PFS Significantly Improved with Frontline Toripalimab Plus Gemcitabine/Cisplatin in Recurrent or Metastatic Nasopharyngeal Carcinoma

Compared to chemotherapy alone, the addition of the immunotherapy agent toripalimab to gemcitabine plus cisplatin (GP) significantly improved progression-free survival (PFS) in the frontline treatment of patients with recurrent or metastatic nasopharyngeal carcinoma, according to data from the phase 3 JUPITER-02 trial (NCT03581786).¹

The toripalimab regimen resulted in a median PFS of 11.7 months (95% CI, 11.0–not evaluable [NE]) via blinded independent review committee (BIRC) per RECIST v1.1 criteria vs 8.0 months (95% CI, 7.0-9.5) with chemotherapy alone (stratified HR, 0.52; 95% CI, 0.36-0.74; P = .0003) in this population, according to data presented during a press briefing ahead of the 2021 ASCO Annual Meeting. Additionally, the median overall survival (OS) was NE in both arms (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462).

“From this first international trial, we can see that the addition of toripalimab to GP as a first-line treatment for nasopharyngeal carcinoma showed better PFS and OS than GP alone. The combination was safe, and no new safety signals were found,” Rui-Hua Xu, MD, PhD, of Sun Yat-Sen University Cancer Center, China, said in a virtual presentation on the data. “These results support the use of the toripalimab combination as a new standard of care in the first-line treatment of patients with recurrent or metastatic [disease].”

Nasopharyngeal carcinoma is endemic in Southern China and Southeast Asia, according to Xu, who explained that the incidence of this cancer is 1.2 per 100,000 globally, while it is 3.0 per 100,000 in China. Moreover, patients with recurrent or metastatic disease have limited therapeutic options available to them, and the current standard-of-care frontline treatment worldwide for this population is GP.

The anti–PD-1 monoclonal antibody toripalimab was designed to block PD-1 interactions with its ligands PD-L1 and PD-L2 and strengthen receptor endocytosis function.2 The tumor checkpoint proteins PD-L1 and PD-L2 recognize the PD-1 receptor on T cells and deplete their antitumor activity. It is hypothesized that blocking PD-1 interactions with the proteins will result in a recharged immune system, boosting its ability to attack and eliminate cancer cells.

In February 2021, toripalimab was granted a conditional approval by the National Medical Products Administration of China for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma in whom at least 2 prior lines of systemic treatment has failed.³

The regulatory decision was supported by data from the phase 2 POLARIS-02 trial (NCT02915432), where the agent elicited an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%), a median duration of response (DOR) of 12.8 months (95% CI, 9.4-NE), a median PFS of 1.9 months (95% CI, 1.8-3.5), and a median OS of 17.4 months (95% CI, 11.7-22.9) in the intent-to-treat population.⁴

In the global, double-blind, placebo-controlled phase 3 JUPITER-02 trial, investigators sought to examine toripalimab in combination with GP vs GP with placebo in the frontline treatment of patients with recurrent or metastatic nasopharyngeal carcinoma.

To be eligible for enrollment, patients needed to be between 18 and 75 years of age and have primary or metastatic nasopharyngeal carcinoma or recurrent disease following curative-intent treatment. Patients also needed to be treatment naïve for recurrent or metastatic disease, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST v1.1 criteria.

A total of 289 participants from mainland China, Taiwan, and Singapore were randomized 1:1 to receive toripalimab at 240 mg plus GP every 3 weeks for 6 treatment cycles followed by toripalimab maintenance at 240 mg every 3 weeks, (n = 146) or GP plus placebo every 3 weeks for 6 cycles followed by placebo maintenance every 3 weeks (n = 143).

Patients were stratified based on disease (recurrent vs primary metastatic) and ECOG performance status (0 vs 1). Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or a maximum of 2 years.

The primary end point of the trial was PFS per BIRC and RECIST v1.1 criteria, while secondary end points include PFS per investigator assessment, ORR, DOR, disease control rate, and OS, as well as 1- and 2-year PFS and OS rates.

Additional data from the trial showed that the 1-year PFS rates in the investigative and control arms were 49.4% (95% CI, 36.4%-61.1%) and 27.9% (95% CI, 18.0%-38.8%), respectively.

The OS data were not mature at the interim analysis, according to Xu. “Nine months after the interim analysis we observed a 40% reduction in risk of death in the toripalimab arm vs the placebo arm,” Xu said.

The 1-year OS rate achieved with the toripalimab regimen was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone; the 2-year OS rates were 77.8% (95% CI, 68.0%-85.0%) and 63.3% (95% CI, 49.8%-74.1%), respectively.

Regarding safety, a similar incidence of any-grade adverse effects (AEs; 100% in both), grade 3 or higher toxicities (89.0% vs 89.5%), infusion reactions (any-grade, 4.1% vs 4.2%), and fatal AEs (2.7% vs 2.8%) was observed between the investigative and control arms, respectively. The most frequently reported grade 3 or higher AEs included leukopenia (61.6% vs 58.0%), neutropenia (57.5% vs 63.6%), and anemia (47.3% vs 39.9%).

“The most common AEs were hematologic toxicity, which were mainly attributed to the GP chemotherapy regimen,” Xu noted. “The incidence of immune-related AEs, such as hypothyroidism, were higher in the toripalimab arm; this was expected [with immunotherapy] and [proved to be] manageable.”

All-grade immune-related AEs were reported in 39.7% of patients who received the toripalimab regimen vs 18.9% of those who received chemotherapy alone; grade 3 or higher immune-related toxicities were experienced by 7.5% and 0.7% of patients, respectively.⁵

Additionally, more patients on the investigative arm discontinued treatment due to AEs compared with the control arm, at 7.5% and 4.9%, respectively.⁵

Study participants will continue to be followed for OS and other secondary end points.

“Treatment advances for late-stage nasopharyngeal carcinoma have lagged behind those of other cancers,” Julie R Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO, commented in a press release about the trial.5 “Findings from the JUPITER-02 study offer new hope for patients with advanced disease, changing how we care for them.”

_References

1. _{Xu R-H, Mai H-Q, Chen Q-Y, et al. JUPITER-02: the randomized, double-blind phase 3 study of toripalimab or placebo plus cisplatin and gemcitabine as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC). J Clin Oncol. 2021;39(suppl 15; abstr LBA2).}

2. _{Anti-PD-1 monoclonal antibody candidate toripalimab. Coherus Biosciences website. Accessed June 2, 2021. https://bit.ly/3vQ5EZh}

3. _{NMPA approves toripalimab in patients with recurrent or metastatic nasopharyngeal carcinoma after failure of at least two lines of prior systemic therapy. News release. Junshi Biosciences. February 22, 2021. Accessed June 2, 2021. https://bit.ly/3yX8U6Z}

4. _{Wang F-H, Wei X-L, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase II clinical trial (POLARIS-02). J Clin Oncol. 2021;39(7):704-712. doi:10.1200/JCO.20.02712}

5. _{Addition of immunotherapy to standard of care first-line regimen delays disease progression in advanced nasopharyngeal carcinoma. News release. ASCO. June 3, 2021. Accessed June 3, 2021. https://bit.ly/3peKykR}