Monotherapy with immune checkpoint inhibitors potentially insufficient for ovarian cancer
Monotherapy using the immune checkpoint inhibitors anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may not be sufficient for ovarian cancer, according to data presented at the European Society for Medical Oncology (ESMO) Asia 2016 Congress held in Singapore.
Since being approved for melanoma in 2011 (anti-CTLA-4 [ipilimumab]; and anti-PD-1 [nivolumab and pembrolizumab]), checkpoint inhibitors continued to get approval for multiple indications in cancer therapy due to positive results.
However, a summary of PD-1/PD-L1 clinical trials that target the PD-1 pathway of ovarian cancer revealed unimpressive objective response rates (ORRs), which represent anti PD-L1/PD-1 monotherapy insufficiency, noted Professor Lana E Kandalaft, Director of the Centre of Experimental Therapeutics, Department of Oncology, UNIL CHUV in Lausanne, Switzerland, who presented several studies on checkpoint inhibitors and their efficacy in ovarian cancer treatment. [Discov Med 2015;20:97-109]
In a phase Ib trial of the anti-PD-L1 avelumab in resistant or relapsing ovarian cancer patients (n=124), a tumour size decrease of ≥30 percent was observed in 12 patients (9.7 percent). In another avelumab trial, 1 out of 17 patients with a PD-L1 negative tumour showed an objective response even with a staining cutoff level of ≥1 percent of tumour cells in ovarian cancer. “[Therefore], PD-L1 target is not a very dependable marker, so one should use multiple markers… [to determine] if patients are eligible for checkpoint blockade inhibitors or not,” noted Kandalaft. [ASCO 2016, abstract 5533]
In a phase II trial of the anti-PD-1 nivolumab, two out of 16 patients with high PD-L1 expression had a durable complete response (3mg/kg cohort); however, one out of four patients with low expression also responded (1mg/kg cohort). [J Clin Oncol 2015;33:4015-4022]
In another CTLA-4 antibody blockade trial, durable regression was observed in advanced ovarian cancer patients. Infusion of the anti-CTLA-4 antibody resulted in the constant decrease of CA-125 until complete regression was achieved. [Proc Natl Acad Sci USA 2008;105:3005-3010]
Of note are two studies that revealed conflicting results. One study considered PD-L1 as a poor prognostic factor for ovarian cancer due to the higher survival rates observed in patients with low PD-L1. However, this finding was contradicted by another study in 2015, which found PD-L1 to be a favourable prognostic factor for OC. [J Clin Oncol 2014:32 (Suppl) Abstract 5511; Proc Natl Acad Sci USA 2007;204:3360-3365; Cancer Immunol Res 2015;3:926-935c] “The field is… very confusing. Here, they show that PD-L1 positive patients have a higher overall survival,” said Kandalaft.
With regards to combination therapy, the benefit was evident in one in vivo study wherein a PD-1/CTLA-4 dual blockade was performed on a mouse model. This resulted in the reversal of CD8+ T-cell dysfunction, which led to tumour rejection in two-thirds of the mice. [Cancer Res 2014;74:633-634]
Another in vivo study revealed increased complete remission rates when PD-L1 was combined with pegylated liposomal doxorubicin [Neoplasia 2015;17:661-670]
Today, there are multiple checkpoint inhibitor trials in ovarian cancer that combine PD-1/PD-L1 with different treatment modalities such as chemotherapy or CTLA-4 antibodies, noted Kandalaft.
Ovarian cancer can be classified into two phenotypes: immunogenic and non-immunogenic. “[However]…. no one looked at these… phenotypes nor tried to personalize therapy and use checkpoint inhibitors based on these phenotypes…. We could use [these phenotypes] as a start to tailor therapy, and create an immunoscore to better understand the immunosuppressive mechanisms in ovarian cancer in order for us to use checkpoint blockade inhibitors in a better way. Finally, we need to try to create smarter clinical trial designs so we can accelerate the integration of checkpoint blockade inhibitors with standard of care,” she noted.