SINGAPORE — A team led by the National Cancer Centre Singapore (NCCS) with members from Singapore General Hospital, A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Genome Institute of Singapore (GIS), National University of Singapore’s Cancer Science Institute of Singapore and National Taiwan University, have evaluated that dual immunotherapy involving PD-1 immune checkpoint inhibitor, nivolumab, and CTLA-4-targeting drug, ipilimumab, is effective in treating recurrent or metastatic nasopharyngeal carcinoma (NPC). The results, published in Nature Communications, introduce a new approach to treating NPC.
NPC is often diagnosed at a late stage when patients present metastatic disease and have an increased chance of recurrence. The current standard treatment for this group of patients is chemotherapy. Recent results of combination therapy targeting PD-1 and CTLA-4 in other tumor types have been successful, prompting the investigation of similar drug combinations to treat metastatic and recurrent NPC. This is the first time this combination has been studied in NPC, globally.
Phase 2 trial and findings
The NCCS-led research team initiated a single-arm, Phase 2 trial to evaluate the safety and efficacy of combination nivolumab and ipilimumab in 40 patients with metastatic and/or recurrent Epstein-Barr virus (EBV)-associated NPC in 2017. EBV is a virus associated with NPC but it is unclear why only some individuals, particularly those from the south of China, develop NPC while over 90 percent of the world’s population is infected with EBV.
The age range of patients recruited to the trial was between 23 and 73 years, with a median of 53 years. Around 82.5 percent were male, which reflects the predominance of NPC incidence in the male population. Patients who didn’t respond as expected to chemotherapy regimes, received nivolumab every two weeks and ipilimumab every six weeks until the disease progressed or toxicities developed.
Trial results were measured based on the patients’ best overall response rate (BOR), partial response (PR) to the therapy, progression-free survival (PFS), and overall survival (OS). Results of the trial showed that the cohort of patients had a BOR of 38 percent and PR of 37.5 percent with a median PFS of 5.3 months and 19.5 months of OS.
This is comparable to historical response rates and survival benefits conferred by chemotherapy as second-line treatment.
Differential gene expression in patients
The research team also analyzed both blood and tumor samples from the patients. There was a better response and PFS in patients with low pretreatment plasma EBV DNA levels suggesting that this could be used to select patients who’d more likely to benefit from the dual immunotherapy. The team also performed whole-exome sequencing and multiplex immunohistochemistry analyses but did not find genetic biomarkers helpful in predicting the treatment response before the start of treatment.
However, researchers found that gene expression was significantly different in patients who partially responded to the treatment compared to those who did not. This suggests that to identify patients who would respond, future studies should focus on obtaining data after the start of treatment rather than before.
They were able to identify that the differences lay in PD-1 and CTLA-4 expressing CD8 gene subpopulations. The CD8 gene subpopulations could potentially predict response to combined immunotherapy and be targeted for better treatment outcomes in the future.
“We are encouraged that this trial has shown efficacy in treating metastatic and/or recurrent NPC by achieving good responses and increased overall survival in a significant proportion of patients,” said Darren Lim, MBBS, MRCP (UK), associate professor, senior consultant, Department of Lung, Head & Neck and Genitourinary Medical Oncology, Division of Medical Oncology, NCCS, and lead author of this study. “We are validating these findings in a larger patient group and hope to determine which subset of patients would benefit most from this combination treatment.”
- This press release was originally published on the SingHealth website