Treatment Shows Promise for Ovarian Clear Cell Carcinoma
Immune checkpoint blockade may offer a new option in a field of limited therapeutic treatments.
Because of its relatively chemoresistant nature, ovarian clear cell carcinoma (OCCC) is difficult to treat and has a high rate of poor outcomes, with limited therapeutic options. However, there is increasing evidence suggesting that certain molecular tumor features correlate with long term benefit from immunotherapy. These molecular alterations include mismatch repair (MMR) deficiency and the presence of inactivating mutations in the PPP2R1A gene (corresponding to the protein phosphatase 2A (PP2A) pathway). However, these mutations are present in only 10% of OCCCs.
Today’s late-breaking presentation of “Combination PP2A inhibition and PD-1 blockade with LB-100 and dostarlimab in ovarian clear cell carcinoma,” discussed an ongoing phase 1b/2 open-label, single-arm trial to determine if the addition of LB-100 to dostarlimab (an anti-PD1 drug) would produce a synergistic, durable response in patients with nonmutated (wild-type) PPP2R1A OCCC. This could lead to extended overall survival for this population.
Helen Clark, MD, fellow at the University of Texas MD Anderson Cancer Center in Houston, and co-author of the study, said that, while other trials have investigated the use of immunotherapy for clear cell carcinoma, many of the participants are patients with known favorable molecular characteristics. The objective of this study is to try to expand the benefit to patients with OCCC who lack these favorable molecular features.
“Prior studies often have heterogeneous study populations including both uterine and ovarian primary sites and limited reporting of MMR status, which impairs one’s ability to interpret the efficacy signal,” she said. “In this study, we observe a clinical efficacy signal in an all ovarian, all pMMR (proficient mismatch repair) population.”
Dr. Clark said that there are 21 patients who have been enrolled and treated, five of whom remain on the study. Median age is 60.5 with an age range of 32-74. At a median follow-up length of 12 months, the median overall survival has not been reached, and the objective response rate is 30%. The median duration of response is 11.7 months, and the disease control rate is 40%.
An additional cohort of 21 patients has been opened for the study, and enrollment is ongoing. Dr. Clark said this cohort will be used to evaluate a regimen with increased exposure to LB-100.
“We hypothesize that additional mid-cycle dosing could increase target engagement and better approximate the immunobiology of PPP2R1A mutations to further improve the efficacy signal,” she said.
Dr. Clark stressed that LB-100 combined with dostarlimab has an acceptable safety profile and exhibits promising clinical activity in OCCC.
“Ovarian clear cell carcinoma is a histologic type with intrinsic platinum-resistance, making treatment of recurring disease challenging with low response rates to therapy,” she said. “In this study of MMR proficient recurrent clear cell carcinoma, high response rates suggest the use of LB-100 inhibition may improve the sensitivity of checkpoint inhibition. Confirmation of these preliminary efficacy signals in the second cohort of patients in this trial will lead to a future more definitive randomized study.”
