The recent approval of mirvetuximab soravtansine-gynx is a testament to the emerging benefit of antibody-drug conjugates in recurrent ovarian cancer. Other agents of this class are now eliciting excitement as they demonstrate high response rates in a population with unmet clinical needs, according to two studies reported at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.
Kathleen Moore, MD, of the Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, reported a nearly 50% response to raludotatug deruxtecan (R-DXd), a novel antibody-drug conjugate targeting cadherin 6 (CDH6), in a phase I trial in heavily pretreated, platinum-resistant advanced ovarian cancer.1 “R-DXd is the first [antibody-drug conjugate] targeting CDH6 to demonstrate promising signals of efficacy in ovarian cancer,” Dr. Moore said.
Kathleen Moore, MD
Vicky Makker, MD
Carol Aghajanian, MD
In another study of patients with HER2-expressing gynecologic malignancies, Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center, described the benefits achieved with fam-trastuzumab deruxtecan-nxki (T-DXd). In the DESTINY-PanTumor02 trial, overall response rates to T-DXd were 45.0% in ovarian cancer, 50.0% in cervical cancer, and 57.5% in endometrial cancer.2 “These data suggest T-DXd is a potential treatment for patients with these gynecologic HER2-expressing tumors who have disease progression, including those with varied prior treatment regimens and with or without disease-relevant biomarkers,” Dr. Makker said.
Invited discussant, Carol Aghajanian, MD, of Memorial Sloan Kettering Cancer Center in New York, called the response rates of approximately 50% with these antibody-drug conjugates “incredibly exciting.”
Promising Phase I Results for R-DXd
CDH6 is a transmembrane protein that is overexpressed in 65% to 85% of epithelial ovarian cancers, making it a promising target for an antibody-drug conjugate. R-DXd is composed of a humanized anti-CDH6 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload.
Dr. Moore presented the results of a first-in-human phase I study of R-DXd that enrolled patients with mostly platinum-resistant advanced or metastatic ovarian cancer not amenable to standard therapy and who were not selected by tumor CDH6 expression.1 The patients received escalating doses (1.6–9.6 mg/kg), after which a second dose expansion cohort received 4.8 to 8.0 mg/kg of R-DXd. Dr. Moore presented findings for 45 patients treated (37 evaluable) with 4.8 to 6.4 mg/kg.
The confirmed objective response rate was 48.6%, which included 1 complete response and 17 partial responses; 18 patients achieved stable disease, yielding a disease control rate of 97.4%. The median duration of response was 11.2 months; median time to response was short, 5.7 weeks, and median progression-free survival was 8.1 months. “Almost every patient who participated in this trial had some reduction in tumor measurement,” she noted.
The safety profile of R-DXd was manageable and comparable to the safety profiles of other deruxtecan antibody-drug conjugates. The most common treatment-related adverse events of any grade were nausea (57.8%), vomiting (40.0%), fatigue (37.8%), and diarrhea (31.1%). Grade ≥ 3 toxicities were reported in 44.4% of patients, including anemia in 15.6%. Drug-related interstitial lung disease/pneumonitis, a toxicity of special concern with antibody-drug conjugates, developed in two patients, both grade 2; at the 8-mg/kg dose level (not part of this analysis), however, grade 5 interstitial lung disease events did occur, she noted. R-DXd discontinuations were noted in 11.1%, dose interruptions in 31.1%, and dose reductions in 15.8%, “speaking to the well-tolerated nature of this agent,” Dr. Moore said.
“The preliminary antitumor activity of R-DXd is promising in heavily pretreated patients,” she concluded. “Preliminary biomarker assessment indicates that antitumor activity is observed in tumors harboring a wide range of CDH6 expression, with no correlation between CDH6 expression and response observed to date. These data support further clinical evaluation of R-DXd in patients with ovarian cancer.”
As such, a phase II/III study of R-DXd in patients with platinum-resistant ovarian cancer, REJOICE-Ovarian01, has been initiated globally. Patients with platinum-resistant disease and one to three prior lines of therapy (including mirvetuximab soravtansine if indicated) will be randomly assigned to one of three doses, with the recommended phase III dose being compared with treatment of physician’s choice. Overall repsonse rate will be the endpoint for phase II, and progession-free survival will be the endpoint for phase III.
T-DXd in DESTINY-PanTumor02
The phase II open-label multicenter DESTINY-PanTumor02 trial of T-DXd included 267 patients with a variety of solid tumors who had HER2 expression (immunohistochemistry [IHC] 3+ or 2+, with some 1+ in the cervical cohort) and at least two prior lines of treatment, which could include HER2-targeting therapy.2 There were 40 patients each in the endometrial, cervical, and ovarian cancer cohorts. Dr. Makker presented response rates (the primary endpoint) and subgroup analyses by HER2 status and other biomarkers.
