The FDA has not sent an action letter regarding the biologics license application for toripalimab in combination with chemotherapy as treatment for patients with recurrent or metastatic nasopharyngeal carcinoma.
Theresa LaVallee, PhD
The FDA has not sent an action letter regarding the biologics license application (BLA) for toripalimab in combination with chemotherapy as treatment for patients with recurrent or metastatic nasopharyngeal carcinoma, according to an announcement from Junshi Biosciences and Coherus BioSciences.1
After the FDA accepted a resubmission of the BLA in July 2022, the regulatory agency set a Prescription Drug User Fee Act action date for December 23, 2022.2 However, the FDA was unable to conduct an on-site inspection of Junshi Biosciences’ manufacturing facility for toripalimab during the current review cycle due to the ongoing effect of COVID-19 related restrictions on travel in China.
The companies said that the BLA for toripalimab remains under review, and discussions are ongoing between the FDA and companies about the pre-approval inspection plans.
“There is a significant unmet need for those living with nasopharyngeal carcinoma, and toripalimab has demonstrated significant and clinically meaningful improvement as recognized by the FDA’s breakthrough therapy designation. Both Coherus and the FDA are highly committed to bringing toripalimab to [patients with] nasopharyngeal carcinoma in the U.S. as quickly as possible,” Theresa LaVallee, PhD, chief development officer of Coherus, stated in a press release. “We are working closely and collaboratively with the FDA to schedule inspections of the manufacturing facility quickly and understand the need to ensure the safety of their inspectors. We continue to support the FDA as needed to allow for their assessment of toripalimab to be finalized.”
In November 2021, the FDA accepted an initial BLA seeking approval for use of the anti–PD-1 monoclonal antibody as a single agent and in combination with chemotherapy for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma.3 However, in May 2022, the agency issued a complete response letter to that BLA requesting a quality process change.4
The companies are seeking the approval of toripalimab plus gemcitabine and cisplatin for frontline treatment and as monotherapy for second- or later-line therapy following platinum-based chemotherapy. The BLA was supported by data from the phase 2 POLARIS-02 trial (NCT02915432) and the phase 3 JUPITER-02 trial (NCT03581786).
In POLARIS-02, previously treated patients with recurrent or metastatic nasopharyngeal carcinoma (n = 190) treated with toripalimab achieved an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%) per independent review committee (IRC) assessment.5
Data from JUPITER-02 demonstrated that toripalimab plus gemcitabine and cisplatin produced a median progression-free survival (PFS) of 11.7 months (95% CI, 11.0–not evaluable [NE]) per blinded IRC assessment and by 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).6
POLARIS-02 trial enrolled patients at least 18 years of age with relapsed metastatic nasopharyngeal cancer, head and neck cancer, gastric cancer, and esophageal cancer who were refractory to prior standard chemotherapy or who had progressed within 6 months of adjuvant chemotherapy or chemoradiation. Patients were required to have measurable disease, an ECOG performance status of 0 or 1, and adequate organ function.
Enrolled patients received 3 mg/kg toripalimab every 2 weeks until disease progression, intolerable toxicity, or withdrawn consent. The primary end point was IRC-assessed ORR by RECIST v1.1 criteria. Secondary end points included safety, duration of response, disease control rate (DCR), PFS, and overall survival (OS).
Additional findings from the phase 2 trial showed that toripalimab elicited a DCR of 40.0% (95% CI, 33.0%-47.3%), a median time to response of 1.8 months (95% CI, 1.8-2.1), and a median DOR of 12.8 months (95% CI, 9.4-NE). 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).
Patients given toripalimab in the second line or later (n = 92) experienced an ORR of 23.9% (95% CI, 15.6%-33.9%) and a DCR of 41.3% (95% CI, 31.1%-52.1%). The median DOR was 21.5 months (95% CI, 7.7-NE), the median PFS was 2.0 months (95% CI, 1.8-3.6), and the median OS was 15.1 months (95% CI, 10.4-20.4).
The most common any-grade adverse effects (AEs) included hypothyroidism (23.7%), anemia (15.3%), aspartate aminotransferase increase (15.3%), alanine aminotransferase increase (13.7%), asthenia (13.2%), proteinuria (12.6%), leukopenia (10.0%), pyrexia (8.4%), pruritus (8.4%), rash (6.3%), and neutropenia (5.3%). Approximately 14% of patients experienced grade 3 or higher AEs.
JUPITER-02 enrolled patients with primary metastatic nasopharyngeal carcinoma or recurrent disease following curative-intent therapy. Eligible patients needed to be between 18 and 75 years of age, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST v1.1 criteria.
The phase 3 trial randomly assigned patients 1:1 to 240 mg toripalimab in combination with gemcitabine plus cisplatin every 3 weeks for up to 6 treatment cycles (n = 146) or gemcitabine/cisplatin alone at the same schedule (n = 143).
Patients in the experimental arm were also administered toripalimab as maintenance at 240 mg every 3 weeks. Those in the chemotherapy-alone arm received maintenance treatment with placebo.
The primary end point was PFS per blinded IRC by RECIST v1.1 criteria, with secondary end points of investigator-assessed PFS, ORR, DOR, DCR, and OS.
The median OS had not yet been reached in either arm (stratified HR, 0.603; 95% CI, 0.364-0.997; P = .0462). Additionally, the combination of toripalimab and chemotherapy led to an ORR of 77.4% (95% CI, 69.8%-83.9%) vs 66.4% (95% CI, 58.1%-74.1%) with chemotherapy alone (P = .0335).
The median DOR with the combination was 10.0 months (95% CI, 8.8-NE) vs 5.7 months (95% CI, 5.4-6.8) with chemotherapy alone (HR, 0.50; 95% CI, 0.33-0.78; P = .0014).
Among patients treated with the combination of toripalimab plus chemotherapy, the most common AEs included leukopenia (91.1%), anemia (88.4%), neutropenia (85.6%), nausea (69.2%), vomiting (67.1%), thrombocytopenia (63.0%), decreased appetite (53.4%), and constipation (39.0%).