost all cervical cancer cells,” Monk said adding that this eliminates the need to test tumors for markers.

Only one ADC has thus far had data read out from a phase 3 evaluation. Mirvetuximab soravtansine, an ADC with a FRα-binding antibody, a cleavable linker, and maytansinoid DM4 payload, was evaluated in the single-arm phase 3 SORAYA trial (NCT04296890).⁵ Investigators assessed the efficacy of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer who had received 1 to 3 prior lines of therapy, experienced disease recurrence within 6 months of the last platinum-based regimen, and who have high FRα expression. This was defined as at least 70% of the cancer cells having 2+ or higher staining of FRα based upon the PS2 method.

Among 105 efficacy-evaluable patients the investigator-assessed overall response rate was 32.4% (95% CI, 23.6%-42.2%), including a 4.8% complete response rate. The disease control rate of 51.4% (95% CI, 41.5%-61.3%). Additionally, a 71.4% tumor reduction rate was reported. The investigator-assessed median duration of response was 6.9 months (95% CI, 5.6-9.7) with a median time to response of 1.5 months (range, 1.0-5.6).⁵

The median investigator-assessed progression-free survival was 4.3 months (95% CI, 3.7-5.2). The median overall survival data were immature, but descriptive data showed a median 13.8-month survival (95% CI, 12.0-not estimable).⁵

“We see with mirvetuximab soravtansine for patients [whose disease] overexpresses FRα, that is a good target because it’s overexpressed in the vast number of ovarian cancers. We’re seeing responses [with mirvetuximab soravtansine], even in combination, that are making us excited about potentially either adding to it chemotherapy or replacing chemotherapy altogether,” Wenham said.

Based on these data the FDA granted priority review to the biologic license application for mirvetuximab soravtansine. The agency is expected to make a decision on the application by November 28, 2022.⁶ Further, the phase 3 MIRASOL trial (NCT04209855) will assess mirvetuximab soravtansine vs investigator’s choice chemotherapy to confirm these findings.⁷

“We are seeing very positive results with ADCs as a novel way of targeting ovarian cancer,” Matulonis said. “I see this as being a very fruitful [part of the] treatment paradigm, moving forward, starting with mirvetuximab.”

Finally, upifitamab rilsodotin (UpRi), which targets NaPi2b, a sodium-dependent phosphate transport protein is under investigation in this patient population. Other NaPi2b agents have not reached clinical success in prior development pursuits, however, in August 2020, UpRi received a fast-track designation from the FDA for the treatment of patients with platinum-resistant high-grade serous ovarian cancer who have received up to 3 prior lines of systemic therapy or those treated with 4 prior lines of systemic therapy regardless of platinum status.⁸

The agent is under evaluation in the phase 1/2 UPLIFT registration trial (NCT03319628), with plans to enroll approximately 100 patients with platinum-resistant ovarian cancer with high NaPi2b expression and approximately 180 patients with platinum-resistant ovarian cancer in the pivotal experimental cohort. Early efficacy data from the trial showed that among the 75 evaluable patients, the ORR was 23%, including 2 patients who achieved a complete response. Of note, among 38 patients with NaPi2b high expression, defined as a tumor proportion score of at least 75, the confirmed ORR was 34% with a CR rate of 5% and a PR rate of 29%.⁹

The phase 3 confirmatory trial UP-NEXT (NCT05329545) will compare UpRi with placebo as postplatinum maintenance therapy for patients with recurrent, platinum-sensitive, ovarian cancer. The trial is not yet recruiting.10 Additionally, investigators are looking at UpRi in combination with carboplatin in the phase 1/2 UPGRADE trial (NCT04907968), an umbrella study enrolling patients with platinum-sensitive ovarian cancer.

Testing and the Future of ADCs in the Landscape

Monk noted that testing for these markers will play a crucial role in getting patients to the right treatments at the right time. “The good news is, is that the FRα is relatively common, [approximately] 40% or so, and [if mirvetuximab soravtansine is] approved by the FDA, it will be integrated into all the biomarker platforms.” He noted that this will allow clinicians to have the report of actionable targets in front of them when they have discussions with their patients following platinum resistance.

Matulonis added that biopsies are critical at the time of diagnosis. “If a patient presents with advanced disease, which most of our patients do, and that patient is not deemed operable by a gynecologic oncology surgeon, then a biopsy must be done.”

Matulonis added that for FRα in particular, the target is still retained upon recurrence and therefore and additional biopsy is not needed at the time. “If there’s any question then a repeat biopsy could be done to assure the oncologist and the patient that that target is still present. But FRα has been shown to be retained at the time of recurrence,” she said. “I see this paradigm that as long as the expression of a specific protein or target is present different ADCs could be used.”

Nakayama noted the importance of testing as it will guide decision-making from maintenance and earlier treatment modalities. “I am a firm believer in both germline testing and somatic testing. Because that will help determine, you know, what is, you know, is this person candidate for maintenance therapy? And if so, which one? What I learned from experience… is be very cognizant of what you’re testing is telling you is extremely important.”

Nakyama supported that sentiment adding, “I think anything that we can do to build up our armamentarium in the platinum resistance setting is of critical value.”

References

1. Calo CA, O’Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2021;21(7):875-887. doi:10.1080/14712598.2020.1776253
2. NCCN. Clinical practice guidelines in oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 2.2022. Accessed July 19, 2022. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
3. Manzano A, Ocaña A. Antibody-drug conjugates: a promising novel therapy for the treatment of ovarian cancer. Cancers (Basel). 2020;12(8):2223. doi:10.3390/cancers12082223
4. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. Updated September 21, 2021. Accessed July 19, 2022. bit.ly/3upkVAr
5. Matulonis UA, Oaknin A, Pignata S, et al. Mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: characterization of antitumor activity in the SORAYA study. J Clin Oncol. 2022;40(suppl 16):5512. doi:10.1200/JCO.2022.40.16_suppl.5512
6. ImmunoGen announces acceptance of biologics license application for mirvetuximab soravtansine in ovarian cancer by US Food and Drug Administration with priority review. News release. ImmunoGen, Inc. May 23, 2022. Accessed July 19, 2022. bit.ly/3MV4Amt
7. 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). ClinicalTrials.gov. Updated June 16, 2022. Accessed July 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04209855
8. Mersana Therapeutics receives FDA fast track designation for XMT-1536 for the treatment of patients with platinum-resistant ovarian cancer. News release. Mersana Therapeutics. August 11, 2020. Accessed July 19, 2022. bit.ly/3viEWLy
9. Interim data from the ovarian cancer expansion cohort and next steps for UpRi development plan. Mersana Therapeutics. September 10, 2021. Accessed July 19, 2022. bit.ly/3KchsM6
10. Upifitamab rilsodotin maintenance in platinum-sensitive recurrent ovarian Cancer (UP-NEXT) (UP-NEXT). ClinicalTrials.gov. Updated April 22, 2022. Accessed July 19, 2022. https://clinicaltrials.gov/ct2/show/NCT05329545

Supported by Immunogen. Content independently developed by OncLive.