“Antitumor activity was observed in heavily pretreated patients across HER2 IHC expression levels and in in situ hybridization–positive and plasma ERBB2 tumor–amplified subgroups,” Dr. Makker said.
Response rates overall and in the IHC 3+ subsets were 57.5% and 84.6%, respectively, in the endometrial cancer group, 50.0% and 75.0% in the cervical cancer group, and 45.0% and 63.8% in the ovarian cancer group.
“Responses were seen regardless of the number of prior lines, with rates across cohorts ranging from 41% to 65% in patients with two or more prior treatments. Also, activity was evinced regardless of treatment with prior HER2-targeting therapy [or TOP1 inhibitors] and, importantly, regardless of biomarker status,” she reported, referring to levels of PD-L1, mutated BRCA or mismatch repair–deficiency (MMR) genes, or CA-125 levels.
The safety findings were consistent with the established profile for T-DXd. Interstitial lung disease or pneumonitis of any grade occurred in 132 patients (10.8%), all grade 1 or 2 except for one grade 5 event. “Interstitial lung disease or pneumonitis remains an important identified risk. Proactive monitoring, early detection, and active management are critical in preventing high-grade events,” Dr. Makker emphasized.
Expert Point of View
“We have two promising new antibody-drug conjugates. This is wonderful news for our patients,” said the session’s invited discussant, Dr. Aghajanian, Chief of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, New York. “For raludotatug deruxtecan (R-DXd), we look forward to further biomarker analysis and the phase II and III results. For [fam-]trastuzumab deruxtecan[-nxki] (T-DXd), which is further developed, we look forward to implementing it in our clinics and to defining which endometrial, cervical, and ovarian cancer subtypes are most likely to be biomarker-positive.”
The early-phase trial of R-DXd “showed an incredible activity level” in recurrent, heavily pretreated ovarian cancer, she said. “The confirmed overall response rate of nearly 50% is incredibly exciting in this population with an unmet medical need.” Dr. Aghajanian lauded the investigators for evaluating a “really representative population … with half of the patients aged 65 and older, who are the patients we are seeing in clinic. This is an important finding.” She predicted the plans for dose optimization and biomarker evaluation in the phase II and III trials will be “very informative.”
For T-DXd, the objective response rates in the study (45.0%–57.5%) “are also just incredible,” she continued. “We see this across IHC 2+ and 3+ tumors and regardless of prior therapies.” She called the “dive into biomarker status” an “important endeavor” that should become a part of future studies, including phase III confirmatory trials.
“After hearing these results, some questions come to mind,” Dr. Aghajanian said: “Are we going to start testing all our gynecologic oncology patients for HER2 status? Can our pathology departments handle that kind of volume? And how do we select which patients should move forward with testing?” The unique characteristics of the various gynecologic cancers will necessitate a refinement of biomarker testing to identify subsets of patients most likely to benefit from these emerging targeted antibody-drug conjugates.
DISCLOSURE: Dr. Moore reported financial relationships with AstraZeneca, Aadi, Blueprint Medicines, Duality, BioNTech, Eisai, GSK, Genentech, Daiichi, Immunogen, Janssen, Merck, Mersana, Verastem Oncology, Novartis, VBL Therapeutics, Zentalis, Regeneron, Exelixis, Gilead, GOG Partners, PRIME Therapeutics, PER, Great Debates and Updates, and Daiichi Sankyo. Dr. Makker reported financial relationships with Eisai, Merck, Clovis Oncology, Cullinan Oncology, DualityBio, Faeth Therapeutics, GlaxoSmithKline, Immunocore, iTeos Therapeutics, Karyopharm Therapeutics, Eli Lilly, Mereo BioPharma, MorphoSys, MSD, Novartis, Regeneron, Sutro Biopharma, and Zymeworks. Dr. Aghajanian reported financial relationships with Artios Pharma, AstraZeneca, and Merck.
REFERENCES
1. Moore K, Philipovskiy A, Harano K, et al: Raludotatug deruxtecan monotherapy among patients with previously treated ovarian cancer: Subgroup analysis of a first-in-human phase I study. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Presented March 16, 2024.
2. Makker V, Oaknin A, Manso L, et al: Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Biomarker and subgroup analyses from the cervical, endometrial, and ovarian cancer cohorts of the DESTINY-PanTumor02 study. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Presented March 16, 2024.
