Platinum resistance occurs in almost all patients whose ovarian cancer recurs. Single-agent chemotherapies are commonly used in this setting, but outcomes are generally poor, leaving a large unmet need for effective treatment. At the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer, investigators unveiled plans for two phase III trials that will evaluate novel agents for the treatment of this challenging malignancy.
Based on encouraging activity in previous small trials, the novel engineered cytokine nemvaleukin alfa will be further assessed in the multicenter phase III ARTISTRY-7 trial, where it will be combined with pembrolizumab for the treatment of patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.1 A selective modulator of the glucocorticoid receptor, relacorilant, is the subject of the phase III ROSELLA trial.2
About Nemvaleukin Alfa
Nemvaleukin alfa in combination with pembrolizumab has been granted Fast Track designation for the treatment of platinum-resistant ovarian cancer by the U.S. Food and Drug Administration, noted Thomas J. Herzog, MD, Deputy Director of the University of Cincinnati Cancer Center and Paul and Carolyn Flory Professor of Obstetrics and Gynecology at the University of Cincinnati College of Medicine, who presented a preview of ARTISTRY-7.1
Thomas J. Herzog, MD
Nemvaleukin alfa is a stable fusion protein that is intrinsically active upon systemic entry and does not degrade into native interleukin-2 (IL-2). IL-2 has both immunosuppressive and immunostimulatory functions, mediated by its interaction with different IL-2 receptor complexes.
Nemvaleukin alfa was designed to harness the validated IL-2 pathway biology, leading to increases in both peripheral and intratumoral immune effector cells. The drug selectively and preferentially binds to the intermediate-affinity IL-2 receptor, activating and expanding antitumor CD8-positive T and natural killer cells, with minimal expansion of T regulatory cells.
“This selectivity may provide enhanced tumor killing and improved safety and tolerability compared with high-dose IL-2,” noted Dr. Herzog.
Phase II Activity
“In clinical studies, responses to nemvaleukin, as monotherapy and in combination with pembrolizumab, were observed in various tumor types, including breast, cervical, head and neck, gastrointestinal, genitourinary, lung, melanoma, and platinum-resistant ovarian cancers,” he said.
When combined with pembrolizumab in a study of platinum-resistant ovarian cancer, the response rate was 28.6%, the disease control rate was 71.4%, and the median duration of response was 53.4 weeks.3 Nemvaleukin alfa was generally well tolerated and did not demonstrate additive toxicity to that of pembrolizumab alone. In the overall population of patients with a variety of solid tumors, the most frequent grade 3 or 4 treatment-related adverse events were hematologic.
ARTISTRY-7 (GOG-3063/ENGOT-OV68/NCT05092360) is recruiting patients from 21 countries who have received at least one prior line of systemic treatment in the platinum-sensitive setting and no more than five lines in the platinum-resistant setting. All patients will have had prior bevacizumab, and those with BRCA mutations will have been treated with PARP inhibitors. Patients cannot have received treatment with a PD-1/PD-L1 therapy or IL-2, IL-5, or IL-12.
The target enrollment is 376 patients, who will be randomly assigned 3:1:1:3 to nemvaleukin alfa plus pembrolizumab combination therapy, pembrolizumab monotherapy, nemvaleukin alfa monotherapy or investigator’s choice of chemotherapy. Treatment will continue until disease progression or intolerability. The primary endpoint will be investigator-assessed progression-free survival.
Kathleen Moore, MD, MS
Kathleen Moore, MD, MS, Associate Director of Clinical Research at Stephenson Cancer Center and Professor of Gynecologic Oncology at the University of Oklahoma Health Sciences Center, commented that the mechanism of action of nemvaleukin alfa is “very interesting,” and the early-phase data have been encouraging, with responses seen even with nemvaleukin alfa as a single agent. “This drug seems to have the benefits of IL-2 without its terrible side effects,” she told The ASCO Post.
Cortisol, which acts by binding to the glucocorticoid receptor, may reduce the efficacy of chemotherapy by suppressing the apoptotic pathways used by cytotoxic agents. This receptor is abundantly expressed in ovarian tumors, and its high expression is associated with poor outcomes. Preclinical and early clinical data indicate that modulation of glucocorticoid receptor signaling with relacorilant, a selective glucocorticoid receptor modulator, may reverse the antiapoptotic effects of cortisol, thereby enhancing the efficacy of chemotherapy, according to Alexander B. Olawaiye, MD, Director of Gynecologic Cancer Research at Magee-Women’s Hospital of the University of Pittsburgh Medical Center, who described the ROSELLA trial.2
Alexander B. Olawaiye, MD
In a previous phase II study, relacorilant plus nab-paclitaxel significantly improved progression-free survival (hazard ratio [HR] = 0.66; P = .038) and duration of response (HR = 0.36; P = .006), with a trend toward improved overall survival.4 “Even greater improvement was seen in patients with one to three prior lines of therapy, including prior bevacizumab, and without primary platinum-refractory disease,” Dr. Olawaiye said.
The phase III ROSELLA study aims to confirm the findings of the phase II study in a larger patient population of approximately 360 patients. The randomized open-label multicenter study is being conducted globally in collaboration with the GOG Foundation and ENGOT.
Patients will have high-grade serous, epithelial ovarian, primary peritoneal, or fallopian tube cancers considered platinum-resistant and will have received one to three prior lines of treatment, including at least one prior line of platinum chemotherapy and bevacizumab. They will be randomly assigned 1:1 to relacorilant at 150 mg the day before, day of, and day after nab-paclitaxel infusion, plus nab-paclitaxel at 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle, or nab-paclitaxel monotherapy at 100 mg/m2 on days 1, 8, and 15. The primary endpoint is progression-free survival by blinded independent review.
DISCLOSURE: Dr. Herzog has served as a consultant or advisor for Aravive, AstraZeneca, Caris MPI, Clovis Oncology, Eisai, Epsilogen, GlaxoSmithKline, Johnson & Johnson, Merck, and Roche/Genentech; and has a leadership position with GOG Partners. Dr. Moore has served as a consultant or advisor for AstraZeneca. Dr. Olawaiye has served as a consultant or advisor for AstraZeneca, GSK, Clovis, Genentech, and Merck; and has received research funding from Corcept.
1. Herzog TJ, Hays JL, Barlin JN, et al: ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 26, 2023.
2. Olawaiye AB, Gorp TV, Monk BJ, et al: GOG-3073, ENGOT-OV72/MITO: A phase 3 study of relacorilant + nab-paclitaxel vs nab-paclitaxel in advanced, platinum-resistant ovarian cancer. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 26, 2023.
3. Vaishampayan UN, Tomczak P, Muzaffar J, et al: Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: ARTISTRY-1. 2022 ASCO Annual Meeting. Abstract 2500.
4. Munster PN, Greenstein AE, Fleming GF, et al: Overcoming taxane resistance: Preclinical and phase 1 studies of relacorilant, a selective glucocorticoid receptor modulator, with nab-paclitaxel in solid tumors. Clin Cancer Res 28:3214-3224, 2022.