What this Trial Is About

Recurrence rate after curative treatment for locally advanced Nasopharyngeal carcinoma (NPC) is reported varying from 15% to 30% of cases, while approximately 5-11% of patients present with de novo metastatic disease. In NPC, the immunogenicity of the cancer cell is derived from accumulated somatic mutations, but also from genomic and proteomic differences between host and Epstein Barr Virus (EBV). However, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including strategies to escape anti-cancer immunity. One of this is switch to immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals like PD-L1, that is over expressed in NPC. In 2017, the landmark KEYNOTE-028 trial firstly reported promising antitumor activities and safety profiles of pembrolizumab in previously treated RM-NPC Overall, after the treatment of PD-1 inhibitors, about 25% and 60% of the recurrent or metastatic nasopharyngeal carcinoma patients achieved ORR and DCR, respectively, with a profile of toxicities in line with the use of immune checkpoint inhibitors in other diseases. Recently, it was found that some non-BRCA-mutated tumors often harbor other alterations in HR genes except for germline BRCA deleterious mutations, thus making these tumors could benefit from PARPi treatment. PARP could contribute to resistance to chemotherapy induced DNA damage, NPC cell platinum resistant could use PARP to repair and escape apoptosis. In nasopharyngeal carcinoma PARP1 is overexpressed in comparison with normal nasopharyngeal cells, LMP1 (latent membrane protein one) activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. A preclinical study demonstrates that LMP1+ cells are more sensitive to PARP1 inhibition. After receiving PARPi treatment, accumulated chromosome rearrangements generate plenty of neoantigens and elevate the immunogenicity of tumor, PARPi-mediated acute inflammation remodels tumor immune microenvironment and drives a systemic Th1-skewing immune response. Patients in the POINT trial will receive pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week dosing cycle (Q3W) and olaparib 300 mg capsules twice a day (BID) every day starting from Day 1 of Cycle 1. Treatment with protocol therapy will continue until objective disease progression, any prohibitive toxicity or until a maximum of 35 treatment cycles (up to 2 years).

Pembrolizumab and Olaparib in Recurrent/Metastatic, Platinum Resistant Nasopharyngeal Cancer