Chemotherapy after immune checkpoint inhibitors (ICIs) may improve survival rates in patients with heavily pretreated, recurrent ovarian cancer, according to our retrospective review of outcomes for 79 women treated at Memorial Sloan Kettering Cancer Center.
Median overall survival (OS) after treatment with chemotherapies following ICIs was 18.3 months (95 percent CI, 11.8–22.7). (1) This is a promising outcome compared to results reported in the recent AURELIA study that tested a combination of bevacizumab and chemotherapy in patients with platinum-resistant ovarian cancer who were treated with fewer previous lines of therapy. (2)
Interestingly, event-free survival (EFS1) for 13 women who received platinum-based therapies in the first line after ICI was 7.3 months, compared to 3.7 months for women who received other therapies (HR 0.77; CI 0.41–1.44; p=0.41). (1)
Our research, published recently in Gynecology Oncology, is the largest study to date reporting on post-ICI therapies in ovarian cancer. The findings suggest that even in the absence of apparent initial clinical benefit, ICIs may improve the response to subsequent chemotherapy and OS in specific patient populations.
Recurrent Ovarian Cancer and ICIs
The typical OS for patients with recurrent, platinum-resistant ovarian cancer is about 12 to 14 months. (3) Therapy options are limited, and response rates to approved chemotherapy range from 10 to 15 percent. (3), (4)
Immunotherapy produces durable responses in other cancers, such as melanoma (5)and lung cancer. (6)It is a promising option for treating recurrent ovarian cancer, (7)but single-agent checkpoint inhibitors have only produced modest response rates of 10 to 15 percent to date. (8), (9), (10), (11)
Several studies have shown that progression-free survival (PFS) was the same whether patients were treated with ICIs or traditional chemotherapy, but they also found significant improvements in OS. (12)These findings suggest that ICIs may have a longer-lasting impact by influencing the ability of subsequent chemotherapies to target cancer cells.
ICIs work by blocking inhibitory receptors on T cells or their ligands, preventing exhaustion in T cells and enhancing their ability to detect and destroy tumors. (13)The duration of the T cell response to ICIs is unknown but has been observed after ICIs are discontinued. Recent studies have identified a subset of “memory T cells” that may play a role in the success and durability of ICIs. (14), (15)
We identified 115 women with recurrent ovarian cancer treated at MSK with ICI and at least one subsequent chemotherapy between January 2013 and May 2017. We assessed OS from the first treatment after ICI and looked for differences in clinical benefit between patients who had received long (>24 weeks) or short (<24 weeks) ICI treatment. (1)
Among 79 evaluable women with a median age of 57 years, 66 (84 percent) had platinum-resistant ovarian cancer. The median time from diagnosis to ICI was 39.7 months. Forty-one (61 percent) patients underwent primary debulking surgery, and 26 (39 percent) were treated with neoadjuvant chemotherapy followed by interval debulking surgery.
The 79 women had received four previous treatments before ICI, on average, with a range of one to 12. Most were treated with a PD1/PD-L1 inhibitor alone (n=35; 44 percent) or a combination of a PD1/PD-L1 inhibitor with another agent (n=39; 49 percent), most commonly an anti-CTLA-4 agent. ICI therapy was administered for a median of 2.8 months. (1)
The number of treatments after ICI ranged from one to eight, with a median of two, and total lines of treatment ranged from four to 16, with a median of seven. (1)The median duration of first-line therapy after ICI was 3.7 months, with decreasing timeframes with each subsequent line of therapy. The most common chemotherapies after ICI were platinum-based regimens, taxanes, and pegylated liposomal doxorubicin (PLD). Forty-seven women (59 percent) were treated with bevacizumab. (1)
Median OS after ICI was 18.3 months (95 percent CI, 11.8–22.7) for our heavily pretreated population of patients. This OS was promising compared to inferior results seen in the recent phase III AURELIA study, where the chemotherapy-only group had a median OS of 13.3 months, and the group that received combination treatment with physician’s choice of paclitaxel, PLD, or topotecan with bevacizumab or placebo had a median OS of 16.6 months. (2)
Forty-seven of 79 patients in our study received bevacizumab at some point following ICI treatment and its use appeared promising. As in the AURELIA study, the addition of bevacizumab prolonged duration of therapy after ICI. There is some evidence that anti-VEGF agents like bevacizumab may improve checkpoint inhibition by boosting T cell infiltration into tumors. (16)Studies are underway investigating combination treatments using VEGF and checkpoint inhibition in a number of gynecologic cancers. (17)
Notably, 47 percent of the women in our study were rechallenged with platinum-based therapy despite showing platinum-resistance to earlier lines of treatment. The median EFS1 for women who received platinum-based therapies in the first line after ICI was 7.3 months, compared to 3.7 months for those who received other therapies (HR 0.77; CI 0.41–1.44; p=0.41). (1)
Given the limited sample size, we did not observe a statistically significant difference in survival with chemotherapy after ICI when comparing women who received a short (<24 weeks) versus a long (>24 weeks) duration of immunotherapy. However, the median OS for the long group was almost a year longer at 28 months compared to 16.3 months for the short group. (1)
We suspect that the biology of the cancer in patients in the long ICI treatment group was more likely to respond to both chemotherapy and immunotherapy. Studies are underway to understand the underlying genetic and immunologic characteristics of the disease with the goal of developing predictive biomarkers in the future.
Advancing Ovarian Cancer Treatment
ICIs may play an essential role in helping patients overcome platinum resistance. Our results provide a rationale for evaluating ICIs in combination with chemotherapy in patients with ovarian cancer in prospective research. The results also underscore the need for collecting post-ICI therapy data within the context of ongoing clinical trials.
At MSK, we are currently conducting 180 clinical trials testing immunotherapies alone or in combination with chemotherapies and other treatment modalities in a variety of cancer types, including 11 clinical trials for patients with ovarian cancer.
Immunotherapy was pioneered by MSK researchers more than a century ago. MSK is one of six founding partners of the Parker Institute for Cancer Immunotherapy, a network of research centers and scientists working toward unlocking the power of the immune system to fight cancer.