A phase 3 randomized clinical trial has found that adding the immunotherapy drug toripalimab to standard chemotherapy significantly improves progression-free and overall survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The study, known as JUPITER-02, was conducted across multiple centers in China, Taiwan and Singapore, and the results were published in JAMA on November 28, 2023.
Nasopharyngeal carcinoma is a rare form of head and neck cancer that is much more prevalent in Southern China and Southeast Asia compared to Western countries. It is closely associated with Epstein-Barr virus infection. Currently, there are no FDA-approved therapies specifically for nasopharyngeal carcinoma. The standard first-line treatment for recurrent or metastatic disease is gemcitabine plus cisplatin chemotherapy.
The JUPITER-02 trial aimed to determine if adding toripalimab, an anti-PD-1 monoclonal antibody, to gemcitabine-cisplatin could improve outcomes compared to chemotherapy alone. The study was funded by Shanghai Junshi Biosciences and Coherus Biosciences, the companies developing toripalimab.
A total of 289 patients with recurrent or metastatic nasopharyngeal carcinoma were enrolled from 35 centers between November 2018 and October 2019. To be eligible, patients had to have histologically or cytologically confirmed disease that was not amenable to curative local-regional treatment. They could not have received prior systemic chemotherapy for recurrent/metastatic disease. Patients were randomly assigned 1:1 to receive either toripalimab (240 mg) or placebo in combination with gemcitabine (1000 mg/m2) and cisplatin (80 mg/m2) for up to 6 cycles, followed by maintenance toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment.
The median age of participants was 46 years in the toripalimab group and 51 years in the placebo group. The majority (over 80%) were male in both groups. About 42% had primary metastatic disease, while the rest had recurrent disease. Other baseline characteristics were generally well-balanced between the two arms.
The primary endpoint was progression-free survival as assessed by blinded independent central review. At the final progression-free survival analysis, with a median follow-up of 36 months, toripalimab dramatically improved median progression-free survival to 21.4 months compared to 8.2 months with placebo (hazard ratio 0.52, 95% CI 0.37-0.73, p<0.001). The 1-year progression-free survival rate was 59% with toripalimab versus 32.9% with placebo, and the 2-year rate was 44.8% versus 25.4%.
More importantly, the addition of toripalimab also led to a significant improvement in overall survival, a key secondary endpoint. Median overall survival was not reached in the toripalimab group compared to 33.7 months in the placebo group (hazard ratio 0.63, 95% CI 0.45-0.89, p=0.008). The 3-year overall survival rate was 64.5% with toripalimab versus 49.2% with placebo.
The objective response rate was higher with toripalimab (78.8% vs 67.1%), including more than double the complete response rate (26.7% vs 13.3%). Responses were also more durable, with a median duration of response of 18 months versus 6 months.
The safety profile was generally consistent with known effects of chemotherapy and anti-PD-1 therapy. The overall incidence of adverse events was similar between groups. However, immune-related adverse events were more frequent with toripalimab (54.1% vs 21.7%), as were grade 3 or higher immune-related events (9.6% vs 1.4%) and adverse events leading to discontinuation (11.6% vs 4.9%).
The researchers also looked at changes in Epstein-Barr virus DNA levels in the blood as an exploratory endpoint. More patients in the toripalimab group had EBV DNA become undetectable after treatment (96.3% vs 84.5%). Fewer patients experienced EBV DNA rebound after initial reduction (36.5% vs 57.4%), and the median time to rebound was longer (20.5 vs 6.0 months).
The study had some limitations. It was conducted exclusively in NPC-endemic Asian regions, where the majority of patients have non-keratinizing histology closely associated with EBV. The results may not be as applicable to keratinizing NPC more common in Western countries. There was also an imbalance in age between the groups, with the toripalimab arm being about 5 years younger on average. However, the treatment effect remained consistent after adjusting for age in a multivariate analysis.
Additionally, extensive crossover to immunotherapy in later lines of treatment may have diluted the overall survival benefit. By the final analysis, about 33% of patients in the toripalimab group and 34% in the placebo group had received subsequent anti-PD-1/PD-L1 therapy. This likely extended survival in the control arm and makes the significant overall survival improvement even more notable.
The authors concluded that the addition of toripalimab to gemcitabine-cisplatin chemotherapy provides statistically significant and clinically meaningful improvements in both progression-free and overall survival as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. They state that these findings support the use of this combination as a new standard of care for this patient population.
The potential clinical impact of these results is substantial. Nasopharyngeal carcinoma has historically had limited treatment options, especially in the recurrent/metastatic setting. The dramatic improvement in progression-free survival and significant overall survival benefit with the addition of immunotherapy represents a major advance. If approved, this combination could become the new first-line standard of care for patients with recurrent or metastatic disease.
The safety profile appears manageable, with immune-related toxicities in line with other anti-PD-1 therapies. The increased efficacy may outweigh the additional side effects for many patients. However, proper patient selection and close monitoring will be important to optimize the risk-benefit ratio.
These results also add to the growing evidence for the efficacy of immunotherapy in virus-associated cancers. The high response rates and durability of benefit seen with toripalimab are encouraging. The correlation between EBV DNA levels and clinical outcomes is also intriguing and merits further study as a potential biomarker.
While conducted primarily in Asian populations, subgroup analyses suggested the benefit of toripalimab was consistent regardless of EBV DNA levels. This provides some reassurance that the results may translate to Western populations with nasopharyngeal carcinoma as well. However, further study in more diverse patient populations would be valuable.
Several questions remain to be addressed in future research. The optimal duration of maintenance immunotherapy is unclear - the protocol allowed up to 2 years of treatment, but the ideal length of therapy is unknown. Additionally, strategies to further improve outcomes, such as combination with other targeted agents or incorporation of immunotherapy into earlier stage disease, warrant investigation.
It will also be important to identify biomarkers beyond PD-L1 expression that can help select patients most likely to benefit from immunotherapy. The dynamics of EBV DNA levels show promise in this regard. Further analysis of this and other potential biomarkers from this trial may yield additional insights.
From a health economics perspective, the addition of two years of immunotherapy to chemotherapy will significantly increase treatment costs. Formal cost-effectiveness analyses will be needed to determine the value proposition of this approach, especially in resource-limited settings. However, the magnitude of clinical benefit observed suggests this combination has the potential to be cost-effective in many healthcare systems.
Regulatory approval will be the next key step to potentially bring this treatment to patients. Toripalimab received conditional approval in China for recurrent/metastatic nasopharyngeal carcinoma in late 2021 based on earlier results from this trial. These mature overall survival data will likely support full approval there and regulatory submissions in other countries.
In the United States, the FDA granted Breakthrough Therapy designation to toripalimab for nasopharyngeal carcinoma in 2021. However, in 2022 the agency issued a Complete Response Letter regarding the Biologics License Application, requesting quality process and method validation data. Assuming these chemistry, manufacturing and controls issues can be resolved, these phase 3 data provide strong support for eventual approval.
In summary, the JUPITER-02 trial represents a significant advance in the treatment of recurrent and metastatic nasopharyngeal carcinoma. The addition of toripalimab immunotherapy to standard chemotherapy yielded major improvements in progression-free and overall survival with a manageable safety profile. If approved, this combination has the potential to become a new standard of care that could meaningfully extend both the quantity and quality of life for patients with this challenging disease. Further research building on these results may lead to additional advances in the coming years.
References
Mai HQ, Chen QY, Chen D, et al. Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial. JAMA. 2023;330(20):1961-1970. doi:10.1001/jama.2023.20181
