Dual immunotherapy shows promise for treating recurrent or metastatic nasopharyngeal cancer

By | June 7, 2023

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Patient response details and outcome data. A Extent and depth of response in trial cohort showing best tumor scan (top) and changes in tumor size over time (bottom). Non-evaluable (NE) in gray, progressive disease (PD) in blue, partial response (PR) in red, and stable disease (SD) in yellow. No=40. b Progression-free (top) and overall (bottom) survivals of the trial cohort. No=40. Source data is provided as source data files. Credit: Nature communications (2023). DOI: 10.1038/s41467-023-38407-7

A team led by the National Cancer Center 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, evaluated that dual immunotherapy, the PD-1 immune checkpoint inhibitor nivolumab and the CTLA-4-targeted drug ipilimumab, is effective in the treatment of recurrent or metastatic nasopharyngeal carcinoma (NPC).

These results, published Nature communicationsintroduce a new approach to dealing with NPCs.

NPC is often diagnosed at an advanced stage where patients have metastatic disease and are more likely to recur. The current standard treatment for this group of patients is chemotherapy. Recent results of combination therapy targeting PD-1 and CTLA-4 in other cancer types, such as malignant melanoma and renal cell carcinoma, have been successful, prompting the study of similar drug combinations for the treatment of NPC metastatic and recurrent. This is the first time this combination has been studied in NPC, globally.

The NCCS-led research team has initiated a single-arm Phase 2 study to evaluate the safety and efficacy of the combination nivolumab and ipilimumab in 40 patients with metastatic and/or recurrent Epstein-Barr virus (EBV)-associated NPC ) in 2017. EBV is an NPC-associated virus but it is unclear why only some individuals, especially Southern Chinese, develop NPC while more than 90% of the world’s population is infected with EBV.

The age range of patients enrolled in the study ranged from 23 to 73 years, with a median of 53 years, and the majority were male (82.5%), reflecting the predominance of NPC incidence in the male population. Patients who had failed prior chemotherapy received nivolumab every two weeks and ipilimumab every six weeks, until disease progression or toxicity developed.

Study outcomes were measured by patients’ best overall response rate (BOR), partial response (PR), progression-free survival (PFS), and overall survival (OS). Study results showed that the patient cohort had a BOR of 38% and PR of 37.5% with a median PFS of 5.3 months and 19.5 months OS. This compares to the historical response rates and survival benefits conferred by chemotherapy as a second-line treatment.

The research team also analyzed blood and tumor samples from the patients. There was improved response and PFS in patients with low pre-treatment EBV DNA plasma levels, suggesting the possibility that this could be used to select patients most likely to benefit from dual immunotherapy. The team also performed complex genetic analyses, including whole-exome sequencing and multiplex immunohistochemistry, but found no genetic biomarkers to predict treatment response before treatment was initiated.

However, they found that during treatment, gene expression between patients who had PR on treatment versus those who did not were significantly different. This suggests that to identify patients who would respond, future studies should focus on obtaining data after treatment initiation rather than before. They were able to identify that these differences reside in the subpopulations of the CD8 gene expressing PD-1 and CTLA-4 and could potentially predict response to this combination therapy and be targeted for better treatment outcomes in the future.

“We are encouraged that this study has demonstrated efficacy in the treatment of metastatic and/or recurrent NPCs, resulting in good responses and increased overall survival in a significant proportion of patients,” said Associate Professor Darren Lim, Senior Consultant, Department of Lung, Head & Neck & 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 subgroup of patients would benefit most from this combination treatment.”

“The results of this study offer new options to NPC patients who currently have limited treatment options outside of chemotherapy. If the efficacy of this new combination treatment is confirmed on the larger cohort we are testing, it would provide a possible therapy alternative for a single Asian-endemic cancer,” said Professor Gopal Iyer, senior author of the study and lead and senior consultant, Department of Head and Neck Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and NCCS.

More information:
Darren Wan-Teck Lim et al, Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma, Nature communications (2023). DOI: 10.1038/s41467-023-38407-7

About the magazine:
Nature communications

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