In recent years, advances in our understanding of ovarian cancer biology and new treatment approaches have improved patient outcomes, but additional therapeutic options are needed. While initial response rates to chemotherapy could be high, I’ve seen many people with ovarian cancer relapse and eventually develop resistance to platinum-based chemotherapy, leading to a poor prognosis. Subsequent cycles of chemotherapy are not beneficial for these patients, and patients living with platinum-resistant ovarian cancer (PROC) often survive for no longer than a year.

 Patients treated with chemotherapy for ovarian cancer face adverse events, which may include nausea, vomiting, alopecia and leukopenia, and are at risk for cumulative effects like renal toxicity, neurotoxicity and thrombocytopenia.

PARP inhibitors have revolutionized the management of ovarian cancer and transformed the treatment landscape for eligible patients; however, a minority of patients experience long-term benefits from this class of agents, and the cancer often recurs.

Furthermore, while the immuno-oncology (I-O) treatments known as anti-PD-1/L1 therapies have been successful in a wide range of solid tumors, the benefit for patients with ovarian cancer has been limited,

and there are currently no FDA-approved I-O treatments specifically for this disease. In a phase 2 trial of single-agent pembrolizumab for patients with advanced recurrent ovarian cancer, overall response rates were only 4-10% and disease control rate was 37%.

 The poor results of single-agent checkpoint inhibitor therapies may be associated with a low tumor mutational burden and other factors, such as infiltrates of M2-polarized tumor-associated macrophages in ovarian cancer

 Because M2 TAMs and T regs have suppressive effects on CD8+ T cells and NK cells,

 the ability to harness the anti-tumor activity of these cells may be hampered in the ovarian cancer tumor microenvironment, particularly after platinum-based chemotherapy, which has been shown to increase M2 macrophages.

 This suggests that innovative approaches are needed to successfully treat PROC patients with I-O therapies.

It is thought that I-O combination therapy may help expand the patient population who can benefit from I-O. In tumor types considered poorly immunogenic, such as PROC, a combination I-O approach may help relieve immunosuppression and potentiate the activity of anti-PD-1/L1 therapy. Indeed, while poor response rates have been observed with single-agent nivolumab, the combination of nivolumab with an additional immune checkpoint inhibitor, ipilimumab, more than doubled the response rate. However, the median progression-free survival (PFS) was low: 2.0 and 3.9 months in the nivolumab and nivolumab plus ipilimumab groups, respectively.

Currently there are no I-O therapies approved in PROC. Additional research is critical to understanding the potential of I-O combination therapies, and clinical trials evaluating these combinations are an important avenue to consider for patients and their families to help progress this research. Fortunately, there are several clinical trials underway evaluating I-O combinations for difficult-to-treat diseases, like PROC, with the goal of developing new treatment options leading to better outcomes for these patients.

Specifically, I’m leading a phase 3, multicenter trial (ARTISTRY-7), investigating the effectiveness and safety of a combination of two I-O therapies, investigational nemvaleukin alfa and pembrolizumab, compared to the standard of non-platinum-based chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. Nemvaleukin alfa is an investigational engineered fusion protein comprised of modified IL-2 and the high affinity IL-2 receptor alpha chain and is designed with a goal to preferentially expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells. In both preclinical and clinical studies, we have seen encouraging data suggesting potential activation and expansion of CD8+ T cells and NK cells and potentially low effects on immunosuppressive regulatory T cells.

 The ARTISTRY-7 trial aims to determine whether this combination I-O approach extends PFS longer than current chemotherapy for patients with PROC. Preliminary findings from the earlier phase 1/2 ARTISTRY-1 trial of the combination of nemvaleukin alfa and pembrolizumab in the cohort of patients with PROC reported an overall response rate of 28.6% and a disease control rate of 71.4%, with a median duration of response of 53.4 weeks. The most frequent grade 3/4 treatment-related adverse events reported in Parts B and C, respectively, were anemia (9%, 10%), neutropenia (34%, 9%) and decreased neutrophil count (12%, 9%). Safety was consistent with previous reports.

We hope that I-O combination therapy will play an important role in the treatment of PROC to help prolong survival with a favorable side effect profile. If the ARTISTRY-7 trial provides successful results, patients with PROC may have a future new treatment option in their arsenal. Our hope is that the ARTISTRY-7 trial may help lay the foundation for a new treatment option for patients and their families to consider in the future.


If you’re interested in learning more about the actively recruiting ARTISTRY-7 clinical trial, please visit: 

https://www.clinicaltrials.gov/ct2/show/NCT05092360

Davis A, et al. “Platinum resistant” ovarian cancer: what is it, who to treat, and how to measure benefit? 

Herzog, TJ. Recurrent ovarian cancer: how important is it to treat to disease progression? 

Huang X, et al.Efficacy and Prognostic Factors for PARP Inhibitors in Patients With Ovarian Cancer. 

Indini A, et al. Immune-Checkpoint Inhibitors in Platinum-Resistant Ovarian Cancer. 

Matulonis UA, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. 

Cummings M, et al. Targeting the tumour microenvironment in platinum-resistant ovarian cancer. 

Toker A, et al. Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma. 

Knutson K, et al. Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer. 

Quaranta V, et al. Macrophage-Mediated Subversion of Anti-Tumour Immunity. 

Pedroza-Pacheco I, et al. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy. 

Chen ML, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals 

Vankerckhoven A, et al. Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study. 

Zamarin D, et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. 

Lopes JE, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. 

Vaishampayan UN, et al. Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1. 

Thomas J. Herzog, M.D., Professor of Obstetrics and Gynecology, Deputy Director, University of Cincinnati Cancer Institute

Articles

Rethinking I-O in PROC: A Potential Answer in Two vs. One