A biologics license application resubmission for toripalimab in combination with gemcitabine and cisplatin and for toripalimab monotherapy has been accepted by the FDA.
The FDA has accepted for review the biologics license application (BLA) resubmission for toripalimab in combination with gemcitabine and cisplatin as first-line treatment for patients with advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) as well as for toripalimab monotherapy as second-line or later treatment of patients with recurrent or metastatic NPC after platinum-containing chemotherapy, according to a press release from Coherus BioSciences, Inc.1
The anti-PD-1 monoclonal antibody, toripalimab, was developed to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization. Through blocking PD-1 interactions with PD-L1 and PD-L2, the immune system can easily attack and kill tumor cells.
The BLA for toripalimab is supported by the results from the phase 2 POLARIS-02 trial (NCT02915432) and phase 3 JUPITER-02 clinical trial (NCT03581786). POLARIS-02 showed that toripalimab alone can induce durable clinical responses with manageable safety, and JUPITER-02 demonstrated the efficacy and safety of using toripalimab in combination with chemotherapy.
Previously in November 2021, a BLA for toripalimab with or without chemotherapywas granted priority review by the FDA for the treatment of advanced recurrent or metastatic NPC. However, in May 2022, the agency issued a complete response letter to the BLA requesting that the developer to alter its quality process.
In August 2021, the FDA also granted breakthrough therapy designation (BTD) for toripalimab in combination with chemotherapy (gemcitabine and cisplatin) as first-line treatment for patients with recurrent, locally advanced or primary metastatic non-keratinizing NPC and for toripalimab monotherapy in patients with recurrent or metastatic non-keratinizing NPC who had disease progression on or after platinum-containing chemotherapy.
“Toripalimab would address a critical unmet medical need for patients with nasopharyngeal carcinoma, an aggressive cancer for which there are currently no FDA-approved immunotherapy treatments. We collaborated closely with our partner, Junshi Biosciences, to complete the quality process changes requested by the FDA and facilitate the rapid resubmission of the toripalimab BLA,” said Theresa LaVallee, MD, chief development officer of Coherus, in the press release.
For the toripalimab plus chemotherapy indication, JUPITER-02, a randomized, double blind, placebo-controlled, international multi-center phase 3 clinical trial, examined 289 chemotherapy-naïve patients with recurrent or metastatic NPC. A total of 146 patients were assigned to the toripalimab combination arm and 143 were assigned to the placebo arm.2
Patients were randomized 1:1 to receive toripalimab at 240 mg and gemcitabine plus cisplatin every 3 weeks for at least 6 treatment cycles. This was followed by toripalimab maintenance at 240 mg every 3 weeks, (n = 146) or chemotherapy combined with placebo every 3 weeks for 6 cycles followed by placebo maintenance every 3 weeks (n = 143). Nearly 80% of patients continued with maintenance therapy of either toripalimab or placebo following the completion of chemotherapy completion.
At the data cutoff in May 2020, patients enrolled in the experimental group had received a median of 12 cycles vs those in the placebo group who had received a median of 11 cycles.
The primary end point of the trial was progression-free survival (PFS) as assessed by a blinded central review committee with secondary end points consisting of overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety. While OS data remained immature, investigators observed a 40% reduction in risk of death in the toripalimab arm compared to the placebo arm (HR, 0.603; 95% CI, 0.364-0.997) as of February 2021.
According to data presented during a press briefing ahead of the 2021 ASCO Annual Meeting, the median PFS observed was in the toripalimab arm was 11.7 months (95% CI, 11.0-not evaluable [NE]) per blinded independent review committee assessment vs 8.0 months (95% CI, 7.0-9.5) in the chemotherapy alone arm (stratified HR, 0.52; 95% CI, 0.36-0.74; P =.0003). Additionally, the combination led to a median overall survival (OS) that was NE in both arms (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462).
PFS rates in the toripalimab and control arms at 1 year were 49.4% (95% CI, 36.4%-61.1%) compared with 27.9% (95% CI, 18.0%-38.8%), respectively. In the toripalimab arm, the 1-year OS rate observed was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone. Further, the OS rate at 2-years with the toripalimab combination was 77.8% (95% CI, 68.0%-85.0%) vs 63.3% (95% CI, 49.8%-74.1%) with chemotherapy.
In regard to safety, any-grade adverse events (AEs) occurred in 100% of patients in the study. Grade 3 or higher AEs occurred in 89.0% vs 89.5%, respectively with 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%).
For the toripalimab alone indication, the multi-center, open-label, pivotal phase 2 POLARIS-02 study demonstrated that toripalimab monotherapy had a manageable safety profile and could achieve durable clinical responses in this patient population.3
A total of 190 patients were included in this study with patients receiving 3 mg/kg toripalimab once every 2 weeks until confirmed disease progression or unacceptable toxicity. The primary end point of the trial was ORR, with secondary end points of safety, DOR, PFS, and OS.
Findings revealed that the ORR observed in the study was 20.5% (95% CI, 15.0%-27.0%), the DCR was 40.0% (95% CI, 33.0% -47.3%), and that there was a 38.4% decrease in target lesions from baseline.
Additionally, the median DOR was observed as 12.8 months (95% CI, 9.4 to not estimable), the median PFS was 1.9 months (95% CI, 1.8-3.5), and the median OS was 17.4 months (95% CI, 11.7-22.9).
In terms of safety, the most common treatment-related adverse events (TRAEs) observed in patients who received toripalimab were hypothyroidism (23.7%), anemia (15.3%), and aspartate aminotransferase increase (15.3%).
The FDA has set a prescription drug user fee act (PDUFA) action date for December 23, 2022. If approved, toripalimab will be the first and only immuno-oncology agent for NPC available in the United States